117915PathwayImmunometabolism Pathway (Viral Activation)The normal response to a virus infection involves viral coat proteins activating the Toll-like receptors TLR4 and TLR2 on the membranes of macrophages, T-cells and dendritic cells. In addition to this protein activation, the viral DNA (or RNA if it is an RNA virus) is taken up by macrophage endosomes. Viral DNA fragments (such as CpG DNA) activates the endosomal TLR9, while viral double-stranded DNA fragments activates the endosomal TLR3 and viral single stranded RNA (if it is an RNA virus) activates endosomal TLR7/8 proteins. Different TRL receptors activate different processes for the innate immune response [1]. The TLR4 activates the production of interferon regulatory factor 3 (IRF3), TIR-domain-containing adapter-inducing interferon-β (TRIF), signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-kB) in the cytoplasm, while TLR9, TRL3 and TLR7/8 activates the production of myeloid differentiation primary response 88 (MyD88), TRIF, interferon regulatory factor 7 (IRF7) and NF-kB in the cytoplasm [1]. The NF-kB protein then goes to nucleus and activates expression of nitric oxide synthase (iNOS) which generates nitric oxide (NO). It also activates aconitate decarboxylase (Irg1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β). These are the pro-inflammatory proteins while nitric oxide (NO) is also a pro-inflammatory molecule that can lead to the production of oxidized tyrosines (i.e., nitrotyrosine). Similarly, the newly expressed IRF3 and IRF7 proteins go to nucleus and activate the production of interferon beta (IFN- β), which is another pro-inflammatory cytokine. The other cytokines, TNF, IL-6, IL-1β and IFN-β move into the bloodstream and head to the brain and into the hypothalamus, leading to release of the hypothalamic corticotropin releasing hormone (CRH) [2]. CRH, in turn, activates the release of pituitary adrenocorticotropic hormone (ACTH), which then moves down through the blood stream towards the adrenal glands (located at the top of the kidneys) to produce cortisol and epinephrine. Cortisol and epinephrine stimulate the ”flight or fight” response, leading to the increased production of glucose from the liver (via glycogen breakdown) and the release of short-chain acylcarnitines (also from the liver) to help support beta-oxidation of fatty acids. These compounds support cell synthesis and growth of the macrophages and neutrophils used in the innate immune response. The liver also produces more IL-6, more TNF and more NO to further stimulate the innate immune response.
Higher nitric oxide (NO) levels lead to blood vessel dilation and reduced blood pressure, which in its most extreme form, can be a major problem in sepsis. Higher iNOS expression in macrophages, neutrophils and dendritic cells consumes the amino acid arginine to produce more NO which disrupts the mitochondrial TCA cycle leading to the accumulation of citrate and the production of fatty acids and acylcarnitines (needed for lipid synthesis). Increased Irg1 (actonitate decarboxylase) expression leads to accumulation of succinate, which results in the succinylation of phosphofructokinase M2 (PKM2) [3]. Succinate also leads to the release of hypoxia inducible factor 1-alpha (HIF-1α) from its PHD-mediated inhibition. HIF-1α interacts with succinylated PKM2 and induces the expression of glycolytic genes such as Glut1 (the glucose transporter) and the pro-inflammatory cytokine IL-1β [3]. As a result of these metabolic changes and the deactivation of the oxidative phosphorylation pathway in their mitochondria, macrophages, neutrophils, T-cells and dendritic cells shift to aerobic glycolysis [4]. This leads to the production of more reactive oxygen species (ROS) which results in the oxidation of certain amino acids, such as methionine. This leads to the increased production of methionine sulfoxide (Met-SO). As the inflammatory response continues, more glucose and arginine in the bloodstream are consumed by dividing white blood cells to produce more lactate and more NO to further push the aerobic glycolytic pathway [4]. This aerobic glycolysis occurs primarily in white blood cells leading to active cell division and rapid white cell propagation (growing by a factor of three to four in a few hours). Hexokinase (HK) along with increased levels of lactate from aerobic glycolysis activate the inflammasome inside macrophages and dendritic cells, leading to the secretion of IL-1β. This cytokine further drives the aerobic glycolysis pathway for these white blood cells. All these signals and effects combine to lead to the rapid and sustained production of large numbers of macrophages, neutrophils, dendritic cells and T-cells to fight the viral infection. This often leads to a reduction in essential amino acids (threonine, lysine, tryptophan, leucine, isoleucine, valine, arginine) and a mild reduction in gluconeogenic acids (glycine, serine) in the bloodstream. The reduction in essential amino acids is intended to “starve” the invading viruses (and other pathogens) of the amino acids they need to reproduce [4]. Some of the reduction in amino acid levels is moderated by the proteolysis of myosin in the muscle and the proteolysis of serum albumin in the blood (the most abundant protein in the blood, which is produced by the liver). These proteins act as amino acid reservoirs to help support rapid immune cell production. The loss of serum albumin in the blood to help support amino acid synthesis elsewhere can lead to hypoalbuminemia, a common feature of infections and inflammation.
As the viruses are cleared, the body goes into the anti-inflammatory response.DiseasePW127044CenterPathwayVisualizationContext12732057006250#000099PathwayVisualization117750117915Immunometabolism Pathway (Viral Activation)The normal response to a virus infection involves viral coat proteins activating the Toll-like receptors TLR4 and TLR2 on the membranes of macrophages, T-cells and dendritic cells. In addition to this protein activation, the viral DNA (or RNA if it is an RNA virus) is taken up by macrophage endosomes. Viral DNA fragments (such as CpG DNA) activates the endosomal TLR9, while viral double-stranded DNA fragments activates the endosomal TLR3 and viral single stranded RNA (if it is an RNA virus) activates endosomal TLR7/8 proteins. Different TRL receptors activate different processes for the innate immune response [1]. The TLR4 activates the production of interferon regulatory factor 3 (IRF3), TIR-domain-containing adapter-inducing interferon-β (TRIF), signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-kB) in the cytoplasm, while TLR9, TRL3 and TLR7/8 activates the production of myeloid differentiation primary response 88 (MyD88), TRIF, interferon regulatory factor 7 (IRF7) and NF-kB in the cytoplasm [1]. The NF-kB protein then goes to nucleus and activates expression of nitric oxide synthase (iNOS) which generates nitric oxide (NO). It also activates aconitate decarboxylase (Irg1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β). These are the pro-inflammatory proteins while nitric oxide (NO) is also a pro-inflammatory molecule that can lead to the production of oxidized tyrosines (i.e., nitrotyrosine). Similarly, the newly expressed IRF3 and IRF7 proteins go to nucleus and activate the production of interferon beta (IFN- β), which is another pro-inflammatory cytokine. The other cytokines, TNF, IL-6, IL-1β and IFN-β move into the bloodstream and head to the brain and into the hypothalamus, leading to release of the hypothalamic corticotropin releasing hormone (CRH) [2]. CRH, in turn, activates the release of pituitary adrenocorticotropic hormone (ACTH), which then moves down through the blood stream towards the adrenal glands (located at the top of the kidneys) to produce cortisol and epinephrine. Cortisol and epinephrine stimulate the ”flight or fight” response, leading to the increased production of glucose from the liver (via glycogen breakdown) and the release of short-chain acylcarnitines (also from the liver) to help support beta-oxidation of fatty acids. These compounds support cell synthesis and growth of the macrophages and neutrophils used in the innate immune response. The liver also produces more IL-6, more TNF and more NO to further stimulate the innate immune response.
Higher nitric oxide (NO) levels lead to blood vessel dilation and reduced blood pressure, which in its most extreme form, can be a major problem in sepsis. Higher iNOS expression in macrophages, neutrophils and dendritic cells consumes the amino acid arginine to produce more NO which disrupts the mitochondrial TCA cycle leading to the accumulation of citrate and the production of fatty acids and acylcarnitines (needed for lipid synthesis). Increased Irg1 (actonitate decarboxylase) expression leads to accumulation of succinate, which results in the succinylation of phosphofructokinase M2 (PKM2) [3]. Succinate also leads to the release of hypoxia inducible factor 1-alpha (HIF-1α) from its PHD-mediated inhibition. HIF-1α interacts with succinylated PKM2 and induces the expression of glycolytic genes such as Glut1 (the glucose transporter) and the pro-inflammatory cytokine IL-1β [3]. As a result of these metabolic changes and the deactivation of the oxidative phosphorylation pathway in their mitochondria, macrophages, neutrophils, T-cells and dendritic cells shift to aerobic glycolysis [4]. This leads to the production of more reactive oxygen species (ROS) which results in the oxidation of certain amino acids, such as methionine. This leads to the increased production of methionine sulfoxide (Met-SO). As the inflammatory response continues, more glucose and arginine in the bloodstream are consumed by dividing white blood cells to produce more lactate and more NO to further push the aerobic glycolytic pathway [4]. This aerobic glycolysis occurs primarily in white blood cells leading to active cell division and rapid white cell propagation (growing by a factor of three to four in a few hours). Hexokinase (HK) along with increased levels of lactate from aerobic glycolysis activate the inflammasome inside macrophages and dendritic cells, leading to the secretion of IL-1β. This cytokine further drives the aerobic glycolysis pathway for these white blood cells. All these signals and effects combine to lead to the rapid and sustained production of large numbers of macrophages, neutrophils, dendritic cells and T-cells to fight the viral infection. This often leads to a reduction in essential amino acids (threonine, lysine, tryptophan, leucine, isoleucine, valine, arginine) and a mild reduction in gluconeogenic acids (glycine, serine) in the bloodstream. The reduction in essential amino acids is intended to “starve” the invading viruses (and other pathogens) of the amino acids they need to reproduce [4]. Some of the reduction in amino acid levels is moderated by the proteolysis of myosin in the muscle and the proteolysis of serum albumin in the blood (the most abundant protein in the blood, which is produced by the liver). These proteins act as amino acid reservoirs to help support rapid immune cell production. The loss of serum albumin in the blood to help support amino acid synthesis elsewhere can lead to hypoalbuminemia, a common feature of infections and inflammation.
As the viruses are cleared, the body goes into the anti-inflammatory response.Disease1118317400SubPathway12017677Compound1169120177122Compound1169120178578ProteinComplex1169118319400SubPathway1201828074ProteinComplex1169118320400ActivatingSubPathway1201838074ProteinComplex51118323Virus ClearedSubPathway118324117912SubPathway118492117952InhibitorySubPathway1204001867Compound116912040163Compound1169120402129Compound1169337729Chen F, Zou L, Williams B, Chao W. Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials. Antioxid Redox Signal 2021; 35(15): 1324-1339.117915Pathway337730 Silverman MN, Pearce BD, Biron CA, Miller AH. Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 2005; 18(1): 41-78.
117915Pathway337731Zheng S, Liu Q, Liu T, Lu X. Posttranslational modification of pyruvate kinase type M2 (PKM2): novel regulation of its biological roles to be further discovered. J Physiol Biochem 2021; 77(3): 355-363.117915Pathway337732O'Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol 2016; 16(9): 553-65. 117915Pathway337733Bello C, Heinisch PP, Mihalj M, Carrel T, Luedi MM. Indoleamine-2,3-Dioxygenase as a Perioperative Marker of the Immune System. Front Physiol 2021; 12:766511.117915Pathway337734Herrera-Van Oostdam AS, Castañeda-Delgado JE, Oropeza-Valdez JJ, et al. Immunometabolic signatures predict risk of progression to sepsis in COVID-19. PLoS One 2021; 16(8): e0256784.117915Pathway337735Guarnieri T. Hypothesis: Emerging Roles for Aryl Hydrocarbon Receptor in Orchestrating CoV-2-Related Inflammation. Cells 2022; 11(4): 648.117915Pathway1CellCL:00000005HepatocyteCL:00001823NeuronCL:000054012AstrocyteCL:00001274CardiomyocyteCL:00007462Platelet CL:00002337Epithelial CellCL:00000666MyocyteCL:00001878Beta cellCL:000063910Glial cellCL:000012528MacrophageCL:000023526Endothelial cellCL:000011523T CellCL:00000841Homo sapiens9606EukaryoteHuman3Escherichia coli562Prokaryote12Mus musculus10090EukaryoteMouse2Bacteria2ProkaryoteBacteria24Solanum lycopersicum4081EukaryoteTomato18Saccharomyces cerevisiae4932EukaryoteYeast21Xenopus laevis8355EukaryoteAfrican clawed frog4Arabidopsis thaliana3702EukaryoteThale cress6Caenorhabditis elegans6239EukaryoteRoundworm25Escherichia coli (strain K12)83333Prokaryote23Pseudomonas aeruginosa287Prokaryote60Nitzschia sp.0001EukaryoteNitzschia417Rattus norvegicus10116EukaryoteRat5Bos taurus9913EukaryoteCattle10Drosophila melanogaster7227EukaryoteFruit fly202Spathaspora passalidarum340170EukaryoteSpathaspora passalidarum49Bathymodiolus platifrons220390EukaryoteDeep sea mussel19Schizosaccharomyces pombe4896Eukaryote135Felinus9685EukaryoteCat240Plasmodium falciparums121Eukaryote157Acinetobacter baumannii 107673Prokaryote138human0046323Eukaryote190Saccharomyces cerevisae15ProkaryoteYeast196Homo1924EukaryoteHuman280Bacteroides fragilis55247009Prokaryote3Mitochondrial MatrixGO:00057595CytoplasmGO:000573711Extracellular SpaceGO:00056152MitochondrionGO:00057391CytosolGO:00058297Endoplasmic Reticulum MembraneGO:000578912Mitochondrial Inner MembraneGO:000574314Mitochondrial Outer MembraneGO:000574124Mitochondrial Intermembrane SpaceGO:000575813Endoplasmic ReticulumGO:000578331Periplasmic SpaceGO:000562035ChloroplastGO:00095074PeroxisomeGO:000577710Cell MembraneGO:000588636MembraneGO:001602053Endoplasmic Reticulum BodyGO:001016834Plant-Type VacuoleGO:000032532Inner MembraneGO:007025819Sarcoplasmic ReticulumGO:00165296LysosomeGO:000576416Lysosomal LumenGO:004320218Melanosome MembraneGO:003316225Golgi ApparatusGO:000579420Endoplasmic Reticulum LumenGO:000578821SynapseGO:004520215NucleusGO:000563440PeriplasmGO:00425978Smooth Endoplasmic Reticulum GO:000579039Mitochondrial membraneGO:003196617NucleoplasmGO:000565469InflammasomeGO:009716968Nucleus MembraneGO:000564037Basolateral cell membraneGO:001632356Basal Cell MembraneGO:000992549Nuclear EnvelopeGO:000563538Apical cell membraneGO:00163241LiverBTO:000075972928StomachBTO:0001307155268Blood VesselBTO:0001102741124BrainBTO:000014289165cardiocyteBTO:00015392Endothelium BTO:00003934Adrenal MedullaBTO:000004971825IntestineBTO:00006487Nervous SystemBTO:000148411HeartBTO:000056273106KidneyBTO:00006717189MuscleBTO:00008871411818PancreasBTO:00009883Sympathetic Nervous SystemBTO:000183243HypothalamusBTO:000061437Blood-Brain BarrierBTO:000624429Pituitary GlandBTO:0001073891632Adrenal 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acidHMDB0000254Succinic acid is a dicarboxylic acid. The anion, succinate, is a component of the citric acid cycle capable of donating electrons to the electron transfer chain. Succinate dehydrogenase (SDH) plays an important role in the mitochondria, being both part of the respiratory chain and the Krebs cycle. SDH with a covalently attached FAD prosthetic group, binds enzyme substrates (succinate and fumarate) and physiological regulators (oxaloacetate and ATP). Oxidizing succinate links SDH to the fast-cycling Krebs cycle portion where it participates in the breakdown of acetyl-CoA throughout the whole Krebs cycle. The succinate can readily be imported into the mitochondrial matrix by the n-butylmalonate- (or phenylsuccinate-) sensitive dicarboxylate carrier in exchange with inorganic phosphate or another organic acid, e. g. malate. (PMID 16143825) Mutations in the four genes encoding the subunits of the mitochondrial respiratory chain succinate dehydrogenase are associated with a wide spectrum of clinical presentations (i.e.: Huntington's disease. (PMID 11803021).110-15-6C00042111015741SUC1078DB00139OC(=O)CCC(O)=OC4H6O4InChI=1S/C4H6O4/c5-3(6)1-2-4(7)8/h1-2H2,(H,5,6)(H,7,8)KDYFGRWQOYBRFD-UHFFFAOYSA-Nbutanedioic acid118.088118.026608680.252succinic acid0-2FDB0019311,2-ethanedicarboxylate;1,2-ethanedicarboxylic acid;1,4-butanedioate;1,4-butanedioic acid;Amber acid;Asuccin;Dihydrofumarate;Dihydrofumaric acid;Katasuccin;Succinate;Wormwood acid;Acide butanedioique;Acide succinique;Acidum succinicum;Bernsteinsaeure;Butandisaeure;Butanedionic acid;E363;Ethylenesuccinic acid;Hooc-ch2-ch2-cooh;Spirit of amber;Butanedionate;EthylenesuccinatePW_C000174Succini1523239450218507867631126554255175383103604215561021616454107645510864891786764117683616673621637455219745622074772221186619812142151132592234236831842369315424023227714313377213134774831117773811277749129784263348002436880721119112846308113428111998440612019240712038512212055541412099040812256538412276712012302913512318945012355537412513812112536447912554948112593048212671348012690650112708220612738950212830439140034Hydrogen IonHMDB0059597Hydrogen ion is recommended by IUPAC as a general term for all ions of hydrogen and its isotopes. Depending on the charge of the ion, two different classes can be distinguished: positively charged ions and negatively charged ions. Under aqueous conditions found in biochemistry, hydrogen ions exist as the hydrated form hydronium, H3O+, but these are often still referred to as hydrogen ions or even protons by biochemists. [WikiPedia])C000801038153781010[H+]HInChI=1S/p+1GPRLSGONYQIRFK-UHFFFAOYSA-Nhydron1.00791.0078250320hydron10H+;H(+);Hydrogen cation;Hydron;ProtonPW_C040034H+21546708753157883184831116214632614645422314927801742502242544245471045761846947052411035327111535311256261085639107569910057201055742117596314760371556070157609316161301596232166648317866011526692101684318869101877100163716820571912067453219745422074722227525213753221075582127572160759017081952258218151824322684131628420224913919591552491191516412015281121812851224628612266287125212271325722313325294153303084232931542354318424013224240531242454320769122937713613377210134773723317780411477955132779903277799134778379345799291308001936880387310803883048072211993823124948233831105503881128559411328039011553739811553911811585633611620510911997340612019340712054912212059340912117042412117142512256941812261538412268712512275812012318313512321813712374245912374346012514145412518812112527313612535947912555048112573048312573629712580929912651749512671748912676648012682330012690250112721320812830850612836139112843039514069288214069388314069916714070716814071514140742788140743597140760185146NADPHHMDB0000221Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (NMN) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2',5'-bisphosphate. It serves as an electron carrier in a number of reactions, being alternately oxidized (NADP+) and reduced (NADPH). (Dorland, 27th ed.).53-57-6C000052283351216474NADPH17215925NC(=O)C1=CN(C=CC1)[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](OP(O)(O)=O)[C@@H]2O)N2C=NC3=C2N=CN=C3N)[C@@H](O)[C@H]1OC21H30N7O17P3InChI=1S/C21H30N7O17P3/c22-17-12-19(25-7-24-17)28(8-26-12)21-16(44-46(33,34)35)14(30)11(43-21)6-41-48(38,39)45-47(36,37)40-5-10-13(29)15(31)20(42-10)27-3-1-2-9(4-27)18(23)32/h1,3-4,7-8,10-11,13-16,20-21,29-31H,2,5-6H2,(H2,23,32)(H,36,37)(H,38,39)(H2,22,24,25)(H2,33,34,35)/t10-,11-,13-,14-,15-,16-,20-,21-/m1/s1ACFIXJIJDZMPPO-NNYOXOHSSA-N{[(2R,3R,4R,5R)-2-(6-amino-9H-purin-9-yl)-5-[({[({[(2R,3S,4R,5R)-5-(3-carbamoyl-1,4-dihydropyridin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)methyl]-4-hydroxyoxolan-3-yl]oxy}phosphonic acid745.4209745.091102105-2.149nadph0-4FDB0219092'-(dihydrogen phosphate) 5'-(trihydrogen pyrophosphate) adenosine 5'-ester with 1,4-dihydro-1-b-d-ribofuranosylnicotinamide;2'-(dihydrogen phosphate) 5'-(trihydrogen pyrophosphate) adenosine 5'-ester with 1,4-dihydro-1-beta-delta-ribofuranosylnicotinamide;Adenosine 5'-(trihydrogen diphosphate) 2'-(dihydrogen phosphate) p'-5'-ester with 1,4-dihydro-1-beta-d-ribofuranosyl-3-pyridinecarboxamide;Adenosine 5'-(trihydrogen diphosphate) 2'-(dihydrogen phosphate) p'-5'-ester with 1,4-dihydro-1-beta-delta-ribofuranosyl-3-pyridinecarboxamide;Dihydrocodehydrogenase ii;Dihydronicotinamide adenine dinucleotide phosphate;Dihydronicotinamide adenine dinucleotide-p;Dihydrotriphosphopyridine nucleotide reduced;Nadp-reduced;Nadph;Nicotinamide-adenine-dinucleotide-phosphorate;Nicotinamide-adenine-dinucleotide-phosphoric acid;Reduced codehydrase ii;Reduced coenzyme ii;Reduced cozymase ii;Reduced triphosphopyridine nucleotide;Triphosphopyridine nucleotide reduced;B-nadph;B-nicotinamide-adenine-dinucleotide-phosphorate;B-nicotinamide-adenine-dinucleotide-phosphoric acid;Beta-nadph;Beta-nicotinamide-adenine-dinucleotide-phosphorate;Beta-nicotinamide-adenine-dinucleotide-phosphoric acid;Nicotinamide adenine dinucleotide phosphate - reducedPW_C000146NADPH185819037781079658211883721609291615494687314793144797145310111578910859721476128159627135677911770681887103163715420572051607315213734521075592127591170819422582191518421224118121981189321112006222121501641224528612596226126482494234331543746322769112937716613277385331773943327746013077504112775111157762333680712119113164941201054071204254051204521221206161231211411251212754291214021241214833831230593761230861351232414471237121361238464641239611181240413981254724811256962971262142991265294951270092061275723881281013901407061681065OxygenHMDB0001377Oxygen is the third most abundant element in the universe after hydrogen and helium and the most abundant element by mass in the Earth's crust. Diatomic oxygen gas constitutes 20.9% of the volume of air. All major classes of structural molecules in living organisms, such as proteins, carbohydrates, and fats, contain oxygen, as do the major inorganic compounds that comprise animal shells, teeth, and bone. Oxygen in the form of O2 is produced from water by cyanobacteria, algae and plants during photosynthesis and is used in cellular respiration for all living organisms. Green algae and cyanobacteria in marine environments provide about 70% of the free oxygen produced on earth and the rest is produced by terrestrial plants. Oxygen is used in mitochondria to help generate adenosine triphosphate (ATP) during oxidative phosphorylation. For animals, a constant supply of oxygen is indispensable for cardiac viability and function. To meet this demand, an adult human, at rest, inhales 1.8 to 2.4 grams of oxygen per minute. This amounts to more than 6 billion tonnes of oxygen inhaled by humanity per year. At a resting pulse rate, the heart consumes approximately 8-15 ml O2/min/100 g tissue. This is significantly more than that consumed by the brain (approximately 3 ml O2/min/100 g tissue) and can increase to more than 70 ml O2/min/100 g myocardial tissue during vigorous exercise. As a general rule, mammalian heart muscle cannot produce enough energy under anaerobic conditions to maintain essential cellular processes; thus, a constant supply of oxygen is indispensable to sustain cardiac function and viability. However, the role of oxygen and oxygen-associated processes in living systems is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death (through reactive oxygen species). Reactive oxygen species (ROS) are a family of oxygen-derived free radicals that are produced in mammalian cells under normal and pathologic conditions. Many ROS, such as the superoxide anion (O2-)and hydrogen peroxide (H2O2), act within blood vessels, altering mechanisms mediating mechanical signal transduction and autoregulation of cerebral blood flow. Reactive oxygen species are believed to be involved in cellular signaling in blood vessels in both normal and pathologic states. The major pathway for the production of ROS is by way of the one-electron reduction of molecular oxygen to form an oxygen radical, the superoxide anion (O2-). Within the vasculature there are several enzymatic sources of O2-, including xanthine oxidase, the mitochondrial electron transport chain, and nitric oxide (NO) synthases. Studies in recent years, however, suggest that the major contributor to O2- levels in vascular cells is the membrane-bound enzyme NADPH-oxidase. Produced O2- can react with other radicals, such as NO, or spontaneously dismutate to produce hydrogen peroxide (H2O2). In cells, the latter reaction is an important pathway for normal O2- breakdown and is usually catalyzed by the enzyme superoxide dismutase (SOD). Once formed, H2O2 can undergo various reactions, both enzymatic and nonenzymatic. The antioxidant enzymes catalase and glutathione peroxidase act to limit ROS accumulation within cells by breaking down H2O2 to H2O. Metabolism of H2O2 can also produce other, more damaging ROS. For example, the endogenous enzyme myeloperoxidase uses H2O2 as a substrate to form the highly reactive compound hypochlorous acid. Alternatively, H2O2 can undergo Fenton or Haber-Weiss chemistry, reacting with Fe2+/Fe3+ ions to form toxic hydroxyl radicals (-.OH). (PMID: 17027622, 15765131).7782-44-7C0000797715379CPD-6641952O=OO2InChI=1S/O2/c1-2MYMOFIZGZYHOMD-UHFFFAOYSA-Ndioxygen31.998831.9898292440singlet oxygen00FDB022589Dioxygen;Molecular oxygen;O2;Oxygen;Oxygen molecule;[oo];Dioxygene;Disauerstoff;E 948;E-948;E948PW_C001065O295911052451650018505854914625286383649106743168820754157634769338362137549201624253122280329426042474713546712354801255493126550812758091085973147612915970061887032163705016073192137533210756021283951511181621611864198118832151189421112057225120631641224728612279226123252491270629112716292130042981301630013026301130383021326022342276174265731576910293770442947721413477350111773631307737733177395332774971137751211577537334776263367772333777736112777471297775634177805114778121337807032978151132783813457880534379111360120047408120383122120426405120542407120553414120594409120601406120883415121045124121104383121605434121656429122117382122573418122689384122798374122822443123027135123060376123128447123139136123163448123176119123187450123219137123226120123459451123609118123669398124163469124214464124669399125145454125275121125425482125706478125731483125737297125740479125884481126100299126272484126522495126721489126825480126964502126986207127198209127214208127219205127222501127305504127345206127557388127574515127835389128081395128095390128312506128432391396L-ArginineHMDB0000517Arginine is an essential amino acid that is physiologically active in the L-form. In mammals, arginine is formally classified as a semi-essential or conditionally essential amino acid, depending on the developmental stage and health status of the individual. Infants are unable to effectively synthesize arginine, making it nutritionally essential for infants. Adults, however, are able to synthesize arginine in the urea cycle. Arginine can be considered to be a basic amino acid as the part of the side chain nearest to the backbone is long, carbon-containing, and hydrophobic, whereas the end of the side chain is a complex guanidinium group. With a pKa of 12.48, the guanidinium group is positively charged in neutral, acidic, and even most basic environments. Because of the conjugation between the double bond and the nitrogen lone pairs, the positive charge is delocalized. This group is able to form multiple H-bonds. L-Arginine is an amino acid that has numerous functions in the body. It helps dispose of ammonia, is used to make compounds such as nitric oxide, creatine, L-glutamate, and L-proline, and it can be converted into glucose and glycogen if needed. In large doses, L-arginine also stimulates the release of the hormones growth hormone and prolactin. Arginine is a known inducer of mTOR (mammalian target of rapamycin) and is responsible for inducing protein synthesis through the mTOR pathway. mTOR inhibition by rapamycin partially reduces arginine-induced protein synthesis (PMID: 20841502). Catabolic disease states such as sepsis, injury, and cancer cause an increase in arginine utilization, which can exceed normal body production, leading to arginine depletion. Arginine also activates AMP kinase (AMPK) which then stimulates skeletal muscle fatty acid oxidation and muscle glucose uptake, thereby increasing insulin secretion by pancreatic beta-cells (PMID: 21311355). Arginine is found in plant and animal proteins, such as dairy products, meat, poultry, fish, and nuts. The ratio of L-arginine to lysine is also important: soy and other plant proteins have more L-arginine than animal sources of protein.74-79-3C000622878216467ARG6082DB00125N[C@@H](CCCNC(N)=N)C(O)=OC6H14N4O2InChI=1S/C6H14N4O2/c7-4(5(11)12)2-1-3-10-6(8)9/h4H,1-3,7H2,(H,11,12)(H4,8,9,10)/t4-/m0/s1ODKSFYDXXFIFQN-BYPYZUCNSA-N(2S)-2-amino-5-carbamimidamidopentanoic acid174.201174.111675712-1.885L-arginine01DBMET00502FDB002257(s)-2-amino-5-[(aminoiminomethyl)amino]pentanoate;(s)-2-amino-5-[(aminoiminomethyl)amino]pentanoic acid;(s)-2-amino-5-[(aminoiminomethyl)amino]-pentanoate;(s)-2-amino-5-[(aminoiminomethyl)amino]-pentanoic acid;2-amino-5-guanidinovalerate;2-amino-5-guanidinovaleric acid;5-[(aminoiminomethyl)amino]-l-norvaline;Arginine;L-(+)-arginine;L-a-amino-d-guanidinovalerate;L-a-amino-d-guanidinovaleric acid;L-alpha-amino-delta-guanidinovalerate;L-alpha-amino-delta-guanidinovaleric acid;N5-(aminoiminomethyl)-l-ornithine;(2s)-2-amino-5-(carbamimidamido)pentanoic acid;(2s)-2-amino-5-guanidinopentanoic acid;(s)-2-amino-5-guanidinopentanoic acid;(s)-2-amino-5-guanidinovaleric acid;Arg;L-arg;L-arginin;R;(2s)-2-amino-5-(carbamimidamido)pentanoate;(2s)-2-amino-5-guanidinopentanoate;(s)-2-amino-5-guanidinopentanoate;(s)-2-amino-5-guanidinovaleratePW_C000396Arg105834483562010756231171184619812732290425313224255431877467111780951127923929379240164120056122122142407122808135124694119125434297126299481126973205127863206723CitrullineHMDB0000904Citrulline is an amino acid made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a by-product of the reaction catalyzed by NOS family (NOS). In this reaction, arginine is first oxidized into N(omega)-hydroxyarginine, which is then further oxidized to citrulline concomitant with the release of nitric oxide (EC 1.14.13.39). Citrulline's name is derived from citrullus, the Latin word for watermelon, from which it was first isolated.372-75-8C00327699209816349L-CITRULLINE9367DB00155N[C@@H](CCCNC(N)=O)C(O)=OC6H13N3O3InChI=1S/C6H13N3O3/c7-4(5(10)11)2-1-3-9-6(8)12/h4H,1-3,7H2,(H,10,11)(H3,8,9,12)/t4-/m0/s1RHGKLRLOHDJJDR-BYPYZUCNSA-N(2S)-2-amino-5-(carbamoylamino)pentanoic acid175.1857175.095691297-0.904L-citrulline00FDB011841(2s)-2-amino-5-(carbamoylamino)pentanoate;(2s)-2-amino-5-(carbamoylamino)pentanoic acid;(s)-2-amino-5-ureidopentanoate;(s)-2-amino-5-ureidopentanoic acid;(s)-2-amino-5-(aminocarbonyl)aminopentanoate;(s)-2-amino-5-(aminocarbonyl)aminopentanoic acid;2-amino-5-uredovalerate;2-amino-5-uredovaleric acid;2-amino-5-ureidovalerate;2-amino-5-ureidovaleric acid;A-amino-d-ureidovalerate;A-amino-d-ureidovaleric acid;Amino-ureidovalerate;Amino-ureidovaleric acid;Cir;Cit;Cytrulline;D-ureidonorvaline;Dl-citrulline;Gammaureidonorvaline;H-cit-oh;L(+)-2-amino-5-ureidovalerate;L(+)-2-amino-5-ureidovaleric acid;L(+)-citrulline;L-2-amino-5-ureido-valerate;L-2-amino-5-ureido-valeric acid;L-2-amino-5-ureidovalerate;L-2-amino-5-ureidovaleric acid;L-citrulline;L-cytrulline;L-n5-carbamoyl-ornithine;N()-carbamylornithine;N(5)-(aminocarbonyl)-dl-ornithine;N(delta)-carbamylornithine;N-carbamylornithine;N5-(aminocarbonyl)-l-ornithine;N5-(aminocarbonyl)ornithine;N5-(aminocarbonyl)-ornithine;N5-carbamoyl-l-ornithine;N5-carbamoylornithine;N5-carbamylornithine;N<sup>5</sup>-(aminocarbonyl)ornithine;Nd-carbamylornithine;Ndelta-carbamy-ornithine;Ndelta-carbamylornithine;Ngamma-carbamylornithine;Sitrulline;Ureidonorvaline;Ureidovalerate;Ureidovaleric acid;Alpha-amino-delta-ureidovalerate;Alpha-amino-delta-ureidovaleric acid;Alpha-amino-gamma-ureidovalerate;Alpha-amino-gamma-ureidovaleric acid;Delta-ureidonorvaline;Citrulline;N(5)-(aminocarbonyl)-l-ornithine;A-amino-delta-ureidovalerate;A-amino-delta-ureidovaleric acid;α-amino-δ-ureidovalerate;α-amino-δ-ureidovaleric acid;δ-ureidonorvaline;N(δ)-carbamylornithine;A-amino-δ-ureidovalerate;A-amino-δ-ureidovaleric acidPW_C000723Citruln728130441184419811881161127002907746411177495133120080122120403406122828135123046120125452297126991205143NADPHMDB0000217Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5-phosphate (NMN) coupled by pyrophosphate linkage to the 5-phosphate adenosine 2,5-bisphosphate. It serves as an electron carrier in a number of reactions, being alternately oxidized (NADP+) and reduced (NADPH). (Dorland, 27th ed.) Hydrogen carrier in biochemical redox systems. In the hexose monophosphoric acid system it is reduced to Dihydrocoenzyme II and reoxidation in the presence of flavoproteins (Dictionary of Organic Compounds).53-59-8C00006588618009NAD(P)5675NC(=O)C1=C[N+](=CC=C1)[C@@H]1O[C@H](COP([O-])(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](OP(O)(O)=O)[C@@H]2O)N2C=NC3=C2N=CN=C3N)[C@@H](O)[C@H]1OC21H28N7O17P3InChI=1S/C21H28N7O17P3/c22-17-12-19(25-7-24-17)28(8-26-12)21-16(44-46(33,34)35)14(30)11(43-21)6-41-48(38,39)45-47(36,37)40-5-10-13(29)15(31)20(42-10)27-3-1-2-9(4-27)18(23)32/h1-4,7-8,10-11,13-16,20-21,29-31H,5-6H2,(H7-,22,23,24,25,32,33,34,35,36,37,38,39)/t10-,11-,13-,14-,15-,16-,20-,21-/m1/s1XJLXINKUBYWONI-NNYOXOHSSA-N1-[(2R,3R,4S,5R)-5-{[({[(2R,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-3-hydroxy-4-(phosphonooxy)oxolan-2-yl]methoxy}(hydroxy)phosphoryl phosphono)oxy]methyl}-3,4-dihydroxyoxolan-2-yl]-3-carbamoyl-1lambda5-pyridin-1-ylium743.405743.075452041-2.2281-[(2R,3R,4S,5R)-5-[({[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3-hydroxy-4-(phosphonooxy)oxolan-2-yl]methoxy(hydroxy)phosphoryl phosphono}oxy)methyl]-3,4-dihydroxyoxolan-2-yl]-3-carbamoyl-1lambda5-pyridin-1-ylium0-3FDB021908Adenine-nicotinamide dinucleotide phosphate;Codehydrase ii;Codehydrogenase ii;Coenzyme ii;Cozymase ii;Nad phosphate;Nadp;Nadp+;Nicotinamide adenine dinucleotide phosphate;Nicotinamide-adenine dinucleotide phosphate;Tpn;Triphosphopyridine nucleotide;B-nadp;B-nicotinamide adenine dinucleotide phosphate;B-tpn;Beta-nadp;Beta-nicotinamide adenine dinucleotide phosphate;Beta-tpn;Oxidized nicotinamide-adenine dinucleotide phosphate;B-nicotinamide adenine dinucleotide phosphoric acid;Beta-nicotinamide adenine dinucleotide phosphoric acid;β-nicotinamide adenine dinucleotide phosphate;β-nicotinamide adenine dinucleotide phosphoric acidPW_C000143NADP18381913768578010824188392161129161749468531479614480114530811157901086017147613215962733567781177069188710516371522057206160731721373462107562212758917081972258220151841922411811198118972111200822212152164122492861259722612650249423443154374532276913293771641327738433177396332774611307751511577624336778143347787011280713119113165941201064071204294051204501221206044081206181231211421251212774291214011241214853831230633761230841351232293741232434471237131361238484641239601181240433981254734811256942971257434821262152991265284951270102061272255021275703881281003901407091681420WaterHMDB0002111Water is a chemical substance that is essential to all known forms of life. It appears colorless to the naked eye in small quantities, though it is actually slightly blue in color. It covers 71% of Earth's surface. Current estimates suggest that there are 1.4 billion cubic kilometers (330 million m3) of it available on Earth, and it exists in many forms. It appears mostly in the oceans (saltwater) and polar ice caps, but it is also present as clouds, rain water, rivers, freshwater aquifers, lakes, and sea ice. Water in these bodies perpetually moves through a cycle of evaporation, precipitation, and runoff to the sea. Clean water is essential to human life. In many parts of the world, it is in short supply. From a biological standpoint, water has many distinct properties that are critical for the proliferation of life that set it apart from other substances. It carries out this role by allowing organic compounds to react in ways that ultimately allow replication. All known forms of life depend on water. Water is vital both as a solvent in which many of the body's solutes dissolve and as an essential part of many metabolic processes within the body. Metabolism is the sum total of anabolism and catabolism. In anabolism, water is removed from molecules (through energy requiring enzymatic chemical reactions) in order to grow larger molecules (e.g. starches, triglycerides and proteins for storage of fuels and information). In catabolism, water is used to break bonds in order to generate smaller molecules (e.g. glucose, fatty acids and amino acids to be used for fuels for energy use or other purposes). Water is thus essential and central to these metabolic processes. Water is also central to photosynthesis and respiration. Photosynthetic cells use the sun's energy to split off water's hydrogen from oxygen. Hydrogen is combined with CO2 (absorbed from air or water) to form glucose and release oxygen. All living cells use such fuels and oxidize the hydrogen and carbon to capture the sun's energy and reform water and CO2 in the process (cellular respiration). Water is also central to acid-base neutrality and enzyme function. An acid, a hydrogen ion (H+, that is, a proton) donor, can be neutralized by a base, a proton acceptor such as hydroxide ion (OH-) to form water. Water is considered to be neutral, with a pH (the negative log of the hydrogen ion concentration) of 7. Acids have pH values less than 7 while bases have values greater than 7. Stomach acid (HCl) is useful to digestion. However, its corrosive effect on the esophagus during reflux can temporarily be neutralized by ingestion of a base such as aluminum hydroxide to produce the neutral molecules water and the salt aluminum chloride. Human biochemistry that involves enzymes usually performs optimally around a biologically neutral pH of 7.4. (Wikipedia).7732-18-5C0000196215377937OH2OInChI=1S/H2O/h1H2XLYOFNOQVPJJNP-UHFFFAOYSA-Nwater18.015318.0105646861water00FDB013390Dihydrogen oxide;Steam;[oh2];Acqua;Agua;Aqua;Bound water;Dihydridooxygen;Eau;H2o;Hoh;Hydrogen hydroxide;WasserPW_C001420H2O55894910951394151316214481135261562428652106912077033823188382109431137749146554159043201824253222267860272746277817280529314370316472363461459836472737494193503027515675195975214100522794523610352971055319111534311353551125402110547012354831255492126550712755341305537114554112955911355608118562210856916575914057781015841143585314658771075890955910147594015160321556059157608716161231636133159621516218166647717865071806600152671311768401886888160716220571812077193206721121172282137238214724321572951987350216738821074012127467222749222475001907588170820122582372268414162926526118502771192216412011281122132851225028612264287123272491252022712632651269329012705291127152921300729813019300130253011303730213261223133272941534030842327315426953184369132276914293770192537710213277131133772151347737833177397332774713337751611577536334776283367772233777759341778163437798234778071329782353527824235378270356791133608001436880039370805912288065611993830383947943841105573901106393911158443981198792321199151221199634061200084071200464081201131241203654121204304051204384091206064151207944141211584251212404291213511211213814191216074341221183821223844361227531201227973741228044431230124461230643761230721371231314471231421361231624481232314511233844501237304601238104641239404551241654691246703991249384711249454721253052971253534791253864811254244821254802991256824831257074781257454871260544901262384951262734841267644801268965011269635021270173881271772081271992091272275041275065071275765151278363891280823951281765131406747901406758341407551851867Nitric oxideHMDB0003378The biologically active molecule nitric oxide (NO) is a simple, membrane-permeable gas with unique chemistry. It is formed by the conversion of L-arginine to L-citrulline, with the release of NO. The enzymatic oxidation of L-arginine to L-citrulline takes place in the presence of oxygen and NADPH using flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, thiol, and tetrahydrobiopterin as cofactors. The enzyme responsible for the generation of NO is nitric oxide synthase (E.C. 1.7.99.7; NOS). Three NOS isoforms have been described and shown to be encoded on three distinct genes: neuronal NOS (nNOS, NOS type I), inducible NOS (NOS type II), and endothelial NOS (eNOS, NOS type III). Two of them are constitutively expressed and dependent on the presence of calcium ions and calmodulin to function (nNOS and eNOS), while iNOS is considered non-constitutive and calcium-independent. However, experience has shown that constitutive expression of nNOS and eNOS is not as rigid as previously thought (i.e. either present or absent), but can be dynamically controlled during development and in response to injury. Functionally, NO may act as a hormone, neurotransmitter, paracrine messenger, mediator, cytoprotective molecule, and cytotoxic molecule. NO has multiple cellular molecular targets. It influences the activity of transcription factors, modulates upstream signaling cascades, mRNA stability and translation, and processes the primary gene products. In the brain, many processes are linked to NO. NO activates its receptor, soluble guanylate cyclase by binding to it. The stimulation of this enzyme leads to increased synthesis of the second messenger, cGMP, which in turn activates cGMP-dependent kinases in target cells. NO exerts a strong influence on glutamatergic neurotransmission by directly interacting with the N-methyl-D-aspartate (NMDA) receptor. Neuronal NOS is connected to NMDA receptors (see below) and sharply increases NO production following activation of this receptor. Thus, the level of endogenously produced NO around NMDA synapses reflects the activity of glutamate-mediated neurotransmission. However, there is recent evidence showing that non-NMDA glutamate receptors (i.e. AMPA and type I metabotropic receptors) also contribute to NO generation. Besides its influence on glutamate, NO is known to have effects on the storage, uptake and/or release of most other neurotransmitters in the CNS (acetylcholine, dopamine, noradrenaline, GABA, taurine, and glycine) as well as of certain neuropeptides. Finally, since NO is a highly diffusible molecule, it may reach extrasynaptic receptors at target cell membranes that are some distance away from the place of NO synthesis. NO is thus capable of mediating both synaptic and nonsynaptic communication processes. NO is a potent vasodilator (a major endogenous regulator of vascular tone), and an important endothelium-dependent relaxing factor. NO is synthesized by NO synthases (NOS) and NOS are inhibited by asymmetrical dimethylarginine (ADMA). ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) and excreted in the kidneys. Lower ADMA levels in pregnant women compared to non-pregnant controls suggest that ADMA has a role in vascular dilatation and blood pressure changes. Several studies show an increase in ADMA levels in pregnancies complicated with preeclampsia. Elevated ADMA levels in preeclampsia are seen before clinical symptoms have developed; these findings suggest that ADMA has a role in the pathogenesis of preeclampsia. In some pulmonary hypertensive states such as ARDS, the production of endogenous NO may be impaired. Nitric oxide inhalation selectively dilates the pulmonary circulation. Significant systemic vasodilation does not occur because NO is inactivated by rapidly binding to hemoglobin. In an injured lung with pulmonary hypertension, inhaled NO produces local vasodilation of well-ventilated lung units and may "steal" blood flow away from unventilated regions. This reduces intrapulmonary shunting and may improve systemic arterial oxygenation. Nitric oxide is a chemical mediator fundamental in the maintenance of adequate tissue perfusion and effective cardiovascular function. The use of nitrates is well established as pharmacological agents but it is only recently that it has been recognized that they act as a source of nitric oxide (PMID: 16966108, 8752507, 17181668, 16005189). Nitric oxide is used as a food additive (EAFUS: Everything Added to Food in the United States).10102-43-9C0053314506816480NITRIC-OXIDE127983DB00435[N]=ONOInChI=1S/NO/c1-2MWUXSHHQAYIFBG-UHFFFAOYSA-Nnitroso30.006129.9979886270nitric oxide00FDB021825Mononitrogen monoxide;Nitric oxide;Nitrogen monoxide;Nitrogen oxide;Nitrogen protoxide;Nitrosyl hydride;Nitrosyl radical;Nitroxide radical;Nitroxyl;(no)(.);[no];Edrf;Endothelium-derived relaxing factor;Monoxido de nitrogeno;Monoxyde d'azote;Nitrogen monooxide;Nitrosyl;No;(.)no;No(.);Oxido de nitrogeno(ii);Oxido nitrico;Oxyde azotique;Oxyde nitrique;Stickstoff(ii)-oxid;StickstoffmonoxidPW_C001867NO47951447991411896211775141158033181204284051230623761799HemeHMDB0003178Heme is the color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic subunit; these are known as hemoproteins.14875-96-8C0003217627HEME_A24604415DB02577CC1=C(CCC(O)=O)C2=CC3=[N+]4C(=CC5=C(C)C(C=C)=C6C=C7C(C)=C(C=C)C8=[N+]7[Fe--]4(N2C1=C8)N56)C(C)=C3CCC(O)=OC34H32FeN4O4InChI=1S/C34H34N4O4.Fe/c1-7-21-17(3)25-13-26-19(5)23(9-11-33(39)40)31(37-26)16-32-24(10-12-34(41)42)20(6)28(38-32)15-30-22(8-2)18(4)27(36-30)14-29(21)35-25;/h7-8,13-16H,1-2,9-12H2,3-6H3,(H4,35,36,37,38,39,40,41,42);/q;+2/p-2/b25-13-,26-13-,27-14-,28-15-,29-14-,30-15-,31-16-,32-16-;KABFMIBPWCXCRK-RGGAHWMASA-L4,20-bis(2-carboxyethyl)-10,15-diethenyl-5,9,14,19-tetramethyl-2lambda5,22,23lambda5,25-tetraaza-1-ferraoctacyclo[11.9.1.1^{1,8}.1^{3,21}.0^{2,6}.0^{16,23}.0^{18,22}.0^{11,25}]pentacosa-2,4,6,8,10,12,14,16(23),17,19,21(24)-undecaene-2,23-bis(ylium)-1,1-diuide616.487616.177297665-5.4824,20-bis(2-carboxyethyl)-10,15-diethenyl-5,9,14,19-tetramethyl-2lambda5,22,23lambda5,25-tetraaza-1-ferraoctacyclo[11.9.1.1^{1,8}.1^{3,21}.0^{2,6}.0^{16,23}.0^{18,22}.0^{11,25}]pentacosa-2,4,6,8,10,12,14,16(23),17,19,21(24)-undecaene-2,23-bis(ylium)-1,1-diuide0-2FDB016272(protoporphyrinato)iron;Ferroheme;Ferroheme b;Ferroprotoheme;Ferroprotoporphyrin;Ferroprotoporphyrin ix;Ferrous protoheme;Ferrous protoheme ix;Haem;Hem;Heme;Iron protoporphyrin;Iron protoporphyrin ix;Iron(ii) protoporphyrin ix;Protoferroheme;Protohaem;Protoheme;Protoheme ix;Reduced hematinPW_C001799Heme247163081032486082766512443135449141336196318280629293893238113367263421143734440433148232851709554721235485125551712958301416246786283165971517044160706016173262131183519811898211120651641300929813021300422781776915293769312497735111177364130773673317739833277517115776293367781333478380133786021327896311279932134120431405120603408120955407121085383121658429121746124121910122122570406122691384123065376123133447123144136123228374123521119123650398124216464124297118124463135125142120125277121125742482125896481126196299126499297126512495126718479126827480127224502127357206127632388128070205128083395128086390128309501128434391964FADHMDB0001248FAD, also known as flavitan or adeflavin, belongs to the class of organic compounds known as flavin nucleotides. These are nucleotides containing a flavin moiety. Flavin is a compound that contains the tricyclic isoalloxazine ring system, which bears 2 oxo groups at the 2- and 4-positions. FAD is a drug which is used to treat eye diseases caused by vitamin b2 deficiency, such as keratitis and blepharitis. FAD is slightly soluble (in water) and a moderately acidic compound (based on its pKa). FAD has been found in human liver and muscle tissues, and has also been detected in multiple biofluids, such as feces and blood. Within the cell, FAD is primarily located in the cytoplasm, mitochondria, endoplasmic reticulum and peroxisome. FAD exists in all living organisms, ranging from bacteria to humans. In humans, FAD is involved in the risedronate action pathway, the ibandronate action pathway, the valine, leucine and isoleucine degradation pathway, and the pyrimidine metabolism pathway. FAD is also involved in several metabolic disorders, some of which include the oncogenic action OF L-2-hydroxyglutarate in hydroxygluaricaciduria pathway, gaba-transaminase deficiency, 4-hydroxybutyric aciduria/succinic semialdehyde dehydrogenase deficiency, and the saccharopinuria/hyperlysinemia II pathway. FAD is a condensation product of riboflavin and adenosine diphosphate. The coenzyme of various aerobic dehydrogenases, e.g., D-amino acid oxidase and L-amino acid oxidase. (Lehninger, Principles of Biochemistry, 1982, p972).146-14-5C0001664397516238FAD559059DB03147CC1=CC2=C(C=C1C)N(C[C@H](O)[C@H](O)[C@H](O)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=NC3=C1N=CN=C3N)C1=NC(=O)NC(=O)C1=N2C27H33N9O15P2InChI=1S/C27H33N9O15P2/c1-10-3-12-13(4-11(10)2)35(24-18(32-12)25(42)34-27(43)33-24)5-14(37)19(39)15(38)6-48-52(44,45)51-53(46,47)49-7-16-20(40)21(41)26(50-16)36-9-31-17-22(28)29-8-30-23(17)36/h3-4,8-9,14-16,19-21,26,37-41H,5-7H2,1-2H3,(H,44,45)(H,46,47)(H2,28,29,30)(H,34,42,43)/t14-,15+,16+,19-,20+,21+,26+/m0/s1VWWQXMAJTJZDQX-UYBVJOGSSA-N{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}[({[(2R,3S,4S)-5-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}-2,3,4-trihydroxypentyl]oxy}(hydroxy)phosphoryl)oxy]phosphinic acid785.5497785.157134455-2.279flavine-adenine dinucleotide0-3FDB0225111h-purin-6-amine flavin dinucleotide;1h-purin-6-amine flavine dinucleotide;Adenine-flavin dinucleotide;Adenine-flavine dinucleotide;Adenine-riboflavin dinuceotide;Adenine-riboflavin dinucleotide;Adenine-riboflavine dinucleotide;Fad;Flamitajin b;Flanin f;Flavin adenine dinucleotide;Flavin adenine dinucleotide oxidized;Flavin-adenine dinucleotide;Flavine adenosine diphosphate;Flavine-adenine dinucleotide;Flavitan;Flaziren;Isoalloxazine-adenine dinucleotide;Riboflavin 5'-adenosine diphosphate;Riboflavin-adenine dinucleotide;Riboflavine-adenine dinucleotide;AdeflavinPW_C000964FAD99911451868192321642531762828825188402118814148942161229162249213358253622372326460236468831474113475810488165268103528510253351115496126551112756131186030155605415660821616116162639016475178649917966661077039163717520573212137465222748722390762241181821611887215118992111229622512328249124431511251922712595226127102911272029213029301130413024362331877080293771261337715213477501113775071127751811577541334776151327772633778054329783753457893033179222336792723588001236880034369807141191199584061199993841200514081201074071204324051204531221204901241212784291212984181214173821214893831227481201227761211228023741228234431230663761230871351231664481238494641238684541239763991240473981253484791253784801254294821254744811256972971259794891261072991262774841268915011269203911269685021269872071270112061273102091274325061276023881278403891407901851407991861170Flavin MononucleotideHMDB0001520Flavin mononucleotide (FMN), or riboflavin-5?-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as prosthetic group of various oxidoreductases including NADH dehydrogenase as well as cofactor in biological blue-light photo receptors. During the catalytic cycle, the reversible interconversion of oxidized (FMN), semiquinone (FMNH) and reduced (FMNH2) forms occurs in the various oxidoreductases. FMN is a stronger oxidizing agent than NAD and is particularly useful because it can take part in both one- and two-electron transfers. Flavin mononucleotide is also used as an orange-red food colour additive. It is the principal form in which riboflavin is found in cells and tissues.146-17-8C0006164397617621FMN559060DB03247CC1=CC2=C(C=C1C)N(C[C@H](O)[C@H](O)[C@H](O)COP(O)(O)=O)C1=NC(=O)NC(=O)C1=N2C17H21N4O9PInChI=1S/C17H21N4O9P/c1-7-3-9-10(4-8(7)2)21(15-13(18-9)16(25)20-17(26)19-15)5-11(22)14(24)12(23)6-30-31(27,28)29/h3-4,11-12,14,22-24H,5-6H2,1-2H3,(H,20,25,26)(H2,27,28,29)/t11-,12+,14-/m0/s1FVTCRASFADXXNN-SCRDCRAPSA-N{[(2R,3S,4S)-5-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}-2,3,4-trihydroxypentyl]oxy}phosphonic acid456.3438456.104614802-2.836riboflavin 5'-phosphate0-3FDB001984Fmn;Flanin;Flavine mononucleotide;Flavol;Riboflavin;Riboflavin 5'-monophosphate;Riboflavin 5'-phosphate;Riboflavin mononucleotide;Riboflavin monophosphate;Riboflavin phosphate;Riboflavin-5'-phosphate na;Riboflavin-5-phosphate;Riboflavine 5'-monophosphate;Riboflavine 5'-phosphate;Riboflavine dihydrogen phosphate;Riboflavine monophosphate;Riboflavine phosphate;Riboflavine-5'-phosphate;Vitamin b2 phosphate;Flavin mononucleotide;Riboflavin 5'-(dihydrogen phosphate)PW_C001170FlvnMnt539811901416922496131577210111900211123132257751911577590111787301321204334051204541221219291241230673761230881351244821181256982971261042991271902051273122091276863881407034919TetrahydrobiopterinHMDB0000027Tetrahydrobiopterin or BH4 is a cofactor in the synthesis of nitric oxide. In fact it is used by all three human nitric-oxide synthases (NOS) eNOS, nNOS, and iNOS as well as the enzyme glyceryl-ether monooxygenase. It is also essential in the conversion of phenylalanine to tyrosine by the enzyme phenylalanine-4-hydroxylase; the conversion of tyrosine to L-dopa by the enzyme tyrosine hydroxylase; and conversion of tryptophan to 5-hydroxytryptophan via tryptophan hydroxylase. Specifically, tetrahydrobiopterin is a cofactor for tryptophan 5-hydroxylase 1, tyrosine 3-monooxygenase, and phenylalanine hydroxylase all of which are essential for the formation of the neurotransmitters dopamine, noradrenaline and adrenaline. Tetrahydrobiopterin has been proposed to be involved in promotion of neurotransmitter release in the brain and the regulation of human melanogenesis. A defect in BH4 production and/or a defect in the enzyme dihydropteridine reductase (DHPR) causes phenylketonuria type IV, as well as dopa-responsive dystonias. BH4 is also implicated in Parkinson's disease, Alzheimer's disease and depression. Tetrahydrobiopterin is present in probably every cell or tissue of higher animals. On the other hand, most bacteria, fungi and plants do not synthesize tetrahydrobiopterin. -- Wikipedia.17528-72-2C00272112515372TETRA-H-BIOPTERIN1093DB00360[H][C@@]1(CNC2=C(N1)C(=O)N=C(N)N2)[C@@H](O)[C@H](C)OC9H15N5O3InChI=1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1FNKQXYHWGSIFBK-RPDRRWSUSA-N(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-1,4,5,6,7,8-hexahydropteridin-4-one241.2471241.117489371-2.046tetrahydrobiopterin00FDB021880(1r,2s)-(2-amino-3,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)-1,2-propandiol;2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydoro-4(1h)-5,6,7,8-tetrahydro-2-amino-6-(1,2-dihydroxypropyl)-4(1h)-pteridinone;2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(1h)-pteridinone;5,6,7,8-erythro-tetrahydrobiopterin;5,6,7,8-tetra-h-biopterin;5,6,7,8-tetrahydro-2-amino-6-(1,2-dihydroxypropyl)-4(1h)-pteridinone;5,6,7,8-tetrahydrobiopterin;L-erythro-2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(3h)-pteridinon;Tetra-h-biopterin;Tetra-hydro-biopterin;Tetrahydrobiopterin;2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydoro-4(1h)-pteridinone;Bh4PW_C000019BH41957240858480014480314496231119012117752011578663132120434405121616124123068376124174118126493299127585388846Coenzyme Q10HMDB0001072Coenzyme Q10 (ubiquinone) is a naturally occurring compound widely distributed in animal organisms and in humans. The primary compounds involved in the biosynthesis of ubiquinone are 4-hydroxybenzoate and the polyprenyl chain. An essential role of coenzyme Q10 is as an electron carrier in the mitochondrial respiratory chain. Moreover, coenzyme Q10 is one of the most important lipophilic antioxidants, preventing the generation of free radicals as well as oxidative modifications of proteins, lipids, and DNA, it and can also regenerate the other powerful lipophilic antioxidant, alpha-tocopherol. Antioxidant action is a property of the reduced form of coenzyme Q10, ubiquinol (CoQ10H2), and the ubisemiquinone radical (CoQ10H*). Paradoxically, independently of the known antioxidant properties of coenzyme Q10, the ubisemiquinone radical anion (CoQ10-) possesses prooxidative properties. Decreased levels of coenzyme Q10 in humans are observed in many pathologies (e.g. cardiac disorders, neurodegenerative diseases, AIDS, cancer) associated with intensive generation of free radicals and their action on cells and tissues. In these cases, treatment involves pharmaceutical supplementation or increased consumption of coenzyme Q10 with meals as well as treatment with suitable chemical compounds (i.e. folic acid or B-group vitamins) which significantly increase ubiquinone biosynthesis in the organism. Estimation of coenzyme Q10 deficiency and efficiency of its supplementation requires a determination of ubiquinone levels in the organism. Therefore, highly selective and sensitive methods must be applied, such as HPLC with UV or coulometric detection. For a number of years, coenzyme Q (CoQ10 in humans) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in plasma, and extensively investigated its antioxidant role. These two functions constitute the basis on which research supporting the clinical use of CoQ10 is founded. Also at the inner mitochondrial membrane level, coenzyme Q is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the transition pore. Furthermore, recent data reveal that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of exogenously administered CoQ10 may be due to this property. Coenzyme Q is the only lipid soluble antioxidant synthesized endogenously. In its reduced form, CoQH2, ubiquinol, inhibits protein and DNA oxidation but it is the effect on lipid peroxidation that has been most deeply studied. Ubiquinol inhibits the peroxidation of cell membrane lipids and also that of lipoprotein lipids present in the circulation. Dietary supplementation with CoQ10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoproteins to the initiation of lipid peroxidation. Moreover, CoQ10 has a direct anti-atherogenic effect, which has been demonstrated in apolipoprotein E-deficient mice fed with a high-fat diet. (PMID: 15928598, 17914161).303-98-0C11378528191546245UBIQUINONE-104445197COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=OC59H90O4InChI=1S/C59H90O4/c1-44(2)24-15-25-45(3)26-16-27-46(4)28-17-29-47(5)30-18-31-48(6)32-19-33-49(7)34-20-35-50(8)36-21-37-51(9)38-22-39-52(10)40-23-41-53(11)42-43-55-54(12)56(60)58(62-13)59(63-14)57(55)61/h24,26,28,30,32,34,36,38,40,42H,15-23,25,27,29,31,33,35,37,39,41,43H2,1-14H3/b45-26+,46-28+,47-30+,48-32+,49-34+,50-36+,51-38+,52-40+,53-42+ACTIUHUUMQJHFO-UPTCCGCDSA-N2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaen-1-yl]-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione863.3435862.683911368-6.650coenzyme-Q1000FDB014621(all-e)-2,3-dimethoxy-5-methyl-6-(3,7,11,15,19,23,27,31-octamethyl-2,6,10,14,18,22,26,30-dotriacontaoctaenyl)-2,5-cyclohexadiene-1,4-dione;(all-e)-2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-1,4-dione;2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl)-5,6-dimethoxy-3-methyl-p-benzoquinone;2-[(2e,6e,10e,14e,18e,22e,26e,30e,34e)-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl]-5,6-dimethoxy-3-methyl- 2,5-cyclohexadiene-1,4-dione;4-ethyl-5-fluoropyrimidine;Aqua q 10l10;Aqua q10;Bio-quinon;Bio-quinone q10;Coq10;Coenzyme q10;Ensorb;Kaneka q10;Kudesan;Li-q-sorb;Liquid-q;Neuquinon;Neuquinone;Puresorb q 40;Q 10aa;Q-gel;Q-gel 100;Ubidecarenone;Ubiquinone 10;Ubiquinone 50;Ubiquinone q10;Ubiquinone-10;Unbiquinone;Unispheres q 10;2-((all-e)-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl)-5,6-dimethoxy-3-methyl-p-benzoquinone;2-[(2e,6e,10e,14e,18e,22e,26e,30e,34e)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaen-1-yl]-5,6-dimethoxy-3-methyl-1,4-benzoquinone;Adelir;All-trans-ubiquinone;Coq;Q;Q 199;Q10;UbiquinonePW_C000846Coq25217425142505245396102605315661151626498179748622377151134783713458003336911780713311999838412256241812266040612277512112513545412523512012537748012671048912679247912691939112830150612839050188Fumaric acidHMDB0000134Fumaric acid is a precursor to L-malate in the Krebs tricarboxylic acid cycle. It is formed by the oxidation of succinate by succinate dehydrogenase. Fumarate is converted by fumarase to malate. A fumarate is a salt or ester of the organic compound fumaric acid, a dicarboxylic acid. (wikipedia).110-17-8C001222188378818012FUM10197150DB04299OC(=O)\C=C\C(O)=OC4H4O4InChI=1S/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+VZCYOOQTPOCHFL-OWOJBTEDSA-N(2E)-but-2-enedioic acid116.0722116.010958616-0.682fumaric acid0-2FDB003291(2e)-but-2-enedioate;(2e)-but-2-enedioic acid;(e)-2-butenedioate;(e)-2-butenedioic acid;2-(e)-butenedioate;2-(e)-butenedioic acid;Allomaleate;Allomaleic acid;Boletate;Boletic acid;Fc 33;Fumarate;Fumaric acid;Lichenate;Lichenic acid;Sodium fumarate;Trans-1,2-ethylenedicarboxylate;Trans-1,2-ethylenedicarboxylic acid;Trans-2-butenedioate;Trans-2-butenedioic acid;Trans-butenedioate;Trans-butenedioic acid;(2e)-2-butenedioic acid;E297;Fumarsaeure;Trans-but-2-enedioic acid;(2e)-2-butenedioate;Trans-but-2-enedioatePW_C000088Fumarat102825417200425053453881026047156610716264581076459108649217967631176837166748022390651511180419812713290424003224249631842497315771481347746611179107132800273691178081331199893841200431221215991241226614061227721211227941351241571181252361201253694801254212971267934791269113911269602051275653881283915011006QH2HMDB0001304QH2, also known as ubiquinol-10 or COQH2, belongs to the class of organic compounds known as ubiquinols. These are coenzyme Q derivatives containing a 5, 6-dimethoxy-3-methylbenzene-1,4-diol moiety to which an isoprenyl group is attached at ring position 2(or 6). QH2 is considered to be a practically insoluble (in water) and relatively neutral molecule. QH2 has been found throughout most human tissues, and has also been primarily detected in blood. Within the cell, QH2 is primarily located in the membrane (predicted from logP), inner mitochondrial membrane, cytoplasm and mitochondria. QH2 exists in all living organisms, ranging from bacteria to humans. Reduced form of ubiquinone, a mobile electron transporter between complex I and III, or II and III of the electron transport chain. Both at complex I or complex II, two electrons and two protons are passed to ubiquinone reducing it to ubiquinol.56275-39-9C003905280344QH24444052COC1=C(O)C(C)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1OC(C5H8)nC14H20O4InChI=1S/C19H28O4/c1-12(2)8-7-9-13(3)10-11-15-14(4)16(20)18(22-5)19(23-6)17(15)21/h8,10,20-21H,7,9,11H2,1-6H3/b13-10+RNUCUWWMTTWKAH-JLHYYAGUSA-N-4.410FDB022543Coqh2;Coenzymes qh2;Reduced ubiquinone;Ubiquinol;Ubiquinone-1;Qh2PW_C001006QH2932FADHHMDB0001197FADH is the reduced form of flavin adenine dinucleotide (FAD). FAD is synthesized from riboflavin and two molecules of ATP. Riboflavin is phosphorylated by ATP to give riboflavin 5-phosphate (FMN). FAD is then formed from FMN by the transfer of an AMP moiety from a second molecule of ATP. FADH is generated in each round of fatty acid oxidation, and the fatty acyl chain is shortened by two carbon atoms as a result of these reactions; because oxidation is on the beta carbon, this series of reactions is called the beta-oxidation pathway. In the citric acid cycle FADH is involved in harvesting of high-energy electrons from carbon fuels; citric acid cycle itself neither generates a large amount of ATP nor includes oxygen as a reactant. Instead, the citric acid cycle removes electrons from acetyl CoA and uses these electrons to form FADH. (Biochemistry. Berg, Jeremy M. Tymoczko, John L. and Stryer, Lubert. New York: W. H. Freeman and Co. 2002.).1910-41-4C0135244601317877FADH2393487CC1=CC2=C(C=C1C)N(C[C@H](O)[C@H](O)[C@H](O)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=NC3=C1N=CN=C3N)C1=C(N2)C(=O)NC(=O)N1C27H35N9O15P2InChI=1S/C27H35N9O15P2/c1-10-3-12-13(4-11(10)2)35(24-18(32-12)25(42)34-27(43)33-24)5-14(37)19(39)15(38)6-48-52(44,45)51-53(46,47)49-7-16-20(40)21(41)26(50-16)36-9-31-17-22(28)29-8-30-23(17)36/h3-4,8-9,14-16,19-21,26,32,37-41H,5-7H2,1-2H3,(H,44,45)(H,46,47)(H2,28,29,30)(H2,33,34,42,43)/t14-,15+,16+,19-,20+,21+,26+/m0/s1YPZRHBJKEMOYQH-UYBVJOGSSA-N{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}[({[(2R,3S,4S)-5-{7,8-dimethyl-2,4-dioxo-1H,2H,3H,4H,5H,10H-benzo[g]pteridin-10-yl}-2,3,4-trihydroxypentyl]oxy}(hydroxy)phosphoryl)oxy]phosphinic acid787.5656787.172784519-2.3711fadh(.)0-2FDB0224831,5-dihydro-fad;1,5-dihydro-p-5-ester with adenosine;1,5-dihydro-riboflavin 5'-(trihydrogen diphosphate) p'->5'-ester with adenosine;Adenosine 5'-(trihydrogen pyrophosphate), 5'-5'-ester with 5,10-dihydro-7,8-dimethyl-10-(d-ribo-2,3,4,5-tetrahydroxypentyl)alloxazine;Adenosine 5'-(trihydrogen pyrophosphate), 5'->5'-ester with 5,10-dihydro-7,8-dimethyl-10-(d-ribo-2,3,4,5-tetrahydroxypentyl)alloxazine;Adenosine 5'-{3-[d-ribo-5-(7,8-dimethyl-2,4-dioxo-1,2,3,4,5,10-tetrahydrobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl] dihydrogen diphosphate};Adenosine 5-(trihydrogen pyrophosphate);Adenosine pyrophosphate 5'-5'-ester with 5,10-dihydro-7,8-dimethyl-10-(d-ribo-2,3,4,5-tetrahydroxypentyl)alloxazine;Adenosine pyrophosphate, 5'-5'-ester with 5,10-dihydro-7,8-dimethyl-10-(d-ribo-2,3,4,5-tetrahydroxypentyl)alloxazine;Adenosine pyrophosphate, 5'->5'-ester with 5,10-dihydro-7,8-dimethyl-10-(d-ribo-2,3,4,5-tetrahydroxypentyl)alloxazine;Benzo[g]pteridine riboflavin 5'-(trihydrogen diphosphate) deriv;Benzo[gr]pteridine riboflavin 5'-(trihydrogen diphosphate) deriv;Dihydro-fad;Dihydroflavine-adenine dinucleotide;Fadh2;Fda;Flavin adenine dinucleotide (reduced);Flavin adenine dinucleotide reduced;Reduced flavine adenine dinucleotidePW_C000932FADH2561710453149042505545398102605615661181626501179748922390772241252322712527249771541347852534580036369117810133120001384121299418122663406122778121123869454125238120125380480125980489126795479126922391127433506128393501405582Fe-2SHMDB0061344Bis(λ²-iron(2+) ion) disulfane tetrasulfanide belongs to the class of inorganic compounds known as transition metal sulfides. These are inorganic compounds containing a sulfur atom of an oxidation state of -2, in which the heaviest atom bonded to the oxygen is a transition metal.S.S.[SH-].[SH-].[SH-].[SH-].[Fe++].[Fe++]Fe2H8S6InChI=1S/2Fe.6H2S/h;;6*1H2/q2*+2;;;;;;/p-4MZMMVZPHZTYDNI-UHFFFAOYSA-Jbis(lambda2-iron(2+) ion) disulfane tetrasulfanide312.11311.7648990bis(lambda2-iron(2+) ion) disulfane tetrasulfanide02PW_C0405582Fe2S37422401284257174389346265475431482994837285056454971265512127704616013030301130423027771511377727337783771347838613279207112117811133121586407121795124122567384122664406123152443123167448124144119124346118125140121125239120126189299126715480126796479127680388128306391128394501105126Adrenocorticotropic 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noyl]pyrrolidin-2-yl]formamido}-3-methylbutanamido]hexanamido]-3-methylbutanamido]-3-(4-hydroxyphenyl)propanoyl]pyrrolidin-2-yl]formamido}-3-carbamoylpropanamido]acetamido}propanamido]-4-carboxybutanamido]-3-carboxypropanamido]-4-carboxybutanamido]-3-hydroxypropanamido]propanamido]-4-{[(1S)-1-{[(2S)-1-[(2S)-2-{[(1S)-1-{[(1S)-3-carboxy-1-{[(1S)-1-carboxy-2-phenylethyl]carbamoyl}propyl]carbamoyl}-3-methylbutyl]carbamoyl}pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]carbamoyl}ethyl]carbamoyl}butanoic acid4541.144538.25937327663corticotropin01;ACTH;Adrenocorticotrophin;Adrenocorticotropic hormone;Corticotrophin;CorticotropinPW_C105126ACTH77D-GlucoseHMDB0000122Glucose is a monosaccharide containing six carbon atoms and an aldehyde group and is therefore referred to as an aldohexose. The glucose molecule can exist in an open-chain (acyclic) and ring (cyclic) form, the latter being the result of an intramolecular reaction between the aldehyde C atom and the C-5 hydroxyl group to form an intramolecular hemiacetal. In water solution both forms are in equilibrium and at pH 7 the cyclic one is the predominant. Glucose is a primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. In animals glucose arises from the breakdown of glycogen in a process known as glycogenolysis. Glucose is synthesized in the liver and kidneys from non-carbohydrate intermediates, such as pyruvate and glycerol, by a process known as gluconeogenesis.2280-44-6C0003157934167GLC5589[H]C1(O)O[C@]([H])(CO)[C@@]([H])(O)[C@]([H])(O)[C@@]1([H])OC6H12O6InChI=1S/C6H12O6/c7-1-2-3(8)4(9)5(10)6(11)12-2/h2-11H,1H2/t2-,3-,4+,5-,6?/m1/s1WQZGKKKJIJFFOK-GASJEMHNSA-N(3R,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol180.1559180.0633881160.645glucose00FDB012530Roferose st;(+)-glucose;Anhydrous dextrose;Cpc hydrate;Cerelose;Cerelose 2001;Clearsweet 95;Clintose l;Corn sugar;D(+)-glucose;Dextropur;Dextrose;Dextrosol;Glucodin;Glucolin;Glucose;Goldsugar;Grape sugar;Meritose;Staleydex 111;Staleydex 95m;Tabfine 097(hs);Vadex;D-glc;D-glcp;D-glucosePW_C000077D-Glc1452501460261461511506215404321939243942679602721152723613027663114293593356926589614859221495923152595415363671076368108686919269041937085200724421511765114117661324244031842441315770853267711732777923336779893467823635278248353782623567888111379056112121166424121167416121169423121251429121361124121373419122098126122385436122388437122399407122676409123738459123739452123741458123821464123920118123932455124649443124939471124959472124969119125251137125937488125967492126034299126046490126254301126540481126809483127397505127423509127486388127498507127817207128113206128408208129L-AcetylcarnitineHMDB0000201L-Acetylcarnitine (ALCAR or ALC) is an acetic acid ester of carnitine that facilitates movement of acetyl-CoA into the matrices of mammalian mitochondria during the oxidation of fatty acids. In addition to his metabolic role, acetyl-L-carnitine posses unique neuroprotective, neuromodulatory, and neurotrophic properties this may play an important role in counteracting various disease processes (PMID ID: 15363640).3040-38-8C02571173024(-)o-acetylcarnitine21243783CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)CC9H17NO4InChI=1S/C9H17NO4/c1-7(11)14-8(5-9(12)13)6-10(2,3)4/h8H,5-6H2,1-4H3/t8-/m1/s1RDHQFKQIGNGIED-MRVPVSSYSA-N(3R)-3-(acetyloxy)-4-(trimethylazaniumyl)butanoate203.238203.115758031-2.860acetyl-L-carnitine00FDB021904(+-)-acetylcarnitine;(-)-acetylcarnitine;(r)-acetylcarnitine;Alcar;Acetyl-l-(-)-carnitine;Acetyl-l-carnitine;Acetyl-carnitine;Acetylcarnitine;L-acetylcarnitine;L-carnitine acetyl ester;L-o-acetylcarnitine;Levocarnitine acetyl;Nicetile;O-acetyl-l-carnitine;O-acetylcarnitine;3-(acetyloxy)-4-(trimethylammonio)butanoate;Acetyl-dl-carnitine;Dl-o-acetylcarnitine;3-(acetyloxy)-4-(trimethylammonio)butanoic acidPW_C000129L-Alcar24615247022506422515477559334775601337757313278441345806313748063212080645118122418408122424406122431418122527124124997454126565482126573479126579489126679299128138502128146501128152506128258388122L-Lactic acidHMDB0000190Lactic acid is an organic acid. It is a chiral molecule, consisting of two optical isomers, L-lactic acid and D-lactic acid, with the L-isomer being the most common in living organisms. Lactic acid plays a role in several biochemical processes and is produced in the muscles during intense activity. In animals, L-lactate is constantly produced from pyruvate via the enzyme lactate dehydrogenase (LDH) in a process of fermentation during normal metabolism and exercise. It does not increase in concentration until the rate of lactate production exceeds the rate of lactate removal. This is governed by a number of factors, including monocarboxylate transporters, lactate concentration, the isoform of LDH, and oxidative capacity of tissues. The concentration of blood lactate is usually 1-2 mmol/L at rest, but can rise to over 20 mmol/L during intense exertion. There are some indications that lactate, and not glucose, is preferentially metabolized by neurons in the brain of several mammalian species, including mice, rats, and humans. Glial cells, using the lactate shuttle, are responsible for transforming glucose into lactate, and for providing lactate to the neurons. Lactate measurement in critically ill patients has been traditionally used to stratify patients with poor outcomes. However, plasma lactate levels are the result of a finely tuned interplay of factors that affect the balance between its production and its clearance. When the oxygen supply does not match its consumption, organisms adapt in many different ways, up to the point when energy failure occurs. Lactate, being part of the adaptive response, may then be used to assess the severity of the supply/demand imbalance. In such a scenario, the time to intervention becomes relevant: early and effective treatment may allow tissues and cells to revert to a normal state, as long as the oxygen machinery (i.e. mitochondria) is intact. Conversely, once the mitochondria are deranged, energy failure occurs even in the presence of normoxia. The lactate increase in critically ill patients may, therefore, be viewed as an early marker of a potentially reversible state (PMID: 16356243). When present in sufficiently high levels, lactic acid can act as an oncometabolite, an immunosuppressant, an acidogen, and a metabotoxin. An oncometabolite is a compound that promotes tumor growth and survival. An immunosuppressant reduces or arrests the activity of the immune system. An acidogen is an acidic compound that induces acidosis, which has multiple adverse effects on many organ systems. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of lactic acid are associated with at least a dozen inborn errors of metabolism, including 2-methyl-3-hydroxybutyryl CoA dehydrogenase deficiency, biotinidase deficiency, fructose-1,6-diphosphatase deficiency, glycogen storage disease type 1A (GSD1A) or Von Gierke disease, glycogenosis type IB, glycogenosis type IC, glycogenosis type VI, Hers disease, lactic acidemia, Leigh syndrome, methylmalonate semialdehyde dehydrogenase deficiency, pyruvate decarboxylase E1 component deficiency, pyruvate dehydrogenase complex deficiency, pyruvate dehydrogenase deficiency, and short chain acyl CoA dehydrogenase deficiency (SCAD deficiency). Locally high concentrations of lactic acid or lactate are found near many tumors due to the upregulation of lactate dehydrogenase (PMID: 15279558). Lactic acid produced by tumors through aerobic glycolysis acts as an immunosuppressant and tumor promoter (PMID: 23729358). Indeed, lactic acid has been found to be a key player or regulator in the development and malignant progression of a variety of cancers (PMID: 22084445). A number of studies have demonstrated that malignant transformation is associated with an increase in aerobic cellular lactate excretion. Lactate concentrations in various carcinomas (e.g. uterine cervix, head and neck, colorectal region) at first diagnosis of the disease, can be relatively low or extremely high (up to 40 µmol/g) in different individual tumors or within the same lesion (PMID: 15279558). High molar concentrations of lactate are correlated with a high incidence of distant metastasis. Low lactate tumors (< median of approximately 8 µmol/g) are associated with both an overall longer and disease-free survival compared to high lactate lesions (lactate > approximately 8 µmol/g). Lactate-induced secretion of hyaluronan by tumor-associated fibroblasts creates a milieu favourable for cell migration and metastases (PMID: 22084445). An acidic environment (pH 6-6.5), which is common in many tumors, allows tumor cells to evade the immune response, and therefore allows them to grow unchecked. Locally high concentrations of lactic acid are known to markedly impede the function of normal immune cells and will lead to a loss of T-cell function of human tumor-infiltrating lymphocytes (PMID: 22084445). Lactic acid is also an organic acid and acts as a general acidogen. Abnormally high levels of organic acids in the blood (organic acidemia), urine (organic aciduria), the brain, and other tissues lead to general metabolic acidosis. Acidosis typically occurs when arterial pH falls below 7.35. In infants with acidosis, the initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These can progress to heart abnormalities, kidney abnormalities, liver damage, seizures, coma, and possibly death. These are also the characteristic symptoms of the untreated IEMs mentioned above. Many affected children with organic acidemias experience intellectual disability or delayed development.79-33-4C00186107689422L-LACTATE96860C[C@H](O)C(O)=OC3H6O3InChI=1S/C3H6O3/c1-2(4)3(5)6/h2,4H,1H3,(H,5,6)/t2-/m0/s1JVTAAEKCZFNVCJ-REOHCLBHSA-N(2S)-2-hydroxypropanoic acid90.077990.0316940582(α)-lactate0-1FDB003294(+)-lactate;(+)-lactic acid;(s)-(+)-2-hydroxypropanoate;(s)-(+)-2-hydroxypropanoic acid;(s)-2-hydroxypropanoate;(s)-2-hydroxypropanoic acid;(s)-2-hydroxypropionate;(s)-2-hydroxypropionic acid;(s)-2-hydroxy-propanoate;(s)-2-hydroxy-propanoic acid;(s)-lactate;(s)-lactic acid;(alpha)-lactate;(alpha)-lactic acid;1-hydroxyethane 1-carboxylate;1-hydroxyethane 1-carboxylic acid;1-hydroxyethanecarboxylate;1-hydroxyethanecarboxylic acid;2-hydroxypropanoate;2-hydroxypropanoic acid;2-hydroxypropionate;L-(+)- lactic acid;L-2-hydroxypropanoate;L-2-hydroxypropanoic acid;Lactate;Lactic acid;Milk acid;Sarcolactic acid;A-hydroxypropanoate;A-hydroxypropanoic acid;A-hydroxypropionate;A-hydroxypropionic acid;Alpha-hydroxypropanoate;Alpha-hydroxypropanoic acid;Alpha-hydroxypropionate;Alpha-hydroxypropionic acid;(s)-(+)-lactic acid;L-(+)-alpha-hydroxypropionic acid;L-(+)-lactic acid;L-lactic acid;L-milchsaeurePW_C000122Lactate1717823992505015779641327876411111783311412121412412143812212267740912378411812399613512525213712606229712678829912681048312751420512838538812840920845CortisolHMDB0000063Cortisol is the main glucocorticoid secreted by the adrenal cortex and it is involved in the stress response. Its synthetic counterpart hydrocortisone is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Hydrocortisone is synthesized from pregnenolone and is used as an immunosuppressive drug given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients who need steroid treatment but cannot take oral medication, and peri-operatively in patients on long-term steroid treatment to prevent an Addisonian crisis. Cortisol increases blood pressure, blood sugar levels, may cause infertility in women, and suppresses the immune system. The amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning and lower levels in the evening, several hours after the onset of sleep. Cortisol is found to be associated with ACTH deficiency and glucocorticoid deficiency, which are inborn errors of metabolism. Cortisol binds to the cytosolic glucocorticoid receptor. After binding the receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA-bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically, glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes and prevents phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products of inflammation, prostaglandins and leukotrienes, are inhibited by the action of glucocorticoids. Glucocorticoids also stimulate the escape of lipocortin-1 into the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes. Additionally, the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding.50-23-7C007355754176505551DB00741[H][C@@]12CC[C@](O)(C(=O)CO)[C@@]1(C)C[C@H](O)[C@@]1([H])[C@@]2([H])CCC2=CC(=O)CC[C@]12CC21H30O5InChI=1S/C21H30O5/c1-19-7-5-13(23)9-12(19)3-4-14-15-6-8-21(26,17(25)11-22)20(15,2)10-16(24)18(14)19/h9,14-16,18,22,24,26H,3-8,10-11H2,1-2H3/t14-,15-,16-,18+,19-,20-,21-/m0/s1JYGXADMDTFJGBT-VWUMJDOOSA-N(1S,2R,10S,11S,14R,15S,17S)-14,17-dihydroxy-14-(2-hydroxyacetyl)-2,15-dimethyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadec-6-en-5-one362.4599362.20932407-3.263(1S,2R,10S,11S,14R,15S,17S)-14,17-dihydroxy-14-(2-hydroxyacetyl)-2,15-dimethyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadec-6-en-5-one00FDB02188811-hydrocortisone;11-beta-hydrocortisone;11-beta-hydroxycortisone;11a-hydroxycorticosterone;11alpha-hydroxycorticosterone;11b,17,21-trihydroxyprogesterone;11b-hydrocortisone;11b-hydroxycortisone;11beta,17,21-trihydroxyprogesterone;11beta-hydrocortisone;11beta-hydroxycortisone;17-hydroxycorticosterone;17a-hydroxycorticosterone;17alpha-hydroxycorticosterone;4-pregnene-11alpha,21-triol 3,20-dione;4-pregnene-11b,17a,21-triol-3,20-dione;Acticort;Aeroseb hc;Aeroseb-hc;Ala-cort;Ala-scalp;Alacort;Algicirtis;Alphaderm;Amberin;Anflam;Anti-inflammatory hormone;Aquacort;Aquanil hc;Barseb hc;Basan-corti;Caldecort spray;Cetacort;Chronocort;Clear aid;Cleiton;Cobadex;Compound f;Cor-tar-quin;Cort-dome;Cort-quin;Cortanal;Cortenema;Cortesal;Corticreme;Cortifan;Cortifoam;Cortiment;Cortisol alcohol;Cortisolonum;Cortisporin;Cortisporin otico;Cortispray;Cortizol;Cortolotion;Cortonema;Cortoxide;Cremesone;Cremicort-h;Cutisol;Delacort;Derm-aid;Dermil;Dermolate;Dihydrocostisone;Dioderm;Dome-cort;Domolene-hc;Drotic;Ef corlin;Efcorbin;Efcortelan;Efcortelin;Eldercort;Epicort;Epiderm h;Esiderm h;Evacort;Ficortril;Fiocortril;Foille insetti;Genacort;Gyno-cortisone;H-cort;Hc;Heb cort;Heb-cort;Hidalone;Hidro-colisona;Hidrocortisona;Hycort;Hycortol;Hycortole;Hydracort;Hydrasson;Hydro-adreson;Hydro-colisona;Hydrocort;Hydrocortal;Hydrocorticosterone;Hydrocortisone;Hydrocortisone alcohol;Hydrocortisone base;Hydrocortisone free alcohol;Hydrocortisonum;Hydrocortistab;Hydrocortisyl;Hydrocortone;Hydroskin;Hydroxycortisone;Hysone;Hytisone;Hytone;Hytone lotion;Idrocortisone;Incortin-h;Incortin-hydrogen;Kendall's compound f;Komed hc;Kyypakkaus;Lacticare hc;Lacticare-hc;Lactisona;Lubricort;Maintasone;Medicort;Meusicort;Mildison;Milliderm;Neo-cort-dome;Neosporin-h ear;Nutracort;Nystaform-hc;Optef;Otalgine;Otic-neo-cort-dome;Otobiotic;Otocort;Otosone-f;Pediotic suspension;Penecort;Permicort;Polcort h;Preparation h hydrocortisone cream;Prepcort;Prestwick_265;Prevex hc;Proctocort;Proctofoam;Protocort;Racet;Rectoid;Reichstein's substance m;Remederm hc;Sanatison;Scalpicin capilar;Schericur;Scheroson f;Sigmacort;Signef;Stiefcorcil;Synacort;Systral hydrocort;Tarcortin;Timocort;Topicort;Transderma h;Traumaide;Uniderm;Vioform-hydrocortisone;Vosol hc;Vytone;ZenoxonePW_C000045HC2274497897533112181438312436739848EpinephrineHMDB0000068Epinephrine is a catecholamine, a sympathomimetic monoamine derived from the amino acids phenylalanine and tyrosine. It is the active sympathomimetic hormone secreted from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. Epinephrine also constricts arterioles in the skin and gut while dilating arterioles in leg muscles. It elevates the blood sugar level by increasing hydrolysis of glycogen to glucose in the liver, and at the same time begins the breakdown of lipids in adipocytes. Epinephrine has a suppressive effect on the immune system.51-43-4C00788581628918L-EPINEPHRINE5611DB00668CNC[C@H](O)C1=CC(O)=C(O)C=C1C9H13NO3InChI=1S/C9H13NO3/c1-10-5-9(13)6-2-3-7(11)8(12)4-6/h2-4,9-13H,5H2,1H3/t9-/m0/s1UCTWMZQNUQWSLP-VIFPVBQESA-N4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol183.2044183.089543287-0.994epinephrine01FDB021889(-)-(r)-epinephrine;(-)-3,4-dihydroxy-a-[2-(methylamino)ethyl]benzyl alcohol;(-)-3,4-dihydroxy-alpha-[2-(methylamino)ethyl]benzyl alcohol;(-)-3,4-dihydroxy-a-[(methylamino)methyl]-benzyl alcohol;(-)-3,4-dihydroxy-alpha-[(methylamino)methyl]-benzyl alcohol;(-)-adrenaline;(-)-epinephrine;(r)-4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol;(r)-adrenaline;(r)-epinephrine;4-[(1r)-1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol;Adnephrine;Adrenal;Adrenalin;Adrenaline;Adrenine;Adrin;Ana-kit;Bosmin;Bronkaid mist;Chelafrin;Epifrin;Epiglaufrin;Epinefrina;Epinephran;Epinephrine;Epipen;Epirenan;Eppy;Exadrin;Glauposine;Hemisine;Hemostasin;Hemostatin;Hypernephrin;Isoptoepinal;L-1-(3,4-dihydroxyphenyl)-2-methylaminoethanol;L-adrenaline;L-epinephrine;L-epirenamine;L-methylaminoethanolcatechol;Levoepinephrine;Levorenen;Levorenin;Levorenine;Levoreninum;Lyodrin;Methylarterenol;Mucidrina;Nephridine;Nieraline;Paranephrin;Primatene mist;R-(-)-epinephrine;Renaglandin;Renaleptine;Renalina;Renoform;Renostypticin;Renostyptin;Scurenaline;Simplene;Styptirenal;Supracapsulin;Supranephrane;Suprarenaline;Suprarenin;Surrenine;Sus-phrine;Takamina;Vasoconstrictine;Vasotonin;(-)-3,4-dihydroxy-alpha-((methylamino)methyl)benzyl alcohol;(r)-(-)-adrenaline;(r)-(-)-adnephrine;(r)-(-)-epinephrine;(r)-(-)-epirenamine;Epinephrin;Epinephrinum;Epipen jr;Primatene;(-)-3,4-dihydroxy-a-((methylamino)methyl)benzyl alcohol;(-)-3,4-dihydroxy-α-((methylamino)methyl)benzyl alcoholPW_C000048Eppy7062074914108715108841116945206824339146356346368750846577774341777763427777734079129132828075182838381121626124124184118127597388544Fe2+HMDB0000692Iron is a chemical element with the symbol Fe and atomic number 26. Iron makes up 5% of the Earth's crust and is second in abundance to aluminium among the metals and fourth in abundance among the elements. Physiologically, it. exists as an ion in the body. Iron (as Fe2+, ferrous ion) is a necessary trace element used by all known living organisms. Iron-containing enzymes, usually containing heme prosthetic groups, participate in catalysis of oxidation reactions in biology, and in transport of a number of soluble gases. Iron is an essential constituent of hemoglobin, cytochrome, and other components of respiratory enzyme systems. Its chief functions are in the transport of oxygen to tissue (hemoglobin) and in cellular oxidation mechanisms. Inorganic iron involved in redox reactions is also found in the iron-sulfur clusters of many enzymes, such as nitrogenase (involved in the synthesis of ammonia from nitrogen and hydrogen) and hydrogenase. A class of non-heme iron proteins is responsible for a wide range of functions such as ribonucleotide reductase (reduces ribose to deoxyribose; DNA biosynthesis) and purple acid phosphatase (hydrolysis of phosphate esters). When the body is fighting a bacterial infection, the body sequesters iron inside of cells (mostly stored in the storage molecule ferritin) so that it cannot be used by bacteria. Depletion of iron stores may result in iron-deficiency anemia. Iron is used to build up the blood in anemia. Humans experience iron toxicity above 20 milligrams of iron for every kilogram of weight, and 60 milligrams per kilogram is a lethal dose. Over-consumption of iron, often the result of children eating large quantities of ferrous sulfate tablets intended for adult consumption, is the most common toxicological cause of death in children under six. The DRI lists the Tolerable Upper Intake Level (UL) for adults as 45 mg/day. For children under fourteen years old the UL is 40 mg/day. Iron is a metal extracted from iron ore, and is almost never found in the free elemental state.15438-31-0C148182728429033Ferric-Hydroxamate-Complexes25394DB01592[Fe++]FeInChI=1S/Fe/q+2CWYNVVGOOAEACU-UHFFFAOYSA-Nlambda2-iron(2+) ion55.84555.9349421330lambda2-iron(2+) ion22FDB016251Armco iron;Carbonyl iron;Fe;Ferrovac e;Hematite;Infed;Loha;Limonite;Magnetite;Malleable iron;Metopirone;Metyrapone;Pzho;Pzh2m;Remko;Suy-b 2;Taconite;Venofer;Wrought iron;Fe (ii) ion;Fe(ii);Fe2+;Fe(2+);Ferrous ion;Iron ion(2+)PW_C000544Fe2+39819641367831692207098177727041163705216012060225121431517717913277740112777511297776034177782111120544407120557414120570122121765124123178119123191450123204135124316118126143299126185481127650388140710491407161831Ascorbic acidHMDB0000044Ascorbic acid is found naturally in citrus fruits and many vegetables and is an essential nutrient in human diets. It is necessary to maintain connective tissue and bone. The biologically active form of ascorbic acid is vitamin C. Vitamin C is a water soluble vitamin. Primates (including humans) and a few other species in all divisions of the animal kingdom, notably the guinea pig, have lost the ability to synthesize ascorbic acid and must obtain it in their food. Vitamin C functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [PubChem] Ascorbic acid is an electron donor for enzymes involved in collagen hydroxylation, biosynthesis of carnitine and norepinephrine, tyrosine metabolism, and amidation of peptide hormones. Ascrobic acid (vitamin C) deficiency causes scurvy. The amount of vitamin C necessary to prevent scurvy may not be adequate to maintain optimal health. The ability of vitamin C to donate electrons also makes it a potent water-soluble antioxidant that readily scavenges free radicals such as molecular oxygen, superoxide, hydroxyl radical, and hypochlorous acid. In this setting, several mechanisms could account for a link between vitamin C and heart disease. One is the relation between LDL oxidation and vitamins C and E. Vitamin C in vitro can recycle vitamin E, which can donate electrons to prevent LDL oxidation in vitro. As the lipid-phase vitamin E is oxidized, it can be regenerated by aqueous vitamin C. Other possibilities are that vitamin C could decrease cholesterol by mechanisms not well characterized, or could improve vasodilatation and vascular reactivity, perhaps by decreasing the interactions of nitric oxide with oxidants. (PMID: 10799361).50-81-7C000725467006729073ASCORBATE10189562DB00126[H][C@@]1(OC(=O)C(O)=C1O)[C@@H](O)COC6H8O6InChI=1S/C6H8O6/c7-1-2(8)5-3(9)4(10)6(11)12-5/h2,5,7-10H,1H2/t2-,5+/m0/s1CIWBSHSKHKDKBQ-JLAZNSOCSA-N(5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one176.1241176.0320879880.144vitamin C0-1FDB001224(+)-sodium l-ascorbate;(+)-ascorbate;(+)-ascorbic acid;3-keto-l-gulofuranolactone;3-oxo-l-gulofuranolactone;Adenex;Allercorb;Antiscorbic vitamin;Antiscorbutic vitamin;Arco-cee;Ascoltin;Ascor-b.i.d.;Ascorb;Ascorbajen;Ascorbate;Ascorbic acid;Ascorbicab;Ascorbicap;Ascorbicin;Ascorbin;Ascorbutina;Ascorin;Ascorteal;Ascorvit;C-level;C-long;C-quin;C-span;C-vimin;Cantan;Cantaxin;Catavin c;Ce lent;Ce-mi-lin;Ce-vi-sol;Cebicure;Cebid;Cebion;Cebione;Cecon;Cee-caps td;Cee-vite;Cegiolan;Ceglion;Ceklin;Celaskon;Celin;Cell c;Cemagyl;Cemill;Cenetone;Cenolate;Cereon;Cergona;Cescorbat;Cetamid;Cetane;Cetane-caps tc;Cetane-caps td;Cetebe;Cetemican;Cevalin;Cevatine;Cevex;Cevi-bid;Cevimin;Cevital;Cevitamate;Cevitamic acid;Cevitamin;Cevitan;Cevitex;Cewin;Chewcee;Ciamin;Cipca;Citriscorb;Citrovit;Colascor;Concemin;Davitamon c;Dora-c-500;Duoscorb;Ferrous ascorbate;Hicee;Hybrin;Ido-c;Juvamine;Kangbingfeng;Kyselina askorbova;L(+)-ascorbate;L(+)-ascorbic acid;L-(+)-ascorbate;L-(+)-ascorbic acid;L-3-ketothreohexuronic acid lactone;L-ascorbate;L-ascorbic acid;L-lyxoascorbate;L-lyxoascorbic acid;L-threo-ascorbic acid;L-xyloascorbate;L-xyloascorbic acid;Laroscorbine;Lemascorb;Liqui-cee;Meri-c;Natrascorb;Natrascorb injectable;Planavit c;Proscorbin;Redoxon;Ribena;Ronotec 100;Rontex 100;Roscorbic;Rovimix c;Scorbacid;Scorbu c;Scorbu-c;Secorbate;Sodascorbate;Suncoat vc 40;Testascorbic;Vasc;Vicelat;Vicin;Vicomin c;Viforcit;Viscorin;Viscorin 100m;Vitace;Vitacee;Vitacimin;Vitacin;Vitamin c;Vitamisin;Vitascorbol;Xitix;Gamma-lactone l-threo-hex-2-enonate;Gamma-lactone l-threo-hex-2-enonic acid;Acide ascorbique;Acido ascorbico;Acidum ascorbicum;Acidum ascorbinicum;Ascorbinsaeure;E 300;E-300;E300PW_C000031VitC67931698201267520211462521071214615112297225134022224250631877752129777663417842933479116115115855336120558414120993408121610405123192450123558374124168376125933482127392502127579209109L-ThreonineHMDB0000167Threonine is an essential amino acid in humans. It is abundant in human plasma, particularly in newborns. Severe deficiency of threonine causes neurological dysfunction and lameness in experimental animals. Threonine is an immunostimulant which promotes the growth of thymus gland. It also can probably promote cell immune defense function. This amino acid has been useful in the treatment of genetic spasticity disorders and multiple sclerosis at a dose of 1 gram daily. It is highly concentrated in meat products, cottage cheese and wheat germ. (http://www.dcnutrition.com/AminoAcids/) The threonine content of most of the infant formulas currently on the market is approximately 20% higher than the threonine concentration in human milk. Due to this high threonine content the plasma threonine concentrations are up to twice as high in premature infants fed these formulas than in infants fed human milk. The whey proteins which are used for infant formulas are sweet whey proteins. Sweet whey results from cheese production. Threonine catabolism in mammals appears to be due primarily (70-80%) to the activity of threonine dehydrogenase (EC 1.1.1.103) that oxidizes threonine to 2-amino-3-oxobutyrate, which forms glycine and acetyl CoA, whereas threonine dehydratase (EC 4.2.1.16) that catabolizes threonine into 2-oxobutyrate and ammonia, is significantly less active. Increasing the threonine plasma concentrations leads to accumulation of threonine and glycine in the brain. Such accumulation affects the neurotransmitter balance which may have consequences for the brain development during early postnatal life. Thus, excessive threonine intake during infant feeding should be avoided. (PMID 9853925).72-19-5C00188628816857THR6051DB00156C[C@@H](O)[C@H](N)C(O)=OC4H9NO3InChI=1S/C4H9NO3/c1-2(6)3(5)4(7)8/h2-3,6H,5H2,1H3,(H,7,8)/t2-,3+/m1/s1AYFVYJQAPQTCCC-GBXIJSLDSA-N(2S,3R)-2-amino-3-hydroxybutanoic acid119.1192119.0582431590.603L-threonine00FDB011999Threonin;(2s,3r)-(-)-threonine;(2s,3r)-2-amino-3-hydroxybutyrate;(2s,3r)-2-amino-3-hydroxybutyric acid;(r-(r*,s*))-2-amino-3-hydroxybutanoate;(r-(r*,s*))-2-amino-3-hydroxybutanoic acid;(s)-threonine;2-amino-3-hydroxybutanoate;2-amino-3-hydroxybutanoic acid;2-amino-3-hydroxybutyrate;2-amino-3-hydroxybutyric acid;L-(-)-threonine;L-2-amino-3-hydroxybutyrate;L-2-amino-3-hydroxybutyric acid;L-alpha-amino-beta-hydroxybutyrate;L-alpha-amino-beta-hydroxybutyric acid;Threonine;[r-(r*,s*)]-2-amino-3-hydroxybutanoate;[r-(r*,s*)]-2-amino-3-hydroxybutanoic acid;[r-(r*,s*)]-2-amino-3-hydroxy-butanoate;[r-(r*,s*)]-2-amino-3-hydroxy-butanoic acid;(2s)-threonine;(2s,3r)-2-amino-3-hydroxybutanoic acid;L-threonin;T;Thr;(2s,3r)-2-amino-3-hydroxybutanoate;L-a-amino-b-hydroxybutyrate;L-a-amino-b-hydroxybutyric acid;L-α-amino-β-hydroxybutyrate;L-α-amino-β-hydroxybutyric acidPW_C000109Thr2689152690256441075645108588510569081886909187837922542414318424153157902613279038114122576124122580409125148118125152137126725299126734483128318388128328208118L-LysineHMDB0000182L-lysine is an essential amino acid. Normal requirements for lysine have been found to be about 8 g per day or 12 mg/kg in adults. Children and infants need more- 44 mg/kg per day for an eleven to-twelve-year old, and 97 mg/kg per day for three-to six-month old. Lysine is highly concentrated in muscle compared to most other amino acids. Lysine is high in foods such as wheat germ, cottage cheese and chicken. Of meat products, wild game and pork have the highest concentration of lysine. Fruits and vegetables contain little lysine, except avocados. Normal lysine metabolism is dependent upon many nutrients including niacin, vitamin B6, riboflavin, vitamin C, glutamic acid and iron. Excess arginine antagonizes lysine. Several inborn errors of lysine metabolism are known. Most are marked by mental retardation with occasional diverse symptoms such as absence of secondary sex characteristics, undescended testes, abnormal facial structure, anemia, obesity, enlarged liver and spleen, and eye muscle imbalance. Lysine also may be a useful adjunct in the treatment of osteoporosis. Although high protein diets result in loss of large amounts of calcium in urine, so does lysine deficiency. Lysine may be an adjunct therapy because it reduces calcium losses in urine. Lysine deficiency also may result in immunodeficiency. Requirements for this amino acid are probably increased by stress. Lysine toxicity has not occurred with oral doses in humans. Lysine dosages are presently too small and may fail to reach the concentrations necessary to prove potential therapeutic applications. Lysine metabolites, amino caproic acid and carnitine have already shown their therapeutic potential. Thirty grams daily of amino caproic acid has been used as an initial daily dose in treating blood clotting disorders, indicating that the proper doses of lysine, its precursor, have yet to be used in medicine. Low lysine levels have been found in patients with Parkinson's, hypothyroidism, kidney disease, asthma and depression. The exact significance of these levels is unclear, yet lysine therapy can normalize the level and has been associated with improvement of some patients with these conditions. Abnormally elevated hydroxylysines have been found in virtually all chronic degenerative diseases and coumadin therapy. The levels of this stress marker may be improved by high doses of vitamin C. Lysine is particularly useful in therapy for marasmus (wasting) and herpes simplex. It stops the growth of herpes simplex in culture, and has helped to reduce the number and occurrence of cold sores in clinical studies. Dosing has not been adequately studied, but beneficial clinical effects occur in doses ranging from 100 mg to 4 g a day. Higher doses may also be useful, and toxicity has not been reported in doses as high as 8 g per day. Diets high in lysine and low in arginine can be useful in the prevention and treatment of herpes. Some researchers think herpes simplex virus is involved in many other diseases related to cranial nerves such as migraines, Bell's palsy and Meniere's disease. Herpes blister fluid will produce fatal encephalitis in the rabbit. (http://www.dcnutrition.com).56-87-1C00047596218019LYS5747DB00123NCCCC[C@H](N)C(O)=OC6H14N2O2InChI=1S/C6H14N2O2/c7-4-2-1-3-5(8)6(9)10/h5H,1-4,7-8H2,(H,9,10)/t5-/m0/s1KDXKERNSBIXSRK-YFKPBYRVSA-N(2S)-2,6-diaminohexanoic acid146.1876146.105527702-0.143L-lysine01FDB000474(+)-s-lysine;(s)-2,6-diaminohexanoate;(s)-2,6-diaminohexanoic acid;(s)-2,6-diamino-hexanoate;(s)-2,6-diamino-hexanoic acid;(s)-lysine;(s)-a,e-diaminocaproate;(s)-a,e-diaminocaproic acid;2,6-diaminohexanoate;2,6-diaminohexanoic acid;6-amino-aminutrin;6-amino-l-norleucine;Aminutrin;L-(+)-lysine;L-2,6-diainohexanoate;L-2,6-diainohexanoic acid;L-2,6-diaminocaproate;L-2,6-diaminocaproic acid;L-lys;Lys;Lysine;Lysine acid;A-lysine;Alpha-lysine;H-lys-oh;(s)-alpha,epsilon-diaminocaproic acid;6-ammonio-l-norleucine;K;L-lysin;(s)-a,epsilon-diaminocaproate;(s)-a,epsilon-diaminocaproic acid;(s)-alpha,epsilon-diaminocaproate;(s)-α,epsilon-diaminocaproate;(s)-α,epsilon-diaminocaproic acidPW_C000118Lys58115632301065310918529910553031075304108555211482142254237031842371315777303387827511278287111120504409120536413120780407120807122123110137123170449123372119123392135125719483741L-TryptophanHMDB0000929Tryptophan is an essential amino acid that is the precursor of both serotonin and melatonin. Melatonin is a hormone that is produced by the pineal gland in animals, which regulates sleep and wakefulness. Serotonin is a brain neurotransmitter, platelet clotting factor, and neurohormone found in organs throughout the body. Metabolism of tryptophan into serotonin requires nutrients such as vitamin B6, niacin, and glutathione. Niacin (also known as vitamin B3) is an important metabolite of tryptophan. It is synthesized via kynurenine and quinolinic acids, which are products of tryptophan degradation. There are a number of conditions or diseases that are characterized tryptophan deficiencies. For instance, fructose malabsorption causes improper absorption of tryptophan in the intestine, which reduces levels of tryptophan in the blood and leads to depression. High corn or other tryptophan-deficient diets can cause pellagra, which is a niacin-tryptophan deficiency disease with symptoms of dermatitis, diarrhea, and dementia. Hartnup's disease is a disorder in which tryptophan and other amino acids are not absorbed properly. Symptoms of Hartnup's disease include skin rashes, difficulty coordinating movements (cerebellar ataxia), and psychiatric symptoms such as depression or psychosis. Tryptophan supplements may be useful for treating Hartnup's. Assessment of tryptophan deficiency is done through studying excretion of tryptophan metabolites in the urine or blood. Blood may be the most sensitive test because the amino acid tryptophan is transported in a unique way. Increased urination of tryptophan breakdown products (such as kynurenine) correlates with increased tryptophan degradation, which occurs with oral contraception, depression, mental retardation, hypertension, and anxiety states. The requirement for tryptophan and protein decreases with age. The minimum daily requirement for adults is 3 mg/kg/day or about 200 mg a day. There is 400 mg of tryptophan in a cup of wheat germ. A cup of low fat cottage cheese contains 300 mg of tryptophan and chicken and turkey contain up to 600 mg of tryptophan per pound (http://www.dcnutrition.com). Tryptophan plays a role in "feast-induced" drowsiness. Ingestion of a meal rich in carbohydrates triggers the release of insulin. Insulin, in turn, stimulates the uptake of large neutral branched-chain amino acids (BCAAs) into muscle, increasing the ratio of tryptophan to BCAA in the bloodstream. The increased tryptophan ratio reduces competition at the large neutral amino acid transporter (which transports both BCAAs and tryptophan), resulting in greater uptake of tryptophan across the blood-brain barrier into the cerebrospinal fluid (CSF). Once in the CSF, tryptophan is converted into serotonin and the resulting serotonin is further metabolized into melatonin by the pineal gland, which promotes sleep. Under certain situations, tryptophan can be a neurotoxin and a metabotoxin. A neurotoxin is a compound that causes damage to the brain and nerve tissues. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of tryptophan can be found in glutaric aciduria type I (glutaric acidemia type I or GA1). GA1 is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine, and tryptophan. Babies with glutaric acidemia type I are often born with unusually large heads (macrocephaly). Affected individuals may also have difficulty moving and may experience spasms, jerking, rigidity or decreased muscle tone, and muscle weakness. High levels of tryptophan have also been implicated in eosinophilia-myalgia syndrome (EMS), an incurable and sometimes fatal flu-like neurological condition linked to the ingestion of large amounts of L-tryptophan. The risk of developing EMS increases with larger doses of tryptophan and increasing age. Some research suggests that certain genetic polymorphisms may be related to the development of EMS. The presence of eosinophilia is a core feature of EMS, along with unusually severe myalgia (muscle pain). It is thought that both tryptophan and certain unidentified tryptophan contaminants may contribute to EMS (PMID: 1763543). It has also been suggested that excessive tryptophan or elevation of its metabolites could play a role in amplifying some of the pathological features of EMS (PMID: 10721094). This pathological damage is further augmented by metabolites of the kynurenine pathway (a tryptophan degradation pathway).73-22-3C00078630516828TRP6066DB00150N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=OC11H12N2O2InChI=1S/C11H12N2O2/c12-9(11(14)15)5-7-6-13-10-4-2-1-3-8(7)10/h1-4,6,9,13H,5,12H2,(H,14,15)/t9-/m0/s1QIVBCDIJIAJPQS-VIFPVBQESA-N(2S)-2-amino-3-(1H-indol-3-yl)propanoic acid204.2252204.089877638-2.183L-tryptophan00FDB002250(-)-tryptophan;(2s)-2-amino-3-(1h-indol-3-yl)propanoate;(2s)-2-amino-3-(1h-indol-3-yl)propanoic acid;(l)-tryptophan;(s)-1h-indole-3-alanine;(s)-2-amino-3-(3-indolyl)propionic acid;(s)-a-amino-1h-indole-3-propanoate;(s)-a-amino-1h-indole-3-propanoic acid;(s)-a-aminoindole-3-propionate;(s)-a-aminoindole-3-propionic acid;(s)-a-amino-b-indolepropionate;(s)-a-amino-b-indolepropionic acid;(s)-alpha-amino-1h-indole-3-propanoate;(s)-alpha-amino-1h-indole-3-propanoic acid;(s)-alpha-amino-beta-(3-indolyl)-propionic acid;(s)-alpha-aminoindole-3-propionate;(s)-alpha-aminoindole-3-propionic acid;(s)-alpha-amino-beta-indolepropionate;(s)-alpha-amino-beta-indolepropionic acid;(s)-tryptophan;1-beta-3-indolylalanine;1h-indole-3-alanine;1beta-3-indolylalanine;2-amino-3-indolylpropanoate;2-amino-3-indolylpropanoic acid;3-(1h-indol-3-yl)-l-alanine;3-indol-3-ylalanine;Ardeytropin;H-trp-oh;Indole-3-alanine;Kalma;L-(-)-tryptophan;L-tryptofan;L-tryptophan;L-tryptophane;L-alpha-amino-3-indolepropionic acid;L-alpha-aminoindole-3-propionic acid;L-b-3-indolylalanine;L-beta-3-indolylalanine;Lopac-t-0254;Lyphan;Optimax;Pacitron;Sedanoct;Triptofano;Trofan;Tryptacin;Tryptan;Tryptophan;Tryptophane;Tryptophanum;Alpha'-amino-3-indolepropionic acid;Alpha-aminoindole-3-propionic acid;Trp;W;(s)-α-amino-1h-indole-3-propanoate;(s)-α-amino-1h-indole-3-propanoic acid;(s)-a-amino-b-(3-indolyl)-propionate;(s)-a-amino-b-(3-indolyl)-propionic acid;(s)-alpha-amino-beta-(3-indolyl)-propionate;(s)-α-amino-β-(3-indolyl)-propionate;(s)-α-amino-β-(3-indolyl)-propionic acid;L-β-3-indolylalaninePW_C000741Trp2977152978256671075668108588710542460318424613157906513279101114121739124121797409124290118124348137127625388127682208540L-LeucineHMDB0000687Branched chain amino acids (BCAA) are essential amino acids whose carbon structure is marked by a branch point. These three amino acids are critical to human life and are particularly involved in stress, energy and muscle metabolism. BCAA supplementation as therapy, both oral and intravenous, in human health and disease holds great promise. 'BCAA' denotes valine, isoleucine and leucine which are branched chain essential amino acids. Despite their structural similarities, the branched amino acids have different metabolic routes, with valine going solely to carbohydrates, leucine solely to fats and isoleucine to both. The different metabolism accounts for different requirements for these essential amino acids in humans: 12 mg/kg, 14 mg/kg and 16 mg/kg of valine, leucine and isoleucine respectively. Furthermore, these amino acids have different deficiency symptoms. Valine deficiency is marked by neurological defects in the brain, while isoleucine deficiency is marked by muscle tremors. Many types of inborn errors of BCAA metabolism exist, and are marked by various abnormalities. The most common form is the maple syrup urine disease, marked by a characteristic urinary odor. Other abnormalities are associated with a wide range of symptoms, such as mental retardation, ataxia, hypoglycemia, spinal muscle atrophy, rash, vomiting and excessive muscle movement. Most forms of BCAA metabolism errors are corrected by dietary restriction of BCAA and at least one form is correctable by supplementation with 10 mg of biotin daily. BCAA are useful because they are metabolized primarily by muscle. Stress state- e.g surgery, trauma, cirrhosis, infections, fever and starvation--require proportionately more BCAA than other amino acids and probably proportionately more leucine than either valine or isoleucine. BCAA and other amino acids are frequently fed intravenously (TPN) to malnourished surgical patients and in some cases of severe trauma. BCAA, particularly leucine, stimulate protein synthesis, increase reutilization of amino acids in many organs and reduce protein breakdown. Furthermore, leucine can be an important source of calories, and is superior as fuel to the ubiquitous intravenous glucose (dextrose). Leucine also stimulates insulin release, which in turn stimulates protein synthesis and inhibits protein breakdown. These effects are particularly useful in athletic training. BCAA should also replace the use of steroids as commonly used by weightlifters. Huntington's chorea and anorexic disorders both are characterized by low serum BCAA. These diseases, as well as forms of Parkinson's, may respond to BCAA therapy. BCAA, and particularly leucine, are among the amino acids most essential for muscle health. (http://www.dcnutrition.com).61-90-5C00123610615603LEU5880DB00149CC(C)C[C@H](N)C(O)=OC6H13NO2InChI=1S/C6H13NO2/c1-4(2)3-5(7)6(8)9/h4-5H,3,7H2,1-2H3,(H,8,9)/t5-/m0/s1ROHFNLRQFUQHCH-YFKPBYRVSA-N(2S)-2-amino-4-methylpentanoic acid131.1729131.094628665-0.272L-leucine00FDB001946(2s)-2-amino-4-methylpentanoate;(2s)-2-amino-4-methylpentanoic acid;(s)-(+)-leucine;(s)-2-amino-4-methylpentanoate;(s)-2-amino-4-methylpentanoic acid;(s)-2-amino-4-methylvalerate;(s)-2-amino-4-methylvaleric acid;(s)-leucine;4-methyl-l-norvaline;L-(+)-leucine;L-a-aminoisocaproate;L-a-aminoisocaproic acid;L-alpha-aminoisocaproate;L-alpha-aminoisocaproic acid;Leu;Leucine;(2s)-alpha-2-amino-4-methylvaleric acid;(2s)-alpha-leucine;2-amino-4-methylvaleric acid;L;L-leucin;L-leuzin;(2s)-a-2-amino-4-methylvalerate;(2s)-a-2-amino-4-methylvaleric acid;(2s)-alpha-2-amino-4-methylvalerate;(2s)-α-2-amino-4-methylvalerate;(2s)-α-2-amino-4-methylvaleric acid;(2s)-a-leucine;(2s)-α-leucinePW_C000540Leu1582250431556461075647108684816671451887146187425393154255731879181132121544124124102118112L-IsoleucineHMDB0000172Branched chain amino acids (BCAA) are essential amino acids whose carbon structure is marked by a branch point. These three amino acids are critical to human life and are particularly involved in stress, energy and muscle metabolism. BCAA supplementation as therapy, both oral and intravenous, in human health and disease holds great promise. "BCAA" denotes valine, isoleucine and leucine which are branched chain essential amino acids. Despite their structural similarities, the branched amino acids have different metabolic routes, with valine going solely to carbohydrates, leucine solely to fats and isoleucine to both. The different metabolism accounts for different requirements for these essential amino acids in humans: 12 mg/kg, 14 mg/kg and 16 mg/kg of valine, leucine and isoleucine respectively. Furthermore, these amino acids have different deficiency symptoms. Valine deficiency is marked by neurological defects in the brain, while isoleucine deficiency is marked by muscle tremors. BCAA are decreased in patients with liver disease, such as hepatitis, hepatic coma, cirrhosis, extrahepatic biliary atresia or portacaval shunt; aromatic amino acids (AAA)-tyrosine, tryptophan and phenylalanine, as well as methionine-are increased in these conditions. Valine, in particular, has been established as a useful supplemental therapy to the ailing liver. All the BCAA probably compete with AAA for absorption into the brain. Supplemental BCAA with vitamin B6 and zinc help normalize the BCAA:AAA ratio. The BCAA are not without side effects. Leucine alone, for example, exacerbates pellagra and can cause psychosis in pellagra patients by increasing excretion of niacin in the urine. Leucine may lower brain serotonin and dopamine. A dose of 3 g of isoleucine added to the niacin regime has cleared leucine-aggravated psychosis in schizophrenic patients. Isoleucine may have potential as an antipsychotic treatment. Leucine is more highly concentrated in foods than other amino acids. A cup of milk contains 800 mg of leucine and only 500 mg of isoleucine and valine. A cup of wheat germ has about 1.6 g of leucine and 1 g of isoleucine and valine. The ratio evens out in eggs and cheese. One egg and an ounce of most cheeses each contain about 400 mg of leucine and 400 mg of valine and isoleucine. The ratio of leucine to other BCAA is greatest in pork, where leucine is 7 to 8 g and the other BCAA together are only 3 to 4 g. (http://www.dcnutrition.com).73-32-5C00407630617191ILE6067DB00167CC[C@H](C)[C@H](N)C(O)=OC6H13NO2InChI=1S/C6H13NO2/c1-3-4(2)5(7)6(8)9/h4-5H,3,7H2,1-2H3,(H,8,9)/t4-,5-/m0/s1AGPKZVBTJJNPAG-WHFBIAKZSA-N(2S,3S)-2-amino-3-methylpentanoic acid131.1729131.094628665-0.062L-isoleucine00FDB012397(2s,3s)-2-amino-3-methylpentanoate;(2s,3s)-2-amino-3-methylpentanoic acid;(2s,3s)-2-amino-3-methyl-pentanoate;(2s,3s)-2-amino-3-methyl-pentanoic acid;(2s,3s)-a-amino-b-methyl-n-valerate;(2s,3s)-a-amino-b-methyl-n-valeric acid;(2s,3s)-a-amino-b-methylvalerate;(2s,3s)-a-amino-b-methylvaleric acid;(2s,3s)-alph-amino-beta-methylvalerate;(2s,3s)-alph-amino-beta-methylvaleric acid;(2s,3s)-alpha-amino-beta-merthyl-n-valerate;(2s,3s)-alpha-amino-beta-merthyl-n-valeric acid;(2s,3s)-alpha-amino-beta-merthylvalerate;(2s,3s)-alpha-amino-beta-merthylvaleric acid;(2s,3s)-alpha-amino-beta-methyl-n-valerate;(2s,3s)-alpha-amino-beta-methyl-n-valeric acid;(2s,3s)-alpha-amino-beta-methylvalerate;(2s,3s)-alpha-amino-beta-methylvaleric acid;(s)-isoleucine;(s,s)-isoleucine;2-amino-3-methylpentanoate;2-amino-3-methylpentanoic acid;2-amino-3-methylvalerate;2-amino-3-methylvaleric acid;2s,3s-isoleucine;Erythro-l-isoleucine;Ile;Iso-leucine;Isoleucine;L-(+)-isoleucine;L-ile;[s-(r*,r*)]-2-amino-3-methylpentanoate;[s-(r*,r*)]-2-amino-3-methylpentanoic acid;Alpha-amino-beta-methylvaleric acid;I;A-amino-b-methylvalerate;A-amino-b-methylvaleric acid;Alpha-amino-beta-methylvalerate;α-amino-β-methylvalerate;α-amino-β-methylvaleric acidPW_C000112Ile172485656107565710871471877148188425423154256231879183111121546122124104135704L-ValineHMDB0000883Valine (abbreviated as Val or V) is an -amino acid with the chemical formula HO2CCH(NH2)CH(CH3)2. It is named after the plant valerian. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar. Along with leucine and isoleucine, valine is a branched-chain amino acid. Branched chain amino acids (BCAA) are essential amino acids whose carbon structure is marked by a branch point. These three amino acids are critical to human life and are particularly involved in stress, energy and muscle metabolism. BCAA supplementation as therapy, both oral and intravenous, in human health and disease holds great promise. "BCAA" denotes valine, isoleucine and leucine which are branched chain essential amino acids. Despite their structural similarities, the branched amino acids have different metabolic routes, with valine going solely to carbohydrates, leucine solely to fats and isoleucine to both. The different metabolism accounts for different requirements for these essential amino acids in humans: 12 mg/kg, 14 mg/kg and 16 mg/kg of valine, leucine and isoleucine respectively. Furthermore, these amino acids have different deficiency symptoms. Valine deficiency is marked by neurological defects in the brain, while isoleucine deficiency is marked by muscle tremors. Many types of inborn errors of BCAA metabolism exist, and are marked by various abnormalities. The most common form is the maple syrup urine disease, marked by a characteristic urinary odor. Other abnormalities are associated with a wide range of symptoms, such as mental retardation, ataxia, hypoglycemia, spinal muscle atrophy, rash, vomiting and excessive muscle movement. Most forms of BCAA metabolism errors are corrected by dietary restriction of BCAA and at least one form is correctable by supplementation with 10 mg of biotin daily. BCAA are decreased in patients with liver disease, such as hepatitis, hepatic coma, cirrhosis, extrahepatic biliary atresia or portacaval shunt; aromatic amino acids (AAA)tyrosine, tryptophan and phenylalanine, as well as methionineare increased in these conditions. Valine in particular, has been established as a useful supplemental therapy to the ailing liver. All the BCAA probably compete with AAA for absorption into the brain. Supplemental BCAA with vitamin B6 and zinc help normalize the BCAA:AAA ratio. (http://www.dcnutrition.com). In sickle-cell disease, valine substitutes for the hydrophilic amino acid glutamic acid in hemoglobin. Because valine is hydrophobic, the hemoglobin does not fold correctly. Valine is an essential amino acid, hence it must be ingested, usually as a component of proteins.72-18-4C00183628716414VAL6050DB00161CC(C)[C@H](N)C(O)=OC5H11NO2InChI=1S/C5H11NO2/c1-3(2)4(6)5(7)8/h3-4H,6H2,1-2H3,(H,7,8)/t4-/m0/s1KZSNJWFQEVHDMF-BYPYZUCNSA-N(2S)-2-amino-3-methylbutanoic acid117.1463117.0789786010.262L-valine00FDB000465(2s)-2-amino-3-methylbutanoate;(2s)-2-amino-3-methylbutanoic acid;(s)-2-amino-3-methylbutanoate;(s)-2-amino-3-methylbutanoic acid;(s)-2-amino-3-methylbutyrate;(s)-2-amino-3-methylbutyric acid;(s)-2-amino-3-methyl-butanoate;(s)-2-amino-3-methyl-butanoic acid;(s)-valine;(s)-a-amino-b-methylbutyrate;(s)-a-amino-b-methylbutyric acid;(s)-alpha-amino-beta-methylbutyrate;(s)-alpha-amino-beta-methylbutyric acid;2-amino-3-methylbutanoate;2-amino-3-methylbutanoic acid;2-amino-3-methylbutyrate;2-amino-3-methylbutyric acid;L-(+)-a-aminoisovalerate;L-(+)-a-aminoisovaleric acid;L-(+)-alpha-aminoisovalerate;L-(+)-alpha-aminoisovaleric acid;L-valine;L-a-amino-b-methylbutyrate;L-a-amino-b-methylbutyric acid;L-alpha-amino-beta-methylbutyrate;L-alpha-amino-beta-methylbutyric acid;Valine;L-valin;V;ValPW_C000704Val1651823134565310756541087144187906922490701519071225422583104254131542560318786251337917811112154012212225440612409813512480712012641647912798250178GlycineHMDB0000123Glycine is a simple, nonessential amino acid, although experimental animals show reduced growth on low-glycine diets. The average adult ingests 3 to 5 grams of glycine daily. Glycine is involved in the body's production of DNA, phospholipids and collagen, and in release of energy. Glycine levels are effectively measured in plasma in both normal patients and those with inborn errors of glycine metabolism. (http://www.dcnutrition.com/AminoAcids/) Nonketotic hyperglycinaemia (OMIM 606899) is an autosomal recessive condition caused by deficient enzyme activity of the glycine cleavage enzyme system (EC 2.1.1.10). The glycine cleavage enzyme system comprises four proteins: P-, T-, H- and L-proteins (EC 1.4.4.2, EC 2.1.2.10 and EC 1.8.1.4 for P-, T- and L-proteins). Mutations have been described in the GLDC (OMIM 238300), AMT (OMIM 238310), and GCSH (OMIM 238330) genes encoding the P-, T-, and H-proteins respectively. The glycine cleavage system catalyses the oxidative conversion of glycine into carbon dioxide and ammonia, with the remaining one-carbon unit transferred to folate as methylenetetrahydrofolate. It is the main catabolic pathway for glycine and it also contributes to one-carbon metabolism. Patients with a deficiency of this enzyme system have increased glycine in plasma, urine and cerebrospinal fluid (CSF) with an increased CSF: plasma glycine ratio. (PMID 16151895).56-40-6C00037525712715428GLY730DB00145NCC(O)=OC2H5NO2InChI=1S/C2H5NO2/c3-1-2(4)5/h1,3H2,(H,4,5)DHMQDGOQFOQNFH-UHFFFAOYSA-N2-aminoacetic acid75.066675.0320284090.872glycine00FDB0004842-aminoacetate;2-aminoacetic acid;Aciport;Amino-acetate;Amino-acetic acid;Aminoacetate;Aminoacetic acid;Aminoethanoate;Aminoethanoic acid;Glicoamin;Glycocoll;Glycolixir;Glycosthene;Gyn-hydralin;Padil;Aminoessigsaeure;G;Gly;Glycin;Glykokoll;Glyzin;H2n-ch2-cooh;Hgly;LeimzuckerPW_C000078Gly314179818122188127282929542010354541205580133564010756411085863105600714770141607439374411667442151179419811872161124291511523322242419318424203157764433677742111780221327830435180708135120028406120097122120117124121687429122283435122850118124236464124837470125406479125466297125484299126448499126946501127003205127021388128018517120L-SerineHMDB0000187Serine is a nonessential amino acid derived from glycine. Like all the amino acid building blocks of protein and peptides, serine can become essential under certain conditions, and is thus important in maintaining health and preventing disease. Low-average concentration of serine compared to other amino acids is found in muscle. Serine is highly concentrated in all cell membranes. (http://www.dcnutrition.com/AminoAcids/) L-Serine may be derived from four possible sources: dietary intake; biosynthesis from the glycolytic intermediate 3-phosphoglycerate; from glycine ; and by protein and phospholipid degradation. Little data is available on the relative contributions of each of these four sources of l-serine to serine homoeostasis. It is very likely that the predominant source of l-serine will be very different in different tissues and during different stages of human development. In the biosynthetic pathway, the glycolytic intermediate 3-phosphoglycerate is converted into phosphohydroxypyruvate, in a reaction catalyzed by 3-phosphoglycerate dehydrogenase (3- PGDH; EC 1.1.1.95). Phosphohydroxypyruvate is metabolized to phosphoserine by phosphohydroxypyruvate aminotransferase (EC 2.6.1.52) and, finally, phosphoserine is converted into l-serine by phosphoserine phosphatase (PSP; EC 3.1.3.3). In liver tissue, the serine biosynthetic pathway is regulated in response to dietary and hormonal changes. Of the three synthetic enzymes, the properties of 3-PGDH and PSP are the best documented. Hormonal factors such as glucagon and corticosteroids also influence 3-PGDH and PSP activities in interactions dependent upon the diet. L-serine plays a central role in cellular proliferation. L-Serine is the predominant source of one-carbon groups for the de novo synthesis of purine nucleotides and deoxythymidine monophosphate. It has long been recognized that, in cell cultures, L-serine is a conditional essential amino acid, because it cannot be synthesized in sufficient quantities to meet the cellular demands for its utilization. In recent years, L-serine and the products of its metabolism have been recognized not only to be essential for cell proliferation, but also to be necessary for specific functions in the central nervous system. The findings of altered levels of serine and glycine in patients with psychiatric disorders and the severe neurological abnormalities in patients with defects of L-serine synthesis underscore the importance of L-serine in brain development and function. (PMID 12534373).56-45-1C00065595117115SER5736DB00133N[C@@H](CO)C(O)=OC3H7NO3InChI=1S/C3H7NO3/c4-2(1-5)3(6)7/h2,5H,1,4H2,(H,6,7)/t2-/m0/s1MTCFGRXMJLQNBG-REOHCLBHSA-N(2S)-2-amino-3-hydroxypropanoic acid105.0926105.0425930950.663L-serine00FDB012739(-)-serine;(s)-2-amino-3-hydroxypropanoate;(s)-2-amino-3-hydroxypropanoic acid;(s)-2-amino-3-hydroxy-propanoate;(s)-2-amino-3-hydroxy-propanoic acid;(s)-serine;(s)-a-amino-b-hydroxypropionate;(s)-a-amino-b-hydroxypropionic acid;(s)-alpha-amino-beta-hydroxypropionate;(s)-alpha-amino-beta-hydroxypropionic acid;(s)-b-amino-3-hydroxypropionate;(s)-b-amino-3-hydroxypropionic acid;(s)-beta-amino-3-hydroxypropionate;(s)-beta-amino-3-hydroxypropionic acid;2-amino-3-hydroxypropanoate;2-amino-3-hydroxypropanoic acid;3-hydroxy-l-alanine;L-(-)-serine;L-3-hydroxy-2-aminopropionate;L-3-hydroxy-2-aminopropionic acid;L-3-hydroxy-alanine;L-ser;Serine;B-hydroxy-l-alanine;Beta-hydroxy-l-alanine;Beta-hydroxyalanine;(2s)-2-amino-3-hydroxypropanoic acid;(s)-(-)-serine;L-2-amino-3-hydroxypropionic acid;L-serin;S;Ser;(2s)-2-amino-3-hydroxypropanoate;(s)-α-amino-β-hydroxypropionate;(s)-α-amino-β-hydroxypropionic acid;β-hydroxy-l-alanine;B-hydroxyalanine;β-hydroxyalanine;L-2-amino-3-hydroxypropionatePW_C000120Ser344818102261745642107564310858841056011147690716370862017087202709071709172720216074383744315744416675222248357225915424912173151126251815379494233531842336315773201117808813378112132799793319485838311575239811992412212205612412213640612271813512466711812468812012531429712620929912629347912686020512777138812785650163Citric acidHMDB0000094Citric acid (citrate) is a weak acid that is formed in the tricarboxylic acid cycle or that may be introduced with diet. The evaluation of plasma citric acid is scarcely used in the diagnosis of human diseases. On the contrary urinary citrate excretion is a common tool in the differential diagnosis of kidney stones, renal tubular acidosis and it plays also a role in bone diseases. The importance of hypocitraturia should be considered with regard to bone mass, urine crystallization and urolithiasis. (PMID 12957820) The secretory epithelial cells of the prostate gland of humans and other animals posses a unique citrate-related metabolic pathway regulated by testosterone and prolactin. This specialized hormone-regulated metabolic activity is responsible for the major prostate function of the production and secretion of extraordinarily high levels of citrate. The key regulatory enzymes directly associated with citrate production in the prostate cells are mitochondrial aspartate aminotransferase, pyruvate dehydrogenase, and mitochondrial aconitase. testosterone and prolactin are involved in the regulation of the corresponding genes associated with these enzymes. The regulatory regions of these genes contain the necessary response elements that confer the ability of both hormones to control gene transcription. Protein kinase c (PKC) is the signaling pathway for the prolactin regulation of the metabolic genes in prostate cells. testosterone and prolactin regulation of these metabolic genes (which are constitutively expressed in all mammalian cells) is specific for these citrate-producing cells. (PMID 12198595) Citric acid is found in citrus fruits, most concentrated in lemons and limes, where it can comprise as much as 8% of the dry weight of the fruit. Citric acid is a natural preservative and is also used to add an acidic (sour) taste to foods and soft drinks. The salts of citric acid (citrates) can be used as anticoagulants due to their calcium chelating ability. Intolerance to citric acid in the diet is known to exist. Little information is available as the condition appears to be rare, but like other types of food intolerance it is often described as a "pseudo-allergic" reaction.77-92-9C001581978290430769CIT305DB04272OC(=O)CC(O)(CC(O)=O)C(O)=OC6H8O7InChI=1S/C6H8O7/c7-3(8)1-6(13,5(11)12)2-4(9)10/h13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)KRKNYBCHXYNGOX-UHFFFAOYSA-N2-hydroxypropane-1,2,3-tricarboxylic acid192.1235192.02700261-0.264citric acid0-3FDB0125862-hydroxy-1,2,3-propanetricarboxylate;2-hydroxy-1,2,3-propanetricarboxylic acid;3-carboxy-3-hydroxypentane-1,5-dioate;3-carboxy-3-hydroxypentane-1,5-dioic acid;Aciletten;Anhydrous citrate;Anhydrous citric acid;Chemfill;Citraclean;Citrate;Citretten;Citric acid;Citro;E 330;Hydrocerol a;Kyselina citronova;Suby g;Uro-trainer;Beta-hydroxytricarballylate;Beta-hydroxytricarballylic acid;2-hydroxytricarballylic acid;Citronensaeure;E330;H3cit;2-hydroxytricarballylatePW_C000063CA219424152537210360341556089161647917874692227713213379053132800163681117128119965406122397124122754120124967118125355479126538299126898501128111388428CpG-DNA NucleicAcidNucleicAcidPW_EC000428CPGDNA889001388Single strand RNARNAPW_NA000388ssRNA1438571169389Double Stranded DNADNAPW_NA000389dsDNA1438581169869Nitric oxide synthase, inducibleP35228Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such COX2.
HMDBP00926NOS217q11.2-q12U2014111.14.13.394087813996648142287214328011341436981164143750117114376211691440381197145Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrialP31040Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q). Can act as a tumor suppressor.
HMDBP00150SDHA5p15AK29131111.3.5.12571750574136976703140491114169955142536102114260712114376711691437711173188Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrialP21912Iron-sulfur protein (IP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
HMDBP00193SDHB1p36.1-p35U1724811.3.5.12581750584136977703140492114170055142537102114260812114376811691437721173116Succinate dehydrogenase cytochrome b560 subunit, mitochondrialQ99643Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
HMDBP00121SDHC1q23.3AK29430512591750594136978703140493114170155142538102114260912114376911691437731173174Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrialO14521Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (By similarity).
HMDBP00179SDHD11q23BC02235012601750604136979703140494114170255142539102114261012114377011691437741173710Pyruvate kinase PKMP14618Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.
HMDBP00763PKM15q22AK30080012.7.1.40506821423009991437891169143790117114788Hypoxia-inducible factor 1-alphaQ16665
Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia.
HIF1A11116998142255214227223143792116923934Hypoxia-inducible factor 1-alphaQ16665
Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331). Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:9887100, PubMed:16543236). Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042). Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298).
HIF1A1142250231422532143793116914379511711808Nuclear factor NF-kappa-B p105 subunitP19838NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF- kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF- kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post- translationally. p50 binds to the kappa-B consensus sequence 5'- GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105HMDBP02145NFKB14q24BC0517651414524147238035681159392714373711691437451171144001328956Interferon regulatory factor 3Q14653
Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction. Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes. Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages.
IRF311437421169143746117114789Interleukin-1 betaP01584
Potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production. Promotes Th17 differentiation of T-cells. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells (PubMed:10653850).
IL1B11117031661117058142274231437531171143755511437642614381611691438221179143824118014382984723940Interleukin-6P05231
Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. Binds to IL6R, then the complex associates to the signaling subunit IL6ST/gp130 to trigger the intracellular IL6-signaling pathway (Probable). The interaction with the membrane-bound IL6R and IL6ST stimulates 'classic signaling', whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable).
IL6114229321437521171143756511437632614382311801438608478910Interferon alpha/beta receptor 1P17181
Associates with IFNAR2 to form the type I interferon receptor. Receptor for interferons alpha and beta. Binding to type I IFNs triggers tyrosine phosphorylation of a number of proteins including JAKs, TYK2, STAT proteins and IFNR alpha- and beta-subunits themselves. Can also transduce IFNB signals without the help of IFNAR2, and not activating the Jak-STAT pathway.
IFNAR1114374711711437575114382611808911Interferon alpha/beta receptor 2P48551
Associates with IFNAR1 to form the type I interferon receptor. Receptor for interferons alpha and beta. Involved in IFN-mediated STAT1, STAT2 and STAT3 activation. Isoform 1 and isoform 2 are directly involved in signal transduction due to their association with the TYR kinase, JAK1. Isoform 3 is a potent inhibitor of type I IFN receptor activity.
IFNAR2114374811711437585114382711802120Interferon beta precursorP01574Has antiviral, antibacterial and anticancer activitiesHMDBP02832IFNB19p21V00546114374911711437595114382811801766Tumor necrosis factorP01375Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiationHMDBP02070TNF6p21.3X01394142442803432288048881344061414057586914088789714201597814327911321437511171143760511437652614382511801438618472449Solute carrier family 2, facilitated glucose transporter member 2P11168Facilitative glucose transporter. This isoform likely mediates the bidirectional transfer of glucose across the plasma membrane of hepatocytes and is responsible for uptake of glucose by the beta cells; may comprise part of the glucose-sensing mechanism of the beta cell. May also participate with the Na(+)/glucose cotransporter in the transcellular transport of glucose in the small intestine and kidney.
HMDBP05474SLC2A23q26.1-q26.2CH47105218451228141627531416866614193167142224308143880511439308681495Solute carrier family 22 member 5O76082Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Also relative uptake activity ratio of carnitine to TEA is 11.3HMDBP01612SLC22A55q31AB29160611411293081439298681439475323930Cis-aconitate decarboxylaseA6NK06
Cis-aconitate decarboxylase that catalyzes production of itaconate and is involved in the inhibition of the inflammatory response (PubMed:23609450, PubMed:23610393). Acts as a negative regulator of the Toll-like receptors (TLRs)-mediated inflammatory innate response by stimulating the tumor necrosis factor alpha-induced protein TNFAIP3 expression via reactive oxygen species (ROS) in LPS-tolerized macrophages (PubMed:23609450). Involved in antimicrobial response of innate immune cells; ACOD1-mediated itaconic acid production contributes to the antimicrobial activity of macrophages (PubMed:23610393). Involved in antiviral response following infection by flavivirus in neurons: ACOD1-mediated itaconate production inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity). Plays a role in the embryo implantation (By similarity).
ACOD114.1.1.6142228414375411711437661169143775117323939Solute carrier family 13 member 3Q8WWT9
High-affinity sodium-dicarboxylate cotransporter that accepts a range of substrates with 4-6 carbon atoms, including succinate, alpha-ketoglutarate and N-acetylaspartate (PubMed:30635937). The stoichiometry is probably 3 Na(+) for 1 divalent succinate.
SLC13A3114228030814394811741794Solute carrier family 2, facilitated glucose transporter member 1P11166Facilitative glucose transporter. This isoform may be responsible for constitutive or basal glucose uptake. Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses.
HMDBP02114SLC2A11p34.2BC1185901143794117114382111691438815114393111681043Monocarboxylate transporter 4O15427Proton-linked monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetateHMDBP01109SLC16A317q25BC112267114393311688257Histone chaperone ASF1AQ9Y294
Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly. Cooperates with chromatin assembly factor 1 (CAF-1) to promote replication-dependent chromatin assembly and with HIRA to promote replication-independent chromatin assembly. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit.
ASF1A1143806117814393511821439891188144006268258Histone chaperone ASF1BQ9NVP2
Histone chaperone that facilitates histone deposition and histone exchange and removal during nucleosome assembly and disassembly. Cooperates with chromatin assembly factor 1 (CAF-1) to promote replication-dependent chromatin assembly. Does not participate in replication-independent nucleosome deposition which is mediated by ASF1A and HIRA. Required for spermatogenesis.
ASF1B1143807117814393611821439901188144007268263Chromatin assembly factor 1 subunit AQ13111
Core component of the CAF-1 complex, a complex thought to mediate chromatin assembly in DNA replication and DNA repair. Assembles histone octamers onto replicating DNA in vitro. CAF-1 performs the first step of the nucleosome assembly process, bringing newly synthesized histones H3 and H4 to replicating DNA; histones H2A/H2B can bind to this chromatin precursor subsequent to DNA replication to complete the histone octamer. CHAF1A binds to histones H3 and H4. It may play a role in heterochromatin maintenance in proliferating cells by bringing newly synthesized cbx proteins to heterochromatic DNA replication foci (By similarity).
CHAF1A1143808117814393711821439911188144008268259Chromatin assembly factor 1 subunit BQ13112
Complex that is thought to mediate chromatin assembly in DNA replication and DNA repair. Assembles histone octamers onto replicating DNA in vitro. CAF-1 performs the first step of the nucleosome assembly process, bringing newly synthesized histones H3 and H4 to replicating DNA; histones H2A/H2B can bind to this chromatin precursor subsequent to DNA replication to complete the histone octamer.
CHAF1B1143809117814393811821439921188144009264648Histone acetyltransferase type B catalytic subunitO14929Acetylates soluble but not nucleosomal histone H4 at 'Lys-5' (H4K5ac) and 'Lys-12' (H4K12ac) and, to a lesser extent, acetylates histone H2A at 'Lys-5' (H2AK5ac). Has intrinsic substrate specificity that modifies lysine in recognition sequence GXGKXG. May be involved in nucleosome assembly during DNA replication and repair as part of the histone H3.1 and H3.3 complexes. May play a role in DNA repair in response to free radical damage.
HMDBP09986HAT12q31.2-q33.1BC01868212.3.1.48143810117814393911821439931188144010268260Histone H3.1P68431
Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
HIST1H3A1143811117814394011821439941188144011268867Histone H4P62805
Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
HIST1H4A1143812117814394111821439951188144012263684Importin-4Q8TEX9Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran- dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Mediates the nuclear import of RPS3A. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLSHMDBP08465IPO414q12BC1108041143813117814394211821439961188144013268261Nuclear autoantigenic sperm proteinP49321
Required for DNA replication, normal cell cycle progression and cell proliferation. Forms a cytoplasmic complex with HSP90 and H1 linker histones and stimulates HSP90 ATPase activity. NASP and H1 histone are subsequently released from the complex and translocate to the nucleus where the histone is released for binding to DNA (By similarity).
NASP1143814117814394311821439971188144014268146Histone-binding protein RBBP4Q09028
Core histone-binding subunit that may target chromatin assembly factors, chromatin remodeling factors and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the chromatin assembly factor 1 (CAF-1) complex, which is required for chromatin assembly following DNA replication and DNA repair; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.
RBBP41143815117814394411821439981188144015268667Interleukin enhancer-binding factor 3Q12906
May facilitate double-stranded RNA-regulated gene expression at the level of post-transcription. Can act as a translation inhibitory protein which binds to coding sequences of acid beta-glucosidase (GCase) and other mRNAs and functions at the initiation phase of GCase mRNA translation, probably by inhibiting its binding to polysomes. Can regulate protein arginine N-methyltransferase 1 activity. May regulate transcription of the IL2 gene during T-cell activation. Can promote the formation of stable DNA-dependent protein kinase holoenzyme complexes on DNA. The phosphorylated form at Thr-188 and Thr-315, in concert with EIF2AK2/PKR can inhibit vesicular stomatitis virus (VSV) replication (By similarity).
ILF3114381911783837Exportin-5Q9HAV4Mediates the nuclear export of micro-RNA precursors, which form short hairpins. Also mediates the nuclear export of synthetic short hairpin RNAs used for RNA interference, and adenovirus VA1 dsRNA. In some circumstances can also mediate the nuclear export of deacylated and aminoacylated tRNAs. Specifically recognizes dsRNAs that lack a 5'-overhang in a sequence- independent manner, have only a short 3'-overhang, and that have a double-stranded length of at least 15 base-pairs. Binding is dependent on Ran-GTPHMDBP08620XPO56p21.1BC062635114382011782352Low affinity cationic amino acid transporter 2P52569Low-affinity, high capacity permease involved in the transport of the cationic amino acids (arginine, lysine and ornithine). Plays a regulatory role in classical or alternative activation of macrophagesHMDBP03488SLC7A28p22-p21.3U763691844314142009308142165531421667514393211685801Solute carrier family 22 member 8Q8TCC7SLC22A818455229141003308141265832143879511439278681439465314395268114395310672409Solute carrier family 22 member 2O15244Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificityHMDBP04308SLC22A26q26AJ25188518462228142330308143878511439288681439455310207UnknownUnknown12.3.1.85; 2.3.1.38; 2.3.1.39; 2.3.1.41; 1.1.1.100; 4.2.1.59; 1.3.1.39; 3.1.2.14; 3.5.99.5; 1.1.1.-640410642931643453916617917049182221167831168521212481212914121332291359735113617871400203081401567681405763091405898321408646014093348140954184141261831141275877141432931141584958141585959141586828142155261421941514226537214233223142671291426739961426839731428137871432728111432735214335575143398106514347411431434761314347896114351511481439341168143951118414395981014409423114412231114349Myeloid differentiation primary response protein MyD88Q99836
Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).
MYD8818011822880483881838308143738116914384811689558TIR domain-containing adapter molecule 1Q8IUC6
Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively.
TICAM11143740116814385011699559TIR domain-containing adapter molecule 2Q86XR7
Functions as sorting adapter in LPS-TLR4 signaling to regulate the MYD88-independent pathway during the innate immune response to LPS. Physically bridges TLR4 and TICAM1 and functionally transmits LPS-TRL4 signal to TICAM1; signaling is proposed to occur in early endosomes after endocytosis of TLR4. May also be involved in IL1-triggered NF-kappa-B activation, functioning upstream of IRAK1, IRAK2, TRAF6, and IKBKB; however, reports are controversial. Involved in IL-18 signaling and is proposed to function as a sorting adaptor for MYD88 in IL-18 signaling during adaptive immune response.
TICAM21143741116814385111692033Toll-like receptor 4O00206Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory responseHMDBP02639TLR49q33.1AF177766180480880907228819343081116641513169780136110152140856797143736116814374311698953Signal transducer and activator of transcription 1-alpha/betaP42224
Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated. It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.
STAT111166188095323143744116924140CorticoliberinP06850
Hormone regulating the release of corticotropin from pituitary gland (By similarity). Induces NLRP6 in intestinal epithelial cells, hence may influence gut microbiota profile (By similarity).
CRH11437616414384611804407Egl nine homolog 2Q96KS0Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death.
HMDBP09211EGLN219q13.2BC00172311.14.11.29896123143791116914389016614389310081438968207Hexokinase-2P52789HMDBP00213HK22p13Z4635812.7.1.122172141351160141621261416645014230810081425101019143805116914347Toll-like receptor 2O60603
Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852, PubMed:17889651). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. May also activate immune cells and promote apoptosis in response to the lipid moiety of lipoproteins (PubMed:10426995, PubMed:10426996). Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR6 (PubMed:11441107). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via this receptor, but also partially via TLR4 (PubMed:16622205). MAPK activation in response to bacterial peptidoglycan also occurs via this receptor (PubMed:16622205). Acts as a receptor for M.tuberculosis lipoproteins LprA, LprG, LpqH and PstS1, some lipoproteins are dependent on other coreceptors (TLR1, CD14 and/or CD36); the lipoproteins act as agonists to modulate antigen presenting cell functions in response to the pathogen (PubMed:19362712). M.tuberculosis HSP70 (dnaK) but not HSP65 (groEL-2) acts via this protein to stimulate NF-kappa-B expression (PubMed:15809303). Recognizes M.tuberculosis major T-antigen EsxA (ESAT-6) which inhibits downstream MYD88-dependent signaling (shown in mouse) (By similarity). Forms activation clusters composed of several receptors depending on the ligand, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway. Forms the cluster TLR2:TLR6:CD14:CD36 in response to diacylated lipopeptides and TLR2:TLR1:CD14 in response to triacylated lipopeptides (PubMed:16880211). Required for normal uptake of M.tuberculosis, a process that is inhibited by M.tuberculosis LppM (By similarity).
TLR2180116228808198818373082085Toll-like receptor 9Q9NR96Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific of microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory responseHMDBP02761TLR93p21.3EU1705421825548889041143847116824143TIR domain-containing adapter molecule 1Q8IUC6
Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis (PubMed:12471095, PubMed:12539043, PubMed:14739303, PubMed:28747347). Ligand binding to these receptors results in TRIF recruitment through its TIR domain (PubMed:12471095, PubMed:12539043, PubMed:14739303). Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively (PubMed:12471095, PubMed:12539043, PubMed:14739303). Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens (PubMed:25636800). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines (By similarity).
TICAM11143852116924144Interferon regulatory factor 7Q92985
Key transcriptional regulator of type I interferon (IFN)-dependent immune responses and plays a critical role in the innate immune response against DNA and RNA viruses. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters (PubMed:17574024, PubMed:32972995). Can efficiently activate both the IFN-beta (IFNB) and the IFN-alpha (IFNA) genes and mediate their induction via both the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Induces transcription of ubiquitin hydrolase USP25 mRNA in response to lipopolysaccharide (LPS) or viral infection in a type I IFN-dependent manner (By similarity). Required during both the early and late phases of the IFN gene induction but is more critical for the late than for the early phase. Exists in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, becomes phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization where along with other coactivators it can activate transcription of the type I IFN and ISG genes. Can also play a role in regulating adaptive immune responses by inducing PSMB9/LMP2 expression, either directly or through induction of IRF1. Binds to the Q promoter (Qp) of EBV nuclear antigen 1 a (EBNA1) and may play a role in the regulation of EBV latency. Can activate distinct gene expression programs in macrophages and regulate the anti-tumor properties of primary macrophages (By similarity) (PubMed:11073981, PubMed:12374802, PubMed:15361868, PubMed:17404045).
IRF711438531169143859117114352Interleukin-1 receptor-associated kinase 1P51617
Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.
IRAK112.7.11.18012016680820228809158818393081438491168143854116914691Toll-like receptor 3O15455
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.
TLR31825578143855116814692Toll-like receptor 7Q9NYK1
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR which is activated by single-stranded RNA. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity).
TLR7182569888922114385611691134Pyruvate kinase PKM1PW_P0011341296710215359Hypoxia-inducible factor 1-alpha1PW_P015359255052393414225123938Nitric oxide synthase, inducible1PW_P000938106386923831799138496413851170138619164Succinate dehydrogenase1PW_P000064751451761881771161781741389641423405581243178072hypoxia-inducible factor-1α1PW_P0080721625814788988Nuclear factor NF-kappa-B p105 subunit1PW_P00098811171808115853Interferon regulatory factor 3 IRF31PW_P0158532603589568074Interleukin-1 beta1PW_P008074162601478915374Interleukin-61PW_P015374255212394014229422353IFNB1-IFNAR1-IFNAR2- complex1PW_P0023535346891015347891115348212011023Tumor necrosis factor1PW_P001023116717663398Solute carrier family 2, facilitated glucose transporter member 21PW_P0003984202449115062Organic cation/carnitine transporter 21PW_P0150622509914951410621415352Cis-aconitate decarboxylase1PW_P0153522549823930142229415368Solute carrier family 13 member 31PW_P0153682551423939142281308419Solute carrier family 2, facilitated glucose transporter member 11PW_P0004194411794115856Monocarboxylate transporter 4 1PW_P0158562603810432319Histone H3.1 complex1PW_P0023195249825715250825815251826315252825915253464815254826015255886715256368415257826115258814612383ILF3-XPO5 complex1PW_P00238354228667154233837115263Cationic amino acid transporter 21PW_P0152632538523521420083081096Solute carrier family 22 member 81PW_P001096125758011580Solute carrier family 22 member 21PW_P000580621240922441415866Interleukin Transport1PW_P01586626048102077544Myeloid differentiation primary response protein MyD881PW_P007544154201434913254TICAM1-TICAM2-TLR4 complex1PW_P0032549471955819472955919473203317828Signal transducer and activator of transcription 1-alpha/beta1PW_P00782815871895380859815854Corticotropin-releasing hormone 1PW_P015854260362414015364Prolyl hydroxylase EGLN21PW_P015364255104407157554415763114227023578Hexokinase-21PW_P00057861920717948Toll-like receptor 91PW_P0079481608420858890330815869TIR domain-containing adapter molecule 11PW_P0158692605124143215870Interferon Regulatory Factor1PW_P01587026052241442605389567944MYD88,IRAK (myddosome)1PW_P007944160791434916080143528887287950Toll-like receptor 31PW_P00795016086146918893187949Toll-like receptor 71PW_P007949160851469288920308213297PW_R213297Right820178400341Compoundfalse8201791463Compoundfalse82018010654Compoundfalse8201813962Compoundfalse8201827232Compoundfalse8201831433Compoundfalse82018414204Compoundfalse82018518672Compoundfalse202881938233falsePW_R000233Both10101741Compoundfalse10118461Compoundtrue25129641Compoundtrue1012881Compoundfalse101310061Compoundtrue25139321Compoundtrue75641.3.5.1218819PW_R218819Right8437651741Compoundfalse84376611341ProteinComplexfalse8437675841Boundfalse218820PW_R218820Right8437685841Boundfalse84377080721ProteinComplexfalse8437695851Boundfalse14463PW_T014463Diffusion149009881ProteinComplex11691171Right14464PW_T014464Diffusion14901158531ProteinComplex11691171Right14465PW_T014465Diffusion1490280741ProteinComplex117151Right14466PW_T014466Diffusion14903153741ProteinComplex117151Right14467PW_T014467Diffusion1490423531ProteinComplex117151Right14468PW_T014468Diffusion1490510231ProteinComplex117151Right14469PW_T014469Diffusion149069381ProteinComplex11711169Right14470PW_T014470Diffusion149071051261Compound64608Right42PW_T00004245771Compound2651Right153982013-07-22T20:27:35-06:002013-07-22T20:27:35-06:005314475PW_T014474Active149131291Compound2651Right5312150622022-07-10T21:33:18-06:002022-07-10T21:33:18-06:005314479PW_T014479Diffusion1491718671Compound2651Right14480PW_T014480Diffusion14918153521ProteinComplex11711169Right14481PW_T014481Active149191741Compound11731169Right5313153682022-07-11T10:45:21-06:002022-07-11T10:45:21-06:00117414482PW_T014482Active14920771Compound511169Right53144192022-07-11T11:26:11-06:002022-07-11T11:26:11-06:00116814485PW_T014485149231221Compound116951Right5315158562022-07-11T12:41:36-06:002022-07-11T12:41:36-06:00116814487PW_T014487Active149255851Bound11691171Right531623192022-07-12T11:21:20-06:002022-07-12T11:31:57-06:00117814488PW_T014488Active1492680741ProteinComplex11711169Right149274191ProteinComplex11711169Right531723832022-07-12T11:52:52-06:002022-07-12T11:52:52-06:00117814489PW_T014489Active149283961Compound511169Right5318152632022-07-12T14:54:36-06:002022-07-12T14:54:36-06:00116814491PW_T014491Diffusion1493080741ProteinComplex11791169Right14493PW_T014493Active14932451Compound60851Right532110962022-07-12T16:25:22-06:002022-07-12T16:25:22-06:005114494PW_T014494Active14933481Compound60851Right53225802022-07-12T16:26:48-06:002022-07-12T16:26:48-06:005114473PW_T014473Active14911481Compound51847Right53245802022-07-12T16:29:33-06:002022-07-12T16:29:33-06:005114472PW_T014472Diffusion14910451Compound51847Right532310962022-07-12T16:28:48-06:002022-07-12T16:28:48-06:005114492PW_T014492Active1493180741ProteinComplex117951Right5320158662022-07-12T16:07:01-06:002022-07-12T16:07:01-06:00116814495PW_T014495Diffusion14934153741ProteinComplex511180Right1493580741ProteinComplex511180Right14496PW_T014496Diffusion1493610231ProteinComplex511180Right1493723531ProteinComplex511180Right14497PW_T014497Diffusion1493880741ProteinComplex84751Right14476PW_T014476Diffusion14914153741ProteinComplex2651Right14478PW_T014478Diffusion1491610231ProteinComplex2651Right14505PW_T014505Diffusion14946158701ProteinComplex11691171Right4175ActivationPW_I00417583497544ProteinComplex18350988ProteinComplex14174ActivationPW_I00417483473254ProteinComplex183487544ProteinComplex14177ActivationPW_I00417783533254ProteinComplex1835415853ProteinComplex14178ActivationPW_I00417883553254ProteinComplex183567828ProteinComplex14179ActivationPW_I004179835715853ProteinComplex183582353ProteinComplex14180ActivationPW_I0041808359988ProteinComplex18360938ProteinComplex14181ActivationPW_I0041818361988ProteinComplex183621023ProteinComplex14182ActivationPW_I0041828363988ProteinComplex1836415374ProteinComplex14183ActivationPW_I0041838365988ProteinComplex183668074ProteinComplex14184ActivationPW_I0041848367988ProteinComplex1836815352ProteinComplex14185ActivationPW_I004185836915854ProteinComplex18370105126Compound13827ActivationPW_I0038277653105126Compound1765445Compound14186ActivationPW_I0041868371105126Compound1837248Compound14187InhibitionPW_I004187837315352ProteinComplex1837464ProteinComplex14190InhibitionPW_I004190837915364ProteinComplex183808072ProteinComplex14191ActivationPW_I0041918381585Bound18382419ProteinComplex14192ActivationPW_I0041928383585Bound183848074ProteinComplex14189InhibitionPW_I0041898377584Bound1837815364ProteinComplex1861ActivationPW_I0008611721428ElementCollection117227948ProteinComplex14203ActivationPW_I00420384057948ProteinComplex1840615869ProteinComplex14204ActivationPW_I004204840715869ProteinComplex1840815870ProteinComplex1866ActivationPW_I00086617317948ProteinComplex117327944ProteinComplex14205ActivationPW_I00420584097944ProteinComplex18410988ProteinComplex1867ActivationPW_I00086717337950ProteinComplex117347944ProteinComplex14206ActivationPW_I00420684117950ProteinComplex1841215869ProteinComplex1869ActivationPW_I00086917377949ProteinComplex117387944ProteinComplex14207ActivationPW_I00420784137949ProteinComplex1841415869ProteinComplex14208ActivationPW_I0042088415388NucleicAcid184167949ProteinComplex14209ActivationPW_I0042098417389NucleicAcid184187950ProteinComplex14210ActivationPW_I004210841915870ProteinComplex184202353ProteinComplex122705841169117750139131645214329680350296284843296812271585116911775013923164522432968635039628504329687350496285143296882272585117111775013933164538432972635059628734329727350696287443297283164521174116981false4277261310regular2001903164522174116981false4204218510regular2001903164538174117181false3629173610regular200190316448840034116955false5008132310regular78783164489146116962false5117137610regular503031644901065116965false5103152110regular78783164491396116981false4797137410regular2001903164492723116981false5437115710regular2001903164493143116961false5422137710regular503031644941420116949false5443151710regular787831644951867116964false5618143510regular78783164496179911699false5302143319regular10025316449796411699false5192142819regular100253164498117011699false519214989regular1003531644991911699false530714989regular100253164500174117381false3372261310regular20019031645018461173139false3302278310regular503031645029641173137false3292260310regular5030316450388117381false2757261310regular200190316450410061173140false2977278810regular503031645059321173138false2987260810regular5030316450696411739false3117274810regular1002531645074055811739false3122272310regular10025316450840034116955false2746380710regular78783164509146116962false2720377510regular503031645101065116965false2731361010regular78783164511396116981false2480364810regular2001903164512723116981false3160364610regular2001903164513143116961false3080378110regular503031645141420116949false3001381610regular787831645151867116964false3011358910regular78783164516179911699false2850368710regular10025316451796411699false2850366710regular100253164518117011699false2855378710regular1003531645191911699false2855376710regular100253164520174116981false3927261310regular2001903164523179911719false3762137310regular10025316452496411719false3657137319regular100253164525117011719false371714539regular1003531645261911719false371714788regular1002531645271051266481false867107310regular200190316452810512660881false867200310regular2001903164529772681false1220341310regular2001903164530775181false1940340810regular20019031645311292681false1008331010regular20019031645321295181false1698331010regular200190316453318672664false671370510regular7878316453418675164false1649386510regular7878316453577116981false2805340810regular2001903164536122116981false3451359310regular20019031645371225181false1946390810regular20019031645393965181false1975364810regular20019031645404560881false1207200310regular2001903164541455181false1807200310regular20019031645424860881false1142228810regular2001903164543485181false1677228810regular20019031645444884781false572307810regular20019031645454584781false797319810regular200190316454754411699false4622266019regular1002531645483111699false4622264019regular10025316455110981false3130437810regular200190316455211881false3345437810regular200190316455374181false3360459710regular200190316455454081false3140459610regular200190316455511281false2920437610regular200190316455670481false2915459710regular200190316455739681false2700438210regular20019031645587881false2700459710regular200190316455912081false3025479710regular200190316719363116981false5557192310regular2001903167194129116981false5312182310regular200190249654281451168false383471012large150704955388121169false464975514150nucleic_acidlarge150704956389121169false424571514150nucleic_acidlarge15070122439171011696false437725488subunitlarge16080122439371011696false436922908subunitlarge16080122439423934116997false4304234011subunitlarge15070122442971011716false382917618subunitlarge16080122443023934117197false3784172111subunitlarge15070122438486911696false521714338subunitlarge16080122438514511732false303227138subunitregular15070122438618811732false315727138subunitregular15070122438711611732false309227588subunitregular15070122438817411732false309726738proteinregular15070122438986911696false282037028subunitlarge16080122439071011696false4097247810subunitlarge16080122439214788116997false459724458subunitlarge1507012243951808116997false30979988subunitlarge1507012243961808117197false3097138812genelarge1507012243978956116997false27778838subunitlarge1507012243988956117197false278213288genelarge1507012243991478911712false285217488genelarge15070122440014789512false164217438subunitlarge1507012244012394011712false293716588genelarge15070122440223940512false171716588subunitlarge1507012244038910117199false283715438subunitlarge1507012244048911117198false271215438subunitlarge150701224405212011712false278215838genelarge15070122440689105199false191715488subunitlarge15070122440789115198false179715488subunitlarge1507012244082120512false184715888subunitlarge1507012244091766117116false273218188genelarge17090122441017665116false155218088subunitlarge17090122441186911716false368213838subunitlarge16080122441224495376false145534738subunitregular15070122441314955376false145333708subunitregular1507012244142393011712false30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1401 C5047 1439 5187 1473 5217 1473 5false184329649M5142 1406 C5142 1429 5187 1473 5217 1473 5false184329650M5142 1521 C5142 1494 5162 1472 5217 1473 5false184329651M4997 1469 C5027 1469 5187 1473 5217 1473 5false184329652M5537 1347 C5538 1387 5492 1473 5377 1473 5false18trueM 2707.9468550441647 213.26155629629605 L 2693 212 L 2699.380887721186 225.57513432307834false4329653M5447 1407 C5447 1444 5407 1473 5377 1473 5false18trueM 2707.9468550441647 213.26155629629605 L 2693 212 L 2699.380887721186 225.57513432307834false4329654M5482 1517 C5482 1482 5407 1473 5377 1473 5false18trueM 2707.9468550441647 213.26155629629605 L 2693 212 L 2699.380887721186 225.57513432307834false4329655M5618 1474 C5588 1474 5407 1473 5377 1473 5false18trueM 2707.9468550441647 213.26155629629605 L 2693 212 L 2699.380887721186 225.57513432307834false4329656M3497 1013 L3497 1063 L3547 1013 z10true184329657M3497 993 L3497 1043 L3547 993 z10true184329658M3497 963 L3497 1013 L3547 963 z10true184329659M3497 943 L3497 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