Browsing Pathways

Cardiolipin (CL) is an important component of the inner mitochondrial membrane, and it is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism . Cardiolipin biosynthesis occurs mainly in the mitochondria. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the chloroplastic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Rhamnolipids (RL) consist of a fatty acyl moiety composed of a 3-(3-hydroxyalkanoyloxy)alkaloid acid (HAA) and a sugar moiety composed of one or two rhamnose sugars. Rhamnolipids function as surfactants and virulence factors and are involved in biofilm formation and cell motility. The rhamnose sugar component is produced via the dTDP-L-rhamnose biosynthetic pathway which forms dTDP-L-rhamnose from glucose 6-phosphate (G6P) in five steps. First, glucose 6-phosphate is converted into glucose 1-phosphate (G1P) via the enzyme phosphoglucomutase (AlgC). Second, glucose 1-phosphate is converted into dTDP-D-glucose via the enzyme glucose-1-phosphate thymidylyltransferase (RmlA). Third, dTDP-D-glucose is converted into dTDP-4-dehydro-6-deoxy-D-glucose via the enzyme dTDP-glucose 4,6-dehydratase (RmlB). Fourth, dTDP-4-dehydro-6-deoxy-D-glucose is converted into dTDP-4-dehydro-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose 3,5-epimerase (RmlC). Fifth, dTDP-4-dehydro-L-rhamnose is converted into dTDP-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose reductase (RmlD). The HAA component is synthesized from 3-hydroxyacyl-[acyl-carrier protein] diverted from fatty acid biosynthesis via the enzyme 3-(3-hydroxydecanoyloxy)decanoate synthase (RhIA). The final step in rhamnolipid biosynthesis is the formation of the glycosidic link between the rhamnose sugar component and the HAA component. This is accomplished by two rhamnosyltransferases (RhlB and RhlC) which catalyze sequential glycosyl transfer reactions to first form mono-rhamnolipids (via RhIB) and then di-rhamnolipids (via RhIC). RHlA, RHlB, and RHlC are associated with the inner membrane.

The Bloch pathway, named after Konrad Bloch, is the pathway following the mevalonate pathway occurring within the cell to complete cholesterol biosynthesis. Cholesterol is a necessary metabolite that helps create many essential hormones within the human body. This pathway, combined with the mevalonate pathway is one of two ways to biosynthesize cholesterol; the Kandutsch-Russell pathway is an alternative pathway that uses different compounds than the Bloch Pathway beginning after lanosterol. The first three reactions occur in the endoplasmic reticulum. Lanosterol, a compound created through the mevalonate pathway, binds with the enzyme lanosterol 14-alpha demethylase to become 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol. Moving to the next reaction, 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol utilizes the enzyme lanosterol 14-alpha demethylase to create 4,4-dimethyl-14α-formyl-5α-cholesta-8,24-dien-3β-ol. Lanosterol 14-alpha demethylase is used one last time in this pathway, converting 4,4-dimethyl-14α-formyl-5α-cholesta-8,24-dien-3β-ol into 4,4-dimethyl-5a-cholesta-8,14,24-trien-3b-ol. Entering the inner nuclear membrane, 4,4-dimethyl-5a-cholesta-8,14,24-trien-3b-ol is catalyzed by a lamin B receptor to create 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol. Entering the endoplasmic reticulum membrane, 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol, with the help of methyl monooxygenase 1 is converted to 4a-hydroxymethyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol. The enzyme methyl monooxygenase 1 uses 4a-hydroxymethyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol to produce 4a-formyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol. This reaction is repeated once more, using 4a-formyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol and methyl monooxygenase 1 to create 4a-carboxy-4b-methyl-5a-cholesta-8,24-dien-3b-ol. Briefly entering the endoplasmic reticulum, 4a-carboxy-4b-methyl-5a-cholesta-8,24-dien-3b-ol then uses sterol-4-alpha-carboxylate-3-dehyrogenase to catalyze into 3-keto-4-methylzymosterol. Back in the endoplasmic reticulum membrane, where the pathway will continue on for the remaining reactions, 3-keto-4-methylzymosterol combines with 3-keto-steroid reductase to create 4a-methylzymosterol. 4a-Methylzymosterol joins the enzyme methylsterol monooxgenase 1 to result in 4a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol. 4a-Hydroxymethyl-5a-cholesta-8,24-dien-3b-ol uses methylsterol monooxygenase 1 to convert to 4a-formyl-5a-cholesta-8,24-dien-3b-ol. 4a-Formyl-5a-cholesta-8,24-dien-3b-ol proceeds to use the same enzyme used in the previous reaction: methylsterol monooxygenase 1, to catalyze into 4a-carboxy-5a-cholesta-8,24-dien-3b-ol. Sterol-4-alpha-carboxylate-3-dehydrogenase is used alongside 4a-carboxy-5a-cholesta-8,24-dien-3b-ol to produce 5a-cholesta-8,24-dien-3-one (also known as zymosterone). Zymosterone (5a-cholesta-8,24-dien-3-one) teams up with 3-keto-steroid reductase to create zymosterol. Zymosterol proceeds to use the enzyme 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase to catalyze into 5a-cholesta-7,24-dien-3b-ol. The compound 5a-cholesta-7,24-dien-3b-ol then joins lathosterol oxidase to convert to 7-dehydrodesmosterol. 7-Dehydrodesmosterol and the enzyme 7-dehydrocholesterol reductase come together to create desmosterol. This brings the pathway to the final reaction, where desmosterol combines with delta(24)-sterol reductase to finally convert to cholesterol.

The mevalonate pathway, also known as the isoprenoid pathway, plays an essential role in creating the chemicals needed for many plants to function. This pathway, combined with the MEP/DOXP pathway give many plants their scents, such as cinnamon and ginger, and are responsible for the red colour in tomatoes. The pathway begins with acetyl-CoA, having come from the glycolysis pathway. Acetyl-CoA immediately becomes acetoacetyl-CoA through the enzyme acetyl-CoA acetyltransferase 1/2. Combined, acetoacetyl-CoA and acetyl-CoA react with hydroxymethylglutaryl-CoA synthase to create 3-hydroxy-3methylglutaryl-CoA. From here, this compound is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 and becomes (R)-mevalonate. Mevalonate is paired with mevalonate kinase to produce mevalonic acid-5P. In turn, mevalonic acid-5P reacts with phosphomevalonate kinase, and entering the peroxisome and becoming (R)-mevalonic acid-5-pyrophosphate. Remaining in the peroxisome, diphosphomevalonate decarboxylase MVD1 is used alongside (R)-mevalonic acid-5-pyrophosphate to create isopentenyl pyrophosphate, bringing the pathway into the chloroplast. Dimethylallylpyrophosphate is produced after isopentenyl pyrophosphate and isopentenyl diphosphate delta-isomerase II team up to catalyze it. Dimethylallylpyrophosphate then joins forces with isopentenyl again, this time adding geranylgeranyl pyrophosphate synthase 6 and moving into the mitochondria to produce geranyl-PP. This is followed by monoterpenoid biosynthesis.

The distal convoluted tubule of the nephron is the part of the kidney between the loop of henle and the collecting duct. When renin is released from the kidneys, it causes the activation of angiotensin I in the blood circulation which is cleaved to become angiotensin II. Angiotensin II stimulates the release of aldosterone from the adrenal cortex and release of vasopressin from the posterior pituitary gland. When in the circulation, vasopressin eventually binds to receptors on epithelial cells in the distal convoluted tubule. This causes vesicles that contain aquaporins to fuse with the plasma membrane. Aquaporins are proteins that act as water channels once they have bound to the plasma membrane. As a result, the permeability of the distal convoluted tubule changes to allow for water reabsorption back into the blood circulation. In addition, sodium, chlorine, and calcium are also reabsorbed back into the systemic circulation via their respective channels and exchangers. However, aldosterone is a major regulator of the reabsorption of these ions as well, as it changes the permeability of the distal convoluted tubule to these ions. As a result, a high concentration of sodium, chlorine, and calcium in the blood vessels occurs. The reabsorption of ions and water increases blood fluid volume and blood pressure.

Pancreatic delta cells produce somatostatin which functions to inhibit glucagon, insulin, and itself. Somatostatin is stored in granules in the delta cell and is released in response to an increase in blood sugar, calcium, and blood amino acids during absorption of a meal. In the process of somatostatin secretion, glucose must first undergo glycolysis in the mitochondrion to increase ATP in the cell. The inside of the alpha cell then becomes electrically positive due to the closure of potassium channels that were inhibited by ATP. From this closure, the potassium is no longer being shuttled out of the cell, thus depolarizing the cell due to the extra intracellular potassium. The resulting action potential from the increased membrane potential causes the voltage gate calcium channels to open, creating an influx of calcium into the cell. This triggers the exocytosis of somatostatin granules from the delta cell.

Juvenile hormones in insects are important for their growth before their adulthood, preventing metamorphosis if they undergo one. In Drosophila, only juvenile hormone III has been identified, while others exist in butterflies and moths. Synthesis of various forms of juvenile hormone III (JH III) start with farnesyl diphosphate interacting with an uncharacterized phosphatase protein, forming farnesol. Farnesol then interacts with NADP+ dependent farensol dehydrogenase, which removes a hydrogen ion from the hydroxyl group in order to form farnesal. Farnesal then enters the mitochondria and interacts with another uncharacterized aldehyde dehydrogenase which allows it to form farnesoic acid. Farnesoic acid can then interact with an unknown protein, similar to farnesoate epoxidase in Bombyx mori, in order to form juvenile hormone III acid (JH III acid). JH III acid can then interact with epoxide hydrolase in the membrane of the endoplasmic reticulum, forming the final product of this pathway, juvenile hormone III acid diol (JH III acid diol). It can also interact with juvenile hormone acid O-methyltransferase in order to form JH III, which is used in another set of reactions in this pathway. If farnesoic acid does not interact with the unknown protein, it may interact with juvenile hormone acid O-methyltransferase to form methyl farnesoate. Methyl farnesoate can then interact with a different unknown protein similar, to methyl farnesoate epoxidase in Diploptera punctata, in order to form JH III. In the mitochondria, JH III can interact with carboxylic ester hydrolase in order to form JH III acid, which then can form the final product, or form JH III again. Alternately, JH III can interact with epoxide hydrolase in the membrane of the endoplasmic reticulum, forming juvenile hormone III diol. This product then interacts with carboxylic ester hydrolase in the mitochondria, forming JH III acid diol, again, the end product of this pathway.

Ether lipids are typically glycerophospholipids where the glycerol backbone has lipids attached by both an ether bond at the sn-1 position and an acyl group at the sn-2 position. This pathway starts with dihydroxyacetone phosphate acyl ester which comes from glycerophospholipid metabolism. In the peroxisome, it reacts with a long chain alcohol, catalyzed by alkyldihydroxyacetonephosphate synthase, and forms an alkyl-glycerone 3-phosphate. Following this, the enzyme acylglycerone-phosphate reductase adds a hydrogen ion to the alkyl-glycerone 3-phosphate, forming a 1-alkyl-sn-glycerol 3-phosphate. Following this, a long-chain fatty acyl group is added, taken from a long-chain fatty acyl-CoA, and catalyzed by an acyltransferase to form a 2-acyl-1-alkyl-sn-glycero-3-phosphate. The phosphate is then removed in a reaction catalyzed by putative phosphatide phosphatase, forming 2-acyl-1-alkyl-sn-glycerol. This can then have a phosphoethanolamine group added by an ethanolaminephosphotransferase in the endoplasmic reticulum membrane, to form 2-acyl-1-alkyl-sn-glycero-3-phosphoethanolamine. This compound then is acted upon by a plasmanylethanolamine desaturase to form O-1-alk-1-enyl-2-acyl-sn-glycero-3-phosphoethanolamine. O-1-alk-1-enyl-2-acyl-sn-glycero-3-phosphoethanolamine can then react via phospholipase A2 to form a 1-alkenylglycerophosphoethanolamine, one of the end products of this pathway, or react via phospholipase D to form a 2-acyl-1-(1-alkenyl)-sn-glycero-3-phosphate, another end product of this pathway. It can also react reversibly using an ethanolaminephosphotransferase in the endoplasmic reticulum membrane to form or be formed from a 1-alkenyl-2-acylglycerol. Alternatively, the 2-acyl-1-alkyl-sn-glycerol can react with CDP-choline, catalyzed by a diacylglycerol cholinephosphotransferase, in order to form a 1-radyl-2-acyl-sn-glycero-3-phosphocholine. This can then react using phospholipase A2 as the enzyme to form a 1-organyl-2-lyso-sn-glycero-3-phosphocholine which can then react using lysophosphatidylcholine acyltransferase in the endoplasmic reticulum membrane to reform 1-radyl-2-acyl-sn-glycero-3-phosphocholine. Alternatively, it can react with the lysophosphatidylcholine acyltransferase to form 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine, also known as platelet-activating factor, the final end product of this pathway. This platelet-activating factor can then interact with platelet-activating factor acetylhydrolase to reform 1-organyl-2-lyso-sn-glycero-3-phosphocholine.

Lipoic acid metabolism starts with caprylic acid being introduced into the cytoplasm, however, no transporter has been identified yet. i) Once caprylic acid is in the cytoplasm, it can react with a holo-acp through an ATP-driven 2-acylglycerophosphoethanolamine acyltransferase/acyl-ACP synthetase resulting in pyrophosphate, AMP, and octanoyl-[acp]. The latter compound can also be obtained from palmitate biosynthesis. ii) Octanoyl-acp then interacts with a lipoyl-carrier protein L-lysine through an octanoyltransferase resulting in a hydrogen ion, a holo-acyl-acp, and an N6-(octanoyl)lysine. iii) N6-(octanoyl)lysine reacts with an S-adenosylmethionine, a sulfurated[sulfur carrier], and a reduced ferredoxin through a lipoate-protein ligase A, resulting in a 5-deoxyadenosine, an L-methionine, an unsulfurated [sulfur carrier], oxidized ferredoxin, and protein N6-(octanoyl)lysine. Caprylic acid can also interact with ATP and a lipoyl-carrier protein-L-lysine through a lipoate-protein ligase A resulting in an AMP, pyrophosphate, hydrogen ion, and protein N6-(octanoyl)lysine. The latter compound reacts with an S-adenosylmethionine, a sulfurated[sulfur carrier] and a reduced ferredoxin through a lipoate-protein ligase A, resulting in a 5-deoxyadenosine, an L-methionine, an unsulfurated [sulfur carrier], oxidized ferredoxin, and a protein N6-(octanoyl)lysine. R-Lipoic acid can be absorbed from the environment, as seen in studies by Morris TW. In this pathway, the lipoyl-protein ligase LplA utilizes pre-existing lipoate that has been imported from outside the cell, and thus catalyzes a salvage pathway. Lipoic acid interacts with ATP and hydrogen ion through a lipoyl-protein ligase A, resulting in a pyrophosphate and a lipoyl-AMP (lipoyl-adenylate). This compound then interacts with a lipoyl-carrier protein-L-lysine through a lipoate-protein ligase A resulting in an AMP, a hydrogen ion, and a protein N6-(lipoyl) lysine. It has been suggested that the conversion of octanoylated-domains into lipoylated ones described in this pathway may be a type of a repair pathway, activated only if the other lipoate biosynthetic pathways are malfunctioning.

L-Alanine is an essential component of both proteins and Peptidoglycan. Peptidoglycan also contain about three molecules of D-alanine for every L-alanine, comprising of only about 10% of the total alanine synthesized flowing into peptidoglycan. (More info can be found at L-alanine metabolism pathway: PW000788 or SMP0000810) In this pathway, D-amino acid dehydrogenase degrades D-alanine to form pyruvate, pyruvate then serving as a source of carbon for central metabolism. D-alanine can be formed by either biosynthetic alanine racemase or catabolic alanine racemase. D-alanine is required for forming cell wall peptidoglycan (murein). D-alanine is metabolized by ATP driven D-alanine ligase A and B resulting in D-alanyl-D-alanine. This product is incorporated into peptidoglycan biosynthesis.