Browsing Pathways

Butanoate or butyrate is the traditional name for the conjugate base of butanoic acid (also known as butyric acid). Butanoate metabolism includes L-glutamate degradation into the signal molecule GABA followed by subsequent reactions to make further products. Glutamate decarboxylase is an enzyme in the cytosol that catalyzes the conversion of L-glutamate into 4-aminobutanoate (GABA). It requires pyridoxal 5'-phosphate as a cofactor. This is followed by GABA permease, belonging to the APC Family of transport proteins, transporting GABA from the cytosol into the mitochondria matrix. Next, gamma-aminobutyrate transaminase degrades gamma-amino butyric acid (GABA) into succinate semialdehyde and uses either pyruvate or glyoxylate as an amino-group acceptor. The pyruvate-dependent activity is reversible while the glyoxylate-dependent activity is irreversible. Afterwards, succinate-semialdehyde dehydrogenase oxidizes succinate semialdehyde into succinate. A predicted succinate semialdehyde transporter in the mitochondria inner membrane is theorized to export succinate semialdehyde from the mitochondrial matrix into the cytosol. There, glyoxylate/succinic semialdehyde reductase catalyzes the reversible conversion of succinate semialdehyde into 4-hydroxybutanoate. Butanoate metabolism in Arabidopsis thaliana also includes reactions involving acetyl-CoA and acetoacetyl-CoA. 3-hydroxybutyryl-CoA dehydrogenase is a predicted enzyme (coloured orange in the image) in the cytosol that is theorized to catalyze the reversible conversion of 3-hydroxybutanoyl-CoA into acetoacetyl-CoA. Acetyl-CoA acetyltransferase then catalyzes the reversible conversion of acetoacetyl-CoA into acetyl-CoA. Then, hydroxymethylglutaryl-CoA synthase condenses acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA. This is followed by a predicted 3-hydroxy-3-methylglutaryl-CoA transporter localized to the mitochondria inner membrane that is theorized to import 3-hydroxy-3-methylglutaryl-CoA into the mitochondrial matrix from the cytosol. Once there, hydroxymethylglutaryl-CoA lyase catalyzes the synthesis of acetoacetate and acetyl-CoA from 3-hydroxy-3-methylglutaryl-CoA.

Phosphatidylcholines (PC) are a class of phospholipids that incorporate a phosphocholine headgroup into a diacylglycerol backbone. They are the most abundant phospholipid in eukaryotic cell membranes and has both structural and signalling roles. In eukaryotes, there exist two phosphatidylcholine biosynthesis pathways: the Kennedy pathway and the methylation pathway. The Kennedy pathway begins with the direct phosphorylation of free choline into phosphocholine followed by conversion into CDP-choline and subsequently phosphatidylcholine. It is the major synthesis route in animals. The methylation pathway involves the 3 successive methylations of phosphoethanolamine to form phosphocholine which is then funnelled into the Kennedy pathway to make phosphatidylcholine. In plants, phosphatidylcholine biosynthesis is implemented using a mix between the two pathways. An alternative of the methylation pathway uses phosphatidylethanolamine as a starting compound, but no enzyme has been found in Arabidopsis to catalyze the first methylation to form phosphatidyl-N-methylethanolamine. Many enzymes involved in this pathway are localized to the cell membrane but are not drawn as such for clarity. Instead, they are indicated with a dark green colour and appear to be free floating in the cytosol. The first reaction of the Kennedy pathway involves the membrane-localized enzyme choline/ethanolamine kinase catalyzing the conversion of choline into phosphocholine. Second, choline-phosphate cytidylyltransferase catalyzes the conversion of phosphocholine to CDP-choline. Last, choline/ethanolaminephosphotransferase, localized to the cell membrane, catalyzes phosphatidylcholine biosynthesis from CDP-choline. It requires either magnesium or manganese ions as cofactors. Note that phosphatidylcholine can be converted to either phosphocholine by a non-specific phospholipase or converted to choline by phospholipase D. Phosphocholine can also be converted to choline via phosphoethanolamine/phosphocholine phosphatase. The methylation pathway begins with serine decarboxylase catalyzing the biosynthesis of ethanolamine from serine. It requires pyridoxal 5'-phosphate as a cofactor. Next, choline/ethanolamine kinase, localized to the cell membrane, catalyzes the conversion of ethanolamine to phosphoethanolamine. Phosphoethanolamine N-methyltransferase (PEAMT), located in the cytosol, then catalyzes three sequential N-methylation steps to convert phosphoethanolamine to phosphocholine. PEAMT uses S-adenosyl-L-methionine as a methyl donor. Phosphocholine then enters the Kennedy pathway. Alternatively, in a subpathway parallel to the Kennedy pathway, phosphoethanolamine can be converted into phosphatidylethanolamine. Phosphatidylethanolamine is also synthesized from phosphatidylserine in the endoplasmic reticulum by phosphatidylserine decarboxylase. Note that phosphatidylethanolamine can be converted to either phosphoethanolamine by a non-specific phospholipase or converted to ethanolamine by phospholipase D. The two methylated intermediates N-methylethanolamine phosphate and N-dimethylethanolamine phosphate can also undergo reactions parallel to the Kennedy pathway to form the methylated intermediates of phosphatidylethanolamine (otherwise catalyzed by phosphatidyl-N-methylethanolamine N-methyltransferase, localized to the endoplasmic reticulum membrane, to form phosphatidylcholine).

Phosphatidylcholines (PC) are a class of phospholipids that incorporate a phosphocholine headgroup into a diacylglycerol backbone. They are the most abundant phospholipid in eukaryotic cell membranes and has both structural and signalling roles. In eukaryotes, there exist two phosphatidylcholine biosynthesis pathways: the Kennedy pathway and the methylation pathway. The Kennedy pathway begins with the direct phosphorylation of free choline into phosphocholine followed by conversion into CDP-choline and subsequently phosphatidylcholine. It is the major synthesis route in animals. The methylation pathway involves the 3 successive methylations of phosphatidylethanolamine to form phosphatidylcholine. The first reaction of the Kennedy pathway involves the cytosol-localized enzyme choline/ethanolamine kinase catalyzing the conversion of choline into phosphocholine. Second, choline-phosphate cytidylyltransferase, localized to the endoplasmic reticulum membrane, catalyzes the conversion of phosphocholine to CDP-choline. Last, choline/ethanolaminephosphotransferase catalyzes phosphatidylcholine biosynthesis from CDP-choline. It requires either magnesium or manganese ions as cofactors. A parallel Kennedy pathway forms phosphatidylethanolamine from ethanolamine - the only difference being a different enzyme, ethanolamine-phosphate cytidylyltransferase, catalyzing the second step. Phosphatidylethanolamine is also synthesized from phosphatidylserine in the mitochondrial membrane by phosphatidylserine decarboxylase. Phosphatidylethanolamine funnels into the methylation pathway in which phosphatidylethanolamine N-methyltransferase (PEMT) then catalyzes three sequential N-methylation steps to convert phosphatidylethanolamine to phosphatidylcholine. PEMT uses S-adenosyl-L-methionine as a methyl donor.

Vitamin B6 is a water-soluble vitamin essential for all living organisms. It is an important cofactor for enzymatic reactions in over one hundred different cellular reactions and processes. Vitamin B6 exists in different natural forms called vitamers, which are produced by plants, bacteria, and fungi, but not by animals and humans. These vitamers include: pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) and their phosphorylated vitamers, PLP, PNP and PMP respectively. Vitamin B6 metabolic pathway was mainly characterized in E. coli, however most organisms, including plants, utilize an alternate pathway. In plants, the various vitamers can be produced via different specific pathways. In A. thaliana, this biosynthetic pathway involves few subpathways, which include: glycolysis, pentose phosphate pathway (PPP), and glyoxylate and dicarboxylate metabolism. Glyceraldehyde 3-phosphate produced by glycolysis and ribulose 5-phosphate produced by PPP are synthesized to pyridoxal 5-phosphate by a synthase. Pyridoxal 5-phosphate is then dephosphorylated to pyridoxal. Pyridoxal, a form of vitamin B6, could act as a precursor for butanoate metabolsim. Moreover, from PPP, 2-Oxo-3-hydroxy-4-phosphobutanoate is produced, this is synthesized to O-phospho-4-hydroxy-L-threonine and then to 4-hydroxy-L-threonine. Pyridoxine could also be produced after a multistep reaction from 4-hydroxy-L-threonine, which is then synthesized to pyridoxal. Glycoaldehyde produced from glyoxylate and dicarboxylate metabolism is converted to pyridoxine. Pyridoxine could also undergo phosphorylation where it is converted to pyridoxine phosphate which is then synthesized to pyridoxal 5-phosphate where the later is dephosphorylated to pyridoxal. Pyridoxal could also be synthesized to pyridoxamine, this that is phosphorylated to pyridoxamin 5-phosphate, which is then synthesized to pyridoxal 5-phosphate.

Androstenedione is an endogenous weak androgen steroid hormone that is a precursor of testosterone and other androgens, as well as of estrogens like estrone . Its metabolism occurs primarily in the endoplasmic reticulum (membrane-associated enzymes are coloured dark green in the image). Conversion of androstenedione to testosterone requires the enzyme testosterone 17-beta-dehydrogenase 3. Conversion of androstenedione to estrone involves three successive reactions catalyzed by the enzyme aromatase (cytochrome P450 19A1). Androstenedione can also be converted into etiocholanolone glucuronide, androsterone glucuronide, and adrenosterone. The three-reaction subpathway to synthesize etiocholanolone glucuronide begins with the enzyme 3-oxo-5-beta-steroid 4-dehydrogenase catalyzing the conversion of androstenedione to etiocholanedione. This is followed by the conversion of etiocholanedione to etiocholanolone which is catalyzed by aldo-keto reductase family 1 member C4. Lastly, the large membrane-associated multimer UDP-glucuronosyltransferase 1-1 catalyzes the conversion of etiocholanolone to etiocholanolone glucuronide. The three-reaction subpathway to synthesize androsterone glucuronide begins with the conversion of androstenedione to androstanedione via 3-oxo-5-alpha-steroid 4-dehydrogenase 1. Anstrostanedione is then converted into androsterone via aldo-keto reductase family 1 member C4. The last reaction to form androsterone glucuronide is catalyzed by the large multimer UDP-glucuronosyltransferase 1-1. The two-reaction subpathway to synthesize adrenosterone begins in the mitochondrial inner membrane where androstenedione is first converted into 11beta-hydroxyandrost-4-ene-3,17-dione by the enzyme cytochrome P450 11B1. Following transport to the endoplasmic reticulum, 11beta-hydroxyandrost-4-ene-3,17-dione is converted into adrenosterone via corticosteroid 11-beta-dehydrogenase isozyme 1.

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.

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.

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.

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.