Browsing Pathways

Nicotinamide adenine dinucleotide (NAD) can be biosynthesized from L-aspartic acid. This amino acid reacts with oxygen through an L-aspartate oxidase resulting in a hydrogen ion, hydrogen peroxide and an iminoaspartic acid. The latter compound interacts with dihydroxyacetone phosphate through a quinolinate synthase A, resulting in a phosphate, water, and a quinolic acid. Quinolic acid interacts with phosphoribosyl pyrophosphate and hydrogen ion through a quinolinate phosphoribosyltransferase resulting in pyrophosphate, carbon dioxide and nicotinate beta-D-ribonucleotide. The latter is adenylated through an ATP driven nicotinate-mononucleotide adenylyltransferase releasing a pyrophosphate and resulting in a nicotinic acid adenine dinucleotide. Nicotinic acid adenine dinucleotide is processed through an NAD synthetase, NH3-dependent in two different manners. In the first case, Nicotinic acid adenine dinucleotide interacts with ATP, L-glutamine and water through the enzyme and results in hydrogen ion, AMP, pyrophosphate, L-glutamic acid and NAD. In the second case, Nicotinic acid adenine dinucleotide interacts with ATP and ammonium through the enzyme resulting in a pyrophosphate, AMP, hydrogen ion and NAD. NAD then proceeds to regulate its own pathway by repressing L-aspartate oxidase. As a general rule, most prokaryotes utilize the aspartate de novo pathway, in which the nicotinate moiety of NAD is synthesized from aspartate , while in eukaryotes, the de novo pathway starts with tryptophan.

NAD molecules have a relatively short half-life. NAD can be degraded by enzymes, and the degraded NAD molecule can be recouped by NAD salvage cycles. NAD salvage cycles can be used for recycling degraded NAD products such as nicotinamide and nicotinamide D-ribonucleotide. NAD salvage cycles can also be used for absorption of exogenous NAD+. NAD reacts spontaneously with water resulting in the release of hydrogen ion, AMP and beta-nicotinamide D-ribonucleotide. This enzyme can either interact spontaneously with water resulting in the release of D-ribofuranose 5-phosphate, hydrogen ion and Nacinamide. On the other hand beta-nicotinamide D-ribonucleotide can also react with water through NMN amidohydrolase resulting in ammonium, and Nicotinate beta-D-ribonucleotide. Also it can interact with water spontaneously resulting in the release of phosphate resulting in a Nicotinamide riboside. Niacinamide interacts with water through a nicotinamidase resulting in a release of ammonium and nicotinic acid. Nicotinic acid interacts with water and phosphoribosyl pyrophosphate through an ATP driven nicotinate phosphoribosyltransferase resulting in the release of ADP, pyrophosphate and phosphate and nicotinate beta-D-ribonucleotide. Nicotinamide riboside interacts with an ATP driven NadR DNA-binding transcriptional repressor and NMN adenylyltransferase (Escherichia coli) resulting in a ADP, hydrogen ion and beta-nicotinamide D-ribonucleotide. The latter interacts with ATP and hydrogen ions through NadR DNA-binding transcriptional repressor and NMN adenylyltransferase resulting in pyrophosphate and NAD. Nicotinate beta-D-ribonucleotide is adenylated through the interaction with ATP and a hydrogen ion through a nicotinate-mononucleotide adenylyltransferase resulting in pyrophosphate and Nicotinic acid adenine dinucleotide. Nicotinic acid adenine dinucleotide interacts with L-glutamine and water through an ATP driven NAD synthease, NH3-dependent resulting in AMP, pyrophosphate, hydrogen ion, L-glutamic acid and NAD.

Isoleucine biosynthesis begins with L-threonine from the threonine biosynthesis pathway. L-threonine interacts with threonine dehydratase biosynthetic releasing water, a hydrogen ion and (2Z)-2-aminobut-2-enoate. The latter is isomerized into a 2-iminobutanoate which interacts with water and a hydrogen ion spontaneously, resulting in the release of ammonium and 2-ketobutyric acid. 2-ketobutyric acid reacts with pyruvic acid and hydrogen ions through an acetohydroxybutanoate synthase / acetolactate synthase 2 resulting in carbon dioxide and (S)-2-Aceto-2-hydroxybutanoic acid. (S)-2-Aceto-2-hydroxybutanoic acid is reduced by an NADPH driven acetohydroxy acid isomeroreductase releasing NADP and acetohydroxy acid isomeroreductase. The latter compound is dehydrated by a dihydroxy acid dehydratase resulting in 3-methyl-2-oxovaleric acid. This compound reacts in a reversible reaction with L-glutamic acid through a Branched-chain-amino-acid aminotransferase resulting in oxoglutaric acid and L-isoleucine. L-isoleucine can also be transported into the cytoplasm through two different methods: a branched chain amino acid ABC transporter or a branched chain amino acid transporter BrnQy.

Isoleucine biosynthesis begins with L-threonine from the threonine biosynthesis pathway. L-threonine interacts with threonine dehydratase biosynthetic releasing water, a hydrogen ion and (2Z)-2-aminobut-2-enoate. The latter is isomerized into a 2-iminobutanoate which interacts with water and a hydrogen ion spontaneously, resulting in the release of ammonium and 2-ketobutyric acid. 2-ketobutyric acid reacts with pyruvic acid and hydrogen ions through an acetohydroxybutanoate synthase / acetolactate synthase 2 resulting in carbon dioxide and (S)-2-Aceto-2-hydroxybutanoic acid. (S)-2-Aceto-2-hydroxybutanoic acid is reduced by an NADPH driven acetohydroxy acid isomeroreductase releasing NADP and acetohydroxy acid isomeroreductase. The latter compound is dehydrated by a dihydroxy acid dehydratase resulting in 3-methyl-2-oxovaleric acid. This compound reacts in a reversible reaction with L-glutamic acid through a Branched-chain-amino-acid aminotransferase resulting in oxoglutaric acid and L-isoleucine. L-isoleucine can also be transported into the cytoplasm through two different methods: a branched chain amino acid ABC transporter or a branched chain amino acid transporter BrnQy.

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.

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.

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 biosynthesis of glutathione starts with the introduction of L-glutamic acid through either a glutamate:sodium symporter, glutamate / aspartate : H+ symporter GltP or a glutamate / aspartate ABC transporter. Once in the cytoplasm, L-glutamice acid reacts with L-cysteine through an ATP glutamate-cysteine ligase resulting in gamma-glutamylcysteine. This compound reacts which Glycine through an ATP driven glutathione synthetase thus catabolizing Glutathione. This compound is metabolized through a spontaneous reaction with an oxidized glutaredoxin resulting in a reduced glutaredoxin and an oxidized glutathione. This compound is reduced by a NADPH glutathione reductase resulting in a glutathione. Glutathione can then be degraded into various different glutathione containing compounds by reacting with a napthalene or Bromobenzene-2,3-oxide through a glutathione S-transferase.

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