Browsing Pathways

Biotin (vitamin H or vitamin B7) is the essential cofactor of biotin-dependent carboxylases, such as pyruvate carboxylase and acetyl-CoA carboxylase. In E. coli and many organisms, pimelate thioester is derived from malonyl-ACP. The pathway starts with a malonyl-[acp] interacting with S-adenosylmethionine through a biotin synthesis protein BioC resulting in an S-adenosylhomocysteine and a malonyl-[acp] methyl ester. The latter compound is then involved in the synthesis of a 3-ketoglutaryl-[acp] methyl ester through a 3-oxoacyl-[acyl-carrier-protein] synthase. The compound 3-ketoglutaryl-[acp] methyl ester is reduced by a NADPH-mediated 3-oxoacyl-[acyl-carrier-protein] reductase resulting in a 3R-hydroxyglutaryl-[acp] methyl ester. It is then dehydrated through a (3R)-hydroxymyristoyl-[acp] dehydratase producing an enoylglutaryl-[acp] methyl ester. enoylglutaryl-[acp] methyl ester is then reduced through an NADPH mediated enoyl-acp-reductase [NADH] resulting in a glutaryl-[acp] methyl ester. Continuing, glutaryl-[acp] methyl ester interacts with a malonyl-[acp] through a 3-oxoacyl-[acp] synthase 2 resulting in a 3-ketopimeloyl [acp] methyl ester then is further reduced through an NADPH 3-oxoacyl [acp] reductase producing a 3-hydroxypimeloyl-[acp] methyl ester and then dehydrated by (3R)-hydroxymyristoyl-[acp] dehydratase to produce an enoylpimeloyl-[acp] methyl ester. The product is then reduced by an NADPH-dependent enoyl-[acp]reductase resulting in a pimeloyl-[acp] methyl ester. Reacting with water through a carboxylesterase, pimeloyl-[acp] methyl ester is converted into a pimeloyl-[acp] and a methanol. The pimeloyl-acp reacts with L-alanine through an 8-amino-7-oxononanoate synthase resulting in 8-amino-7-oxononanoate which in turn reacts with S-adenosylmethionine through a 7,8-diaminonanoate transaminase resulting in an S-adenosyl-4-methylthio-2-oxobutanoate and 7,8-diaminononanoate. The latter compound is then dephosphorylated through a dethiobiotin synthetase resulting in a dethiobiotin. This compound interacts with a sulfurated[sulfur carrier), a hydrogen ion, and an S-adenosylmethionine through a biotin synthase to produce biotin and releasing L-methionine and a 5-deoxyadenosine. Finally, biotin is then metabolized by a bifunctional protein resulting in pyrophosphate and biotinyl-5-AMP which in turn reacts with the same protein (bifunctional protein birA resulting in a biotin carboxyl carrying protein. This product then enters fatty acid biosynthesis.

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.

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.

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.

Lysine is biosynthesized from L-aspartic acid. L-Aspartic acid can be incorporated into the cell through various methods: C4 dicarboxylate/orotate:H+ symporter, glutamate/aspartate:H+ symporter GltP, dicarboxylate transporter, C4 dicarboxylate/C4 monocarboxylate transporter DauA, and glutamate/aspartate ABC transporter. L-Aspartic acid is phosphorylated by an ATP-driven aspartate kinase resulting in ADP and L-aspartyl-4-phosphate. L-Aspartyl-4-phosphate is then dehydrogenated through an NADPH-driven aspartate semialdehyde dehydrogenase resulting in a release of phosphate, NADP, and L-aspartic 4-semialdehyde (involved in methionine biosynthesis). L-Aspartic 4-semialdehyde interacts with a pyruvic acid through a 4-hydroxy-tetrahydrodipicolinate synthase resulting in a release of hydrogen ion, water, and (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate. The latter compound is then reduced by an NADPH-driven 4-hydroxy-tetrahydrodipicolinate reductase resulting in a release of water, NADP, and (S)-2,3,4,5-tetrahydrodipicolinate, This compound interacts with succinyl-CoA and water through a tetrahydrodipicolinate succinylase resulting in a release of coenzyme A and N-succinyl-2-amino-6-ketopimelate. This compound interacts with L-glutamic acid through an N-succinyldiaminopimelate aminotransferase resulting in oxoglutaric acid and N-succinyl-L,L-2,6-diaminopimelate. The latter compound is then desuccinylated by reacting with water through an N-succinyl-L-diaminopimelate desuccinylase resulting in a succinic acid and L,L-diaminopimelate. This compound is then isomerized through a diaminopimelate epimerase resulting in a meso-diaminopimelate (involved in peptidoglycan biosynthesis I). This compound is then decarboxylated by a diaminopimelate decarboxylase resulting in a release of carbon dioxide and L-lysine. L-Lysine is then incorporated into the lysine degradation pathway. Lysine also regulates its own biosynthesis by repressing dihydrodipicolinate synthase and also by repressing lysine-sensitive aspartokinase 3. Diaminopielate is a precursor for lysine as well as other cell wall components. Synthesis of lysine starts by converting L-aspartic acid (L-aspartate) to L-Aspartyl-4-phosphate by aspartate kinase. L-Aspartyl-4-phosphate transforms to form L-aspartic 4-semialdehyde (L-aspartate semialdehyde) by aspartate semialdehyde dehydrogenase with NADPH. L-aspartic 4-semialdehyde can start the metabolic pathway of synthesis of methionine as well as synthesis of threonine. Aspartate kinase can be regulated by its end product: L-Lysine.

Phospholipids are membrane components in E. coli. The major phospholipids of E. coli are phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. All phospholipids contain sn-glycerol-3-phosphate esterified with fatty acids at the sn-1 and sn-2 positions. The reaction starts from a glycerone phosphate (dihydroxyacetone phosphate) produced in glycolysis. The glycerone phosphate is transformed into an sn-glycerol 3-phosphate (glycerol 3 phosphate) by NADPH-driven glycerol-3-phosphate dehydrogenase. sn-Glycerol 3-phosphate is transformed to a 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid). This can be achieved by an sn-glycerol-3-phosphate acyltransferase that interacts either with a long-chain acyl-CoA or with an acyl-[acp]. The 1-acyl-sn-glycerol 3-phosphate is transformed into a 1,2-diacyl-sn-glycerol 3-phosphate (phosphatidic acid) through a 1-acylglycerol-3-phosphate O-acyltransferase. This compound is then converted into a CPD-diacylglycerol through a CTP phosphatidate cytididyltransferase. CPD-diacylglycerol can be transformed either into an L-1-phosphatidylserine or an L-1-phosphatidylglycerol-phosphate through a phosphatidylserine synthase or a phosphatidylglycerophosphate synthase, respectively. The L-1-phosphatidylserine transforms into L-1-phosphatidylethanolamine through a phosphatidylserine decarboxylase. On the other hand, L-1-phosphatidylglycerol-phosphate gets transformed into an L-1-phosphatidyl-glycerol through a phosphatidylglycerophosphatase. These 2 products combine to produce a cardiolipin and an ethanolamine. The L-1 phosphatidyl-glycerol can also interact with cardiolipin synthase resulting in a glycerol and a cardiolipin.

Phospholipids are membrane components in E. coli. The major phospholipids of E. coli are phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. All phospholipids contain sn-glycerol-3-phosphate esterified with fatty acids at the sn-1 and sn-2 positions. The reaction starts from a glycerone phosphate (dihydroxyacetone phosphate) produced in glycolysis. The glycerone phosphate is transformed into an sn-glycerol 3-phosphate (glycerol 3 phosphate) by NADPH-driven glycerol-3-phosphate dehydrogenase. sn-Glycerol 3-phosphate is transformed to a 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid). This can be achieved by an sn-glycerol-3-phosphate acyltransferase that interacts either with a long-chain acyl-CoA or with an acyl-[acp]. The 1-acyl-sn-glycerol 3-phosphate is transformed into a 1,2-diacyl-sn-glycerol 3-phosphate (phosphatidic acid) through a 1-acylglycerol-3-phosphate O-acyltransferase. This compound is then converted into a CPD-diacylglycerol through a CTP phosphatidate cytididyltransferase. CPD-diacylglycerol can be transformed either into an L-1-phosphatidylserine or an L-1-phosphatidylglycerol-phosphate through a phosphatidylserine synthase or a phosphatidylglycerophosphate synthase, respectively. The L-1-phosphatidylserine transforms into L-1-phosphatidylethanolamine through a phosphatidylserine decarboxylase. On the other hand, L-1-phosphatidylglycerol-phosphate gets transformed into an L-1-phosphatidyl-glycerol through a phosphatidylglycerophosphatase. These 2 products combine to produce a cardiolipin and an ethanolamine. The L-1 phosphatidyl-glycerol can also interact with cardiolipin synthase resulting in a glycerol and a cardiolipin.

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.