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.

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 thiamin begins with a PRPP being degraded by reacting with a water molecule and an L-glutamine through a amidophosphoribosyl transferase resulting in the release of an L-glutamate, a diphosphate and a 5-phospho-beta-d-ribosylamine(PRA). The latter compound, PRA, is further degrade through a phosphoribosylamine glycine ligase by reacting with a glycine and an ATP. This reaction results in the release of a hydrogen ion, an ADP, a phosphate and a N1-(5-phospho-beta-d-ribosyl)glycinamide(GAR). GAR can be metabolized by two different phosphoribosylglycinamide formyltransferase. GAR reacts with a N10-formyl tetrahydrofolate, in this case 10-formyl-tetrahydrofolate mono-L-glutamate, through a phosphoribosylglycinamide formyltransferase 1 resulting in the release of a hydroge ion, a tetrahydrofolate and a N2-formyl-N1-(5-phospho-Beta-D-ribosyl)glycinamide(FGAR). On the other hand, GAR can react with a formate and an ATP molecule through a phosphoribosylglycinamide formyltransferase 2 resulting in a release of a ADP, a phosphate, a hydrogen ion and a FGAR. The FGAR compound gets degraded by interacting with a water molecule, an L-glutamine and an ATP molecule thorugh a phosphoribosylformylglycinamide synthase resulting in the release of a L-glutamate, a phosphate, an ADP molecule, a hydrogen ion and a 2-(formamido)-N1-(5-phopho-Beta-D-ribosyl)acetamidine (FGAM). This compound is further degraded by reacting with an ATP molecule through a phosphoribosylformylglycinamide cyclo-ligase resulting in the release of a phosphate, an ADP, a hydrogen ion and a 5-amino-1-(5-phospho-beta-d-ribosyl)imidazole (AIR). The AIR molecule is degraded by reacting with a S-adenosyl-L-methionine through a HMP-P synthase resulting in the release of 3 hydrogen ions, a carbon monoxide, a formate molecule, L-methionine, 5'-deoxyadenosine and 4- amino-2-methyl-5-phophomethylpyrimidine (HMP-P). This resulting compound is phosphorylated thorugh a ATP driven phosphohydroxymethylpyrimidine kinase resulting in the release of an ADP and 4-amino-2-methyl-5-diphosphomethylpyrimidine (HMP-PP). The resulting compound interacts with a thiazole tautomer and 2 hydrogen ion through a Thiamine phosphate synthase resulting in the release of a pyrophosphate, a carbon dioxide molecule and Thiamin phosphate. This compound is phosphorylated through an ATP driven thiamin monophosphate kinase resulting in a release of an ADP and a thiamin diphosphate.

The biosynthesis of thiamin begins with a PRPP being degraded by reacting with a water molecule and an L-glutamine through a amidophosphoribosyl transferase resulting in the release of an L-glutamate, a diphosphate and a 5-phospho-beta-d-ribosylamine(PRA). The latter compound, PRA, is further degrade through a phosphoribosylamine glycine ligase by reacting with a glycine and an ATP. This reaction results in the release of a hydrogen ion, an ADP, a phosphate and a N1-(5-phospho-beta-d-ribosyl)glycinamide(GAR). GAR can be metabolized by two different phosphoribosylglycinamide formyltransferase. GAR reacts with a N10-formyl tetrahydrofolate, in this case 10-formyl-tetrahydrofolate mono-L-glutamate, through a phosphoribosylglycinamide formyltransferase 1 resulting in the release of a hydroge ion, a tetrahydrofolate and a N2-formyl-N1-(5-phospho-Beta-D-ribosyl)glycinamide(FGAR). On the other hand, GAR can react with a formate and an ATP molecule through a phosphoribosylglycinamide formyltransferase 2 resulting in a release of a ADP, a phosphate, a hydrogen ion and a FGAR. The FGAR compound gets degraded by interacting with a water molecule, an L-glutamine and an ATP molecule thorugh a phosphoribosylformylglycinamide synthase resulting in the release of a L-glutamate, a phosphate, an ADP molecule, a hydrogen ion and a 2-(formamido)-N1-(5-phopho-Beta-D-ribosyl)acetamidine (FGAM). This compound is further degraded by reacting with an ATP molecule through a phosphoribosylformylglycinamide cyclo-ligase resulting in the release of a phosphate, an ADP, a hydrogen ion and a 5-amino-1-(5-phospho-beta-d-ribosyl)imidazole (AIR). The AIR molecule is degraded by reacting with a S-adenosyl-L-methionine through a HMP-P synthase resulting in the release of 3 hydrogen ions, a carbon monoxide, a formate molecule, L-methionine, 5'-deoxyadenosine and 4- amino-2-methyl-5-phophomethylpyrimidine (HMP-P). This resulting compound is phosphorylated thorugh a ATP driven phosphohydroxymethylpyrimidine kinase resulting in the release of an ADP and 4-amino-2-methyl-5-diphosphomethylpyrimidine (HMP-PP). The resulting compound interacts with a thiazole tautomer and 2 hydrogen ion through a Thiamine phosphate synthase resulting in the release of a pyrophosphate, a carbon dioxide molecule and Thiamin phosphate. This compound is phosphorylated through an ATP driven thiamin monophosphate kinase resulting in a release of an ADP and a thiamin diphosphate.

This pathway demonstrate the biosynthesis of thiazole moiety in E.coli K-12 strain and Salmonella enterica serovar Typhimurium. L-Tyrosine is generated from tyrosine biosynthesis. With S-Adenosylmethionine and NADPH, L-Tyrosine can be catalyzed into four different small molecules: 4-methylcatechol, dehydroglycine, 5'-deoxyadenosine and L-methionine as well as NADP by dehydroglycine synthase (encoded by thiH gene). Meanwhile, 1-deoxyxylulose-5-phosphate synthase (encoded by dxs gene) catalyzes pyruvic acid and D-Glyceraldehyde 3-phosphate into 1-Deoxy-D-xylulose 5-phosphate. The final reaction of the pathway is facilitated by thiazole synthase (encoded by thiG and thiH), which require a thiocarboxy-[ThiS-Protein], 1-deoxy-D-xylulose 5-phosphate and 2-iminoacetate to form 2-((2R,5Z)-2-Carboxy-4-methylthiazol-5(2H)-ylidene)ethyl phosphate for Thiamin Diphosphate Biosynthesis, as well as a ThiS sulfur-carrier protein and water.

Aminopropylcadaverine, a polyamine, is the final product of aminopropylcadaverine biosynthesis pathway. Polyamines are involved in protein synthesis, DNA and RNA related processes, as well as the facilitation of cell stress resistance and membrane integrity; therefore polyamines are essential for cell growth. In this pathway, L-lysine is produced by lysine biosynthesis, then lysine decarboxylase will convert L-lysine into cadaverine. In the final step, spermidine synthase will catalyze cadaverine and decarboxy-SAM to aminopropylcadaverine as well as 5'-Methylthioadenosine.

The degradation of N-acetylneuraminate begins with its incorporation into the cytosol through a hydrogen symporter. Once inside the cytosol it is degraded by a N-acetylneuraminate lyase resulting in a release of a pyruvic acid and N-acetymannosamine. The latter compound is phosphorylated by an ATP driven N-Acetylmannosamine kinase resulting in the release of an ADP, a hydrogen ion and a N-Acetyl-D-mannosamine 6-phosphate. This phosphorylated compound is then metabolized by a putative N-acetylmannosamine-6-phosphate 2-epimerase resulting in the release of a N-Acetyl-D-glucosamine 6-phosphate. This compound is then deacetylated through a N-acetylglucosamine-6-phosphate deacetylase resulting in the release of an Acetic acid and a glucosamine 6-phosphate This compound can then be deaminated through a glucosamine-6-phosphate deaminase resulting in the release of an ammonium and a beta-D-fructofuranose 6-phosphate which can then be incorporated into the glycolysis pathway.

Aminopropylcadaverine, a polyamine, is the final product of aminopropylcadaverine biosynthesis pathway. Polyamines are involved in protein synthesis, DNA and RNA related processes, as well as the facilitation of cell stress resistance and membrane integrity; therefore polyamines are essential for cell growth. In this pathway, L-lysine is produced by lysine biosynthesis, then lysine decarboxylase will convert L-lysine into cadaverine. In the final step, spermidine synthase will catalyze cadaverine and decarboxy-SAM to aminopropylcadaverine as well as 5'-Methylthioadenosine.

The biosynthesis of thiamin begins with a PRPP being degraded by reacting with a water molecule and an L-glutamine through a amidophosphoribosyl transferase resulting in the release of an L-glutamate, a diphosphate and a 5-phospho-beta-d-ribosylamine(PRA). The latter compound, PRA, is further degrade through a phosphoribosylamine glycine ligase by reacting with a glycine and an ATP. This reaction results in the release of a hydrogen ion, an ADP, a phosphate and a N1-(5-phospho-beta-d-ribosyl)glycinamide(GAR). GAR can be metabolized by two different phosphoribosylglycinamide formyltransferase. GAR reacts with a N10-formyl tetrahydrofolate, in this case 10-formyl-tetrahydrofolate mono-L-glutamate, through a phosphoribosylglycinamide formyltransferase 1 resulting in the release of a hydroge ion, a tetrahydrofolate and a N2-formyl-N1-(5-phospho-Beta-D-ribosyl)glycinamide(FGAR). On the other hand, GAR can react with a formate and an ATP molecule through a phosphoribosylglycinamide formyltransferase 2 resulting in a release of a ADP, a phosphate, a hydrogen ion and a FGAR. The FGAR compound gets degraded by interacting with a water molecule, an L-glutamine and an ATP molecule thorugh a phosphoribosylformylglycinamide synthase resulting in the release of a L-glutamate, a phosphate, an ADP molecule, a hydrogen ion and a 2-(formamido)-N1-(5-phopho-Beta-D-ribosyl)acetamidine (FGAM). This compound is further degraded by reacting with an ATP molecule through a phosphoribosylformylglycinamide cyclo-ligase resulting in the release of a phosphate, an ADP, a hydrogen ion and a 5-amino-1-(5-phospho-beta-d-ribosyl)imidazole (AIR). The AIR molecule is degraded by reacting with a S-adenosyl-L-methionine through a HMP-P synthase resulting in the release of 3 hydrogen ions, a carbon monoxide, a formate molecule, L-methionine, 5'-deoxyadenosine and 4- amino-2-methyl-5-phophomethylpyrimidine (HMP-P). This resulting compound is phosphorylated thorugh a ATP driven phosphohydroxymethylpyrimidine kinase resulting in the release of an ADP and 4-amino-2-methyl-5-diphosphomethylpyrimidine (HMP-PP). The resulting compound interacts with a thiazole tautomer and 2 hydrogen ion through a Thiamine phosphate synthase resulting in the release of a pyrophosphate, a carbon dioxide molecule and Thiamin phosphate. This compound is phosphorylated through an ATP driven thiamin monophosphate kinase resulting in a release of an ADP and a thiamin diphosphate.

This pathway demonstrate the biosynthesis of thiazole moiety in E.coli K-12 strain and Salmonella enterica serovar Typhimurium. L-Tyrosine is generated from tyrosine biosynthesis. With S-Adenosylmethionine and NADPH, L-Tyrosine can be catalyzed into four different small molecules: 4-methylcatechol, dehydroglycine, 5'-deoxyadenosine and L-methionine as well as NADP by dehydroglycine synthase (encoded by thiH gene). Meanwhile, 1-deoxyxylulose-5-phosphate synthase (encoded by dxs gene) catalyzes pyruvic acid and D-Glyceraldehyde 3-phosphate into 1-Deoxy-D-xylulose 5-phosphate. The final reaction of the pathway is facilitated by thiazole synthase (encoded by thiG and thiH), which require a thiocarboxy-[ThiS-Protein], 1-deoxy-D-xylulose 5-phosphate and 2-iminoacetate to form 2-((2R,5Z)-2-Carboxy-4-methylthiazol-5(2H)-ylidene)ethyl phosphate for Thiamin Diphosphate Biosynthesis, as well as a ThiS sulfur-carrier protein and water.