Browsing Pathways

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane 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.

Glycolic acid is introduced into the cytoplasm through either a glycolate / lactate:H+ symporter or a acetate / glycolate transporter. Once inside, glycolic acid reacts with an oxidized electron-transfer flavoprotein through a glycolate oxidase resulting in a reduced acceptor and glyoxylic acid. Glyoxylic acid can also be obtained from the introduction of glyoxylic acid. It can also be obtained from the metabolism of (S)-allantoin. S-allantoin is introduced into the cytoplasm through a purine and pyrimidine transporter(allantoin specific). Once inside, the compound reacts with water through a allantoinase resulting in hydrogen ion and allantoic acid. Allantoic acid then reacts with water and hydrogen ion through a allantoate amidohydrolase resulting in a carbon dioxide, ammonium and S-ureidoglycine. The latter compound reacts with water through a S-ureidoglycine aminohydrolase resulting in ammonium and S-ureidoglycolic acid which in turn reacts with a Ureidoglycolate lyase resulting in urea and glyoxylic acid. Glyoxylic acid can either be metabolized into L-malic acid by a reaction with acetyl-CoA and Water through a malate synthase G which also releases hydrogen ion and Coenzyme A. L-malic acid is then incorporated into the TCA cycle. Glyoxylic acid can also be metabolized by glyoxylate carboligase, releasing a carbon dioxide and tartronate semialdehyde. The latter compound is then reduced by an NADH driven tartronate semialdehyde reductase 2 resulting in glyceric acid. Glyceric acid is phosphorylated by a glycerate kinase 2 resulting in a 3-phosphoglyceric acid. This compound is then integrated into various other pathways: cysteine biosynthesis, serine biosynthesis and glycolysis and pyruvate dehydrogenase.

In E. coli, L-fucose and L-rhamnose are metabolized through parallel pathways. The pathways converge after their corresponding aldolase reactions yielding the same products: lactaldehye. Proton symporter can facilitate the import of alpha-L-rhamnopyranose, methylpentose and beta-L-rhamnopyranose into cell for further metabolism, which allow E.coli to grow with carbon and energy. For alpha-L-rhamnopyranose, it is isomerized by a l-rhamnose mutarotase resulting in a beta-L-rhamnopyranose which is then isomerized into a keto-L-rhamnulose by a l-rhamnose isomerase. The keto-L-rhamnulose spontaneously changes into a L-rhamnulofuranose which is phosphorylated by a rhamnulokinase resulting in a L-rhamnulose 1-phosphate. This compound reacts with a rhamnulose-1-phosphate aldolase resulting in a dihydroxyacetone phosphate and a lactaldehyde. For beta-L-rhamnopyranose, it is isomerized by a L-fucose mutarotase resulting in a alpha-L-fucopyranose. This compound is then isomerized by an L-fucose isomerase resulting in a L-fuculose which in turn gets phosphorylated into an L-fuculose 1-phosphate through an L-fuculokinase. The compound L-fuculose 1-phosphate reacts with an L-fuculose phosphate aldolase through a dihydroxyacetone phosphate and a lactaldehyde. Two pathways can both be used for degrading L-lactaldehyde, which the aerobic pathway facilitates the conversion from L-lactic acid to pyruvic acid via L-lactate dehydrogenase, and the anaerobic pathway facilitates conversion from lactaldehyde to propane-1,2-diol via lactaldehyde reductase. Under aerobic conditions, L-lactaldehyde is oxidized in two steps to pyruvate, thereby channeling all the carbons from fucose or rhamnose into central metabolic pathways. Under anaerobic conditions, L-lactaldehyde is reduced to L-1,2-propanediol, which is secreted into the environment.

D-allose can be used as source of carbon for E.coli. D-allose is imported into E.coli by D-allose ABC transporter without phosphorylation. Allose-6-phosphate isomerase and allulose-6-phosphate 3-epimerase catalyze the remaining reactions resulting in D-allulose 6 phosphate and Beta-D-fructofuranose 6-phosphate respectively. Once Beta D fructofuranose 6-phosphate is synthesized, it can be used in the glycolysis and pyruvatedehydrogenase pathway.

The biosynthesis of L-tryptophan begins with L-glutamine interacting with a chorismate through a anthranilate synthase which results in a L-glutamic acid, a pyruvic acid, a hydrogen ion and a 2-aminobenzoic acid. The aminobenzoic acid interacts with a phosphoribosyl pyrophosphate through an anthranilate synthase component II resulting in a pyrophosphate and a N-(5-phosphoribosyl)-anthranilate. The latter compound is then metabolized by an indole-3-glycerol phosphate synthase / phosphoribosylanthranilate isomerase resulting in a 1-(o-carboxyphenylamino)-1-deoxyribulose 5'-phosphate. This compound then interacts with a hydrogen ion through a indole-3-glycerol phosphate synthase / phosphoribosylanthranilate isomerase resulting in the release of carbon dioxide, a water molecule and a (1S,2R)-1-C-(indol-3-yl)glycerol 3-phosphate. The latter compound then interacts with a D-glyceraldehyde 3-phosphate and an Indole. The indole interacts with an L-serine through a tryptophan synthase, β subunit dimer resulting in a water molecule and an L-tryptophan. The metabolism of L-tryptophan starts with L-tryptophan being dehydrogenated by a tryptophanase / L-cysteine desulfhydrase resulting in the release of a hydrogen ion, an Indole and a 2-aminoacrylic acid. The latter compound is isomerized into a 2-iminopropanoate. This compound then interacts with a water molecule and a hydrogen ion spontaneously resulting in the release of an Ammonium and a pyruvic acid. The pyruvic acid then interacts with a coenzyme A through a NAD driven pyruvate dehydrogenase complex resulting in the release of a NADH, a carbon dioxide and an Acetyl-CoA

Gluconeogenesis from L-malic acid starts from the introduction of L-malic acid into cytoplasm either through a C4 dicarboxylate / orotate:H+ symporter or a dicarboxylate transporter (succinic acid antiporter). L-malic acid is then metabolized through 3 possible ways: NAD driven malate dehydrogenase resulting in oxalacetic acid, NADP driven malate dehydrogenase B resulting pyruvic acid or malate dehydrogenase, NAD-requiring resulting in pyruvic acid. Oxalacetic acid is processed by phosphoenolpyruvate carboxykinase (ATP driven) while pyruvic acid is processed by phosphoenolpyruvate synthetase resulting in phosphoenolpyruvic acid. This compound is dehydrated by enolase resulting in an 2-phosphoglyceric acid which is then isomerized by 2,3-bisphosphoglycerate-independent phosphoglycerate mutase resulting in a 3-phosphoglyceric acid which is phosphorylated by an ATP driven phosphoglycerate kinase resulting in a glyceric acid 1,3-biphosphate. This compound undergoes an NADH driven glyceraldehyde 3-phosphate dehydrogenase reaction resulting in a D-Glyceraldehyde 3-phosphate which is first isomerized into dihydroxyacetone phosphate through an triosephosphate isomerase. D-glyceraldehyde 3-phosphate and Dihydroxyacetone phosphate react through a fructose biphosphate aldolase protein complex resulting in a fructose 1,6-biphosphate. Fructose 1,6-biphosphateis is metabolized by a fructose-1,6-bisphosphatase resulting in a Beta-D-fructofuranose 6-phosphate which is then isomerized into a Beta-D-glucose 6-phosphate through a glucose-6-phosphate isomerase.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane 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.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane 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.

The pathway of valine biosynthesis starts with pyruvic acid interacting with a hydrogen ion through a acetolactate synthase / acetohydroxybutanoate synthase or a acetohydroxybutanoate synthase / acetolactate synthase resulting in the release of carbon dioxide and (S)-2-acetolactate. The latter compound then interacts with a hydrogen ion through an NADPH driven acetohydroxy acid isomeroreductase resulting in the release of a NADP and an (R) 2,3-dihydroxy-3-methylvalerate. The latter compound is then dehydrated by a dihydroxy acid dehydratase resulting in the release of water and isovaleric acid. Isovaleric acid interacts with an L-glutamic acid through a Valine Transaminase resulting in a oxoglutaric acid and an L-valine. L-valine is then transported into the periplasmic space through a L-valine efflux transporter.

Leucine biosynthesis involves a five-step conversion process starting with the valine precursor 2-keto-isovalerate interacting with acetyl-CoA and water through a 2-isopropylmalate synthase resulting in Coenzyme A, hydrogen Ion and 2-isopropylmalic acid. The latter compound reacts with isopropylmalate isomerase which dehydrates the compound resulting in a Isopropylmaleate. This compound reacts with water through a isopropylmalate isomerase resulting in 3-isopropylmalate. This compound interacts with a NAD-driven D-malate / 3-isopropylmalate dehydrogenase results in 2-isopropyl-3-oxosuccinate. This compound interacts spontaneously with hydrogen resulting in the release of carbon dioxide and ketoleucine. Ketoleucine interacts in a reversible reaction with L-glutamic acid through a branched-chain amino-acid aminotransferase resulting in Oxoglutaric acid and L-leucine. L-leucine can then be exported outside the cytoplasm through a transporter: L-amino acid efflux transporter. In the final step, ketoleucine can be catalyzed to form L-leucine by branched-chain amino-acid aminotransferase (IlvE) and tyrosine aminotransferase (TryB). L-Glutamic acid can also be transformed into oxoglutaric acid by these two enzymes. Tyrosine aminotransferase can be suppressed by lecuine, and inhibited by 2-keto-isovarlerate and its end product, tyrosine. 2-ketoisocaproate can not be introduced if 2-keto-isovarlerate inhibit TyrB and IlvE is absent.