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.

Beta-Alanine metabolism starts as a product of aspartate metabolism. Aspartate is decarboxylated by aspartate 1-decarboxylase, releasing carbon dioxide and beta-alanine. Beta-Alanine is then metabolized through a pantothenate synthease resulting in pantothenic acid. Pantothenic acid then undergoes phosphorylation through an ATP-driven pantothenate kinase, resulting in D-4-phosphopantothenate. Pantothenate, vitamin B5, is a precursor for synthesis of 4'-phosphopantetheine moiety of coenzyme A and acyl carrier protein. Plants and microorganisms can synthesize pantothenate de novo, but animals must obtain it from diet. Enzymes of beta-alanine metabolism are targets for anti-microbial drugs.

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 phosphoribosyl pyrophosphate begins as a product of the pentose phosphate and D-ribose 5-phosphate interaction. When catalyzed with a phosphopentomutase, the product is a ribose 1-phosphate. Ribose 1-phosphate can interact spontaneously with ATP resulting in a release of hydrogen ion, ADP and a ribose 1,5-biphosphate. Ribose 1,5-biphosphate is then phosphorylated through a ribose 1,5-bisphosphokinase resulting in the release of ADP and phosphoribosyl pyrophosphate. Phosphoribosyl pyrophosphate will then participate in the purine nucleotides de novo biosynthesis pathway. Alternatively pentose phosphate and D-ribose 5-phosphate's interaction can be phosphorylated through an ATP driven ribose-phosphate diphosphokinase resulting in a release of a hydrogen ion, an AMP and a phosphoribosyl pyrophosphate which will again participate in the purine nucleotides de novo biosynthesis pathway.

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 folic acid begins as a product of purine nucleotides de novo biosynthesis pathway. Purine nucleotides are involved in a reaction with water through a GTP cyclohydrolase 1 protein complex, resulting in a hydrogen ion, formic acid and 7,8-dihydroneopterin 3-triphosphate. The latter compound is dephosphorylated through a dihydroneopterin triphosphate pyrophosphohydrolase resulting in the release of a pyrophosphate, hydrogen ion and 7,8-dihydroneopterin 3-phosphate. The latter product reacts with water spontaneously resulting in the release of a phosphate and a 7,8 -dihydroneopterin. 7,8 -dihydroneopterin reacts with a dihydroneopterin aldolase, releasing a glycoaldehyde and 6-hydroxymethyl-7,9-dihydropterin. Continuing, 6-hydroxymethyl-7,9-dihydropterin is phosphorylated with a ATP-driven 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase resulting in a (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate. Chorismate is metabolized by reacting with L-glutamine through a 4-amino-4-deoxychorismate synthase resulting in L-glutamic acid and 4-amino-4-deoxychorismate. The latter product is then catalyzed via an aminodeoxychorismate lyase resulting in pyruvic acid, hydrogen ion and p-aminobenzoic acid. (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate and p-aminobenzoic acid react with the help of a dihydropteroate synthase resulting in pyrophosphate and 7,8-dihydropteroic acid. This compound then reacts with L-glutamic acid through an ATP driven bifunctional folylpolyglutamate synthease / dihydrofolate synthease resulting in a 7,8-dihydrofolate monoglutamate. 7,8-dihydrofolate monoglutamate is then reduced via a NADPH mediated dihydrofolate reductase resulting in a tetrahydrofate which will continue and become a metabolite of the folate pathway

Fructose metabolism begins with the transport of Beta-D-fructofuranose through a fructose PTS permease, resulting in a Beta-D-fructofuranose 1-phosphate. This compound is phosphorylated by an ATP driven 1-phosphofructokinase resulting in a fructose 1,6-biphosphate. This compound can either react with a fructose bisphosphate aldolase class 1 resulting in D-glyceraldehyde 3-phosphate and a dihydroxyacetone phosphate or through a fructose biphosphate aldolase class 2 resulting in a D-glyceraldehyde 3-phosphate. This compound can then either react in a reversible triosephosphate isomerase resulting in a dihydroxyacetone phosphate or react with a phosphate through a NAD dependent Glyceraldehyde 3-phosphate dehydrogenase resulting in a glyceric acid 1,3-biphosphate. This compound is desphosphorylated by a phosphoglycerate kinase resulting in a 3-phosphoglyceric acid.This compound in turn can either react with a 2,3-bisphosphoglycerate-independent phosphoglycerate mutase or a 2,3-bisphosphoglycerate-independent phosphoglycerate mutase resulting in a 2-phospho-D-glyceric acid. This compound interacts with an enolase resulting in a phosphoenolpyruvic acid and water. Phosphoenolpyruvic acid can react either through a AMP driven phosphoenoylpyruvate synthase or a ADP driven pyruvate kinase protein complex resulting in a pyruvic acid. Pyruvic acid reacts with CoA through a NAD driven pyruvate dehydrogenase complex resulting in a carbon dioxide and a Acetyl-CoA which gets incorporated into the TCA cycle pathway.

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 fatty acid biosynthesis starts from acetyl-CoA reacting either with a holo-[acp] through a 3-oxoacyl-[acp] synthase 3 resulting in an acetyl-[acp] or react with hydrogen carbonate through an ATP driven acetyl-CoA carboxylase resulting in a malonyl-CoA. Malonyl-CoA reacts with a holo-acp] through a malonyl-CoA-ACP transacylase resulting in a malonyl-[acp]. This compound can react with a KASI protein resulting in an acetyl-[acp]. A malonyl-[acp] can also react with an acetyl-[acp] through KASI and KASII or with acetyl-CoA through a beta-ketoacyl-ACP synthase to produce an acetoacetyl-[acp]. An acetoacetyl-[acp] is also known as a 3-oxoacyl-[acp]. A 3-oxoacyl-[acp] is reduced through a NDPH mediated 3-oxoacyl-[acp] reductase resulting in a (3R)-3-hydroxyacyl-[acp] (R3 hydroxydecanoyl-[acp]) which can either join the fatty acid metabolism, be dehydrated by an 3R-hydroxymyristoyl-[acp] dehydratase to produce a trans-2-enoyl-[acp] or be dehydrated by a hydroxydecanoyl-[acp] to produce a trans-delta2 decenoyl-[acp]. Trans-2-enoyl-[acp] is reduced by a NADH driven enoyl-[acp] reductase resulting in a 2,3,4-saturated fatty acyl-[acp]. This product then reacts with malonyl-[acp] through KASI and KASII resulting in a holo-acyl carrier protein and a 3- oxoacyl-[acp]. Trans-delta2 decenoyl-[acp] reacts with a 3-hydroxydecanoyl-[acp] dehydrase producing a cis-delta 3-decenoyl-ACP. This product then reacts with KASI to produce a 3-oxo-cis-delta5-dodecenoyl-[acp], which in turn is reduced by a NADPH driven 3-oxoacyl-[acp] resulting in a 3R-hydroxy cis delta5-dodecenoyl-acp. This product is dehydrated by a (3R)-hydroxymyristoyl-[acp] dehydratase resulting in a trans-delta 3- cis-delta 5-dodecenoyl-[acp] which in turn is reduced by a NADH driven enoyl-[acp] reductase resulting in a cis-delta5-dodecenoyl-acp which becomes a metabolite of fatty acid metabolism

The biosynthesis of phosphoribosyl pyrophosphate begins as a product of the pentose phosphate and D-ribose 5-phosphate interaction. When catalyzed with a phosphopentomutase, the product is a ribose 1-phosphate. Ribose 1-phosphate can interact spontaneously with ATP resulting in a release of hydrogen ion, ADP and a ribose 1,5-biphosphate. Ribose 1,5-biphosphate is then phosphorylated through a ribose 1,5-bisphosphokinase resulting in the release of ADP and phosphoribosyl pyrophosphate. Phosphoribosyl pyrophosphate will then participate in the purine nucleotides de novo biosynthesis pathway. Alternatively pentose phosphate and D-ribose 5-phosphate's interaction can be phosphorylated through an ATP driven ribose-phosphate diphosphokinase resulting in a release of a hydrogen ion, an AMP and a phosphoribosyl pyrophosphate which will again participate in the purine nucleotides de novo biosynthesis pathway.