Pathways

Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency, Creatine Deficiency Syndrome, Creatine Deficiency due to AGAT Deficiency, GATM Deficiency) is caused by mutation in the GATM gene, which codes for L-arginine:glycine amidinotransferase, which catalyzes the reaction between L-arginine and glycine, transferring an amidino group from L-arginine to glycine, producing L-ornithine and guanidinoacetate, a precursor of creatine. A defect in this enzyme causes a decrease in concentration of creatine and guanidinoacetate in plasma and urine. Symptoms include mental and motor retardation, seizures, and delayed or abnormal speech development.

Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency, Creatine Deficiency Syndrome, Creatine Deficiency due to AGAT Deficiency, GATM Deficiency) is caused by mutation in the GATM gene, which codes for L-arginine:glycine amidinotransferase, which catalyzes the reaction between L-arginine and glycine, transferring an amidino group from L-arginine to glycine, producing L-ornithine and guanidinoacetate, a precursor of creatine. A defect in this enzyme causes a decrease in concentration of creatine and guanidinoacetate in plasma and urine. Symptoms include mental and motor retardation, seizures, and delayed or abnormal speech development.

The metabolism of L-arginine starts with the acetylation of L-glutamic acid resulting in a N-acetylglutamic acid while releasing a coenzyme A and a hydrogen ion. N-acetylglutamic acid is then phosphorylated via an ATP driven acetylglutamate kinase which yields a N-acetyl-L-glutamyl 5-phosphate. This compound undergoes a NDPH dependent reduction resulting in N-acetyl-L-glutamate 5-semialdehyde, which then reacts with L-glutamic acid through a acetylornithine aminotransferase / N-succinyldiaminopimelate aminotransferase to produce an N-acetylornithine. Next N-acetylornithine is deacetylated through a acetylornithine deacetylase yielding an ornithine. L-glutamine is used to synthesize carbamoyl phosphate through the interaction of L-glutamine, water, ATP, and hydrogen carbonate. This reaction yields ADP, L-glutamic acid, phosphate, and hydrogen ion. Carbamoyl phosphate and ornithine are used to catalyze the production of citrulline through an ornithine carbamoyltransferase. Citrulline reacts with L-aspartic acid through an ATP dependent enzyme, argininosuccinate synthase to produce pyrophosphate, AMP and argininosuccinic acid. Argininosussinic acid is then lyase to produce L-arginine and fumaric acid. L-arginine can be metabolized into succinic acid by two different sets of reactions: 1. Arginine reacts with succinyl-CoA through a arginine N-succinyltransferase resulting in N2-succinyl-L-arginine while releasing CoA and Hydrogen Ion. N2-succinyl-L-arginine is then dihydrolase to produce a N2-succinyl-L-ornithine through a N-succinylarginine dihydrolase which in turn reacts with oxoglutaric acid through succinylornithine transaminase resulting in L-glutamic acid and N2-succinyl-L-glutamic acid 5-semialdehyde. Next N2-succinyl-L-glutamic acid 5-semialdehyde reacts with a NAD dependent dehydrogenase resulting in N2-succinylglutamate and releases NADH and hydrogen ion. Finally, N2-succinylglutamate reacts with water through a succinylglutamate desuccinylase resulting in L-glutamic acid and a succinic acid. The succinic acid is then incorporated in the TCA cycle 2. Argine reacts with carbon dioxide and a hydrogen ion through a biodegradative arginine decarboxylase, resulting in Agmatine. Agmatine is transformed into putrescine by reacting with water and an agmatinase, and releasing urea. Putrescine can be metabolized by reaction with either l-glutamic acid or oxoglutaric acid. If putrescine reacts with L-glutamic acid, it reacts through an ATP mediated gamma-glutamylputrescine producing a hydrogen ion, ADP, phosphate and gamma-glutamyl-L-putrescine. Gamma-glutamyl-L-putrescine is reduced via interactions with oxygen, water and a gamma-glutamylputrescine oxidoreductase resulting in ammonium, hydrogen peroxide and 4-gamma-glutamylamino butanal. Dehydrogenated through a NADP mediated reaction lead by gamma-glutamyl-gamma-aminobutaryaldehyde dehydrogenase, 4-gamma-glutamylamino butanal is converted into hydrogen ions, NADPH and 4-glutamylamino butanoate. In turn, the latter compound reacts with water through a gamma-glutamyl-gamma-aminobutyrate hydrolase resulting in L-glutamic acid and Gamma aminobutyric acid. On the other hand, if putrescine reacts with oxoglutaric acid through a putrescine aminotransferase, it results in L-glutamic acid, and a 4-aminobutyraldehyde, which continues and reacts with water through a NAD dependent gamma aminobutyraldehyde dehydrogenase resulting in hydrogen ion, NADH and gamma-aminobutyric acid. Gamma Aaminobutyric acid reacts with oxoglutaric acid through 4-aminobutyrate aminotransferase resulting in L-glutamic acid and succinic acid semialdehyde. Succinic acid semialdehyde then reacts with either NADP or NAD to produce succinic acid through succinate-semialdehyde dehydrogenase or aldehyde dehydrogenase-like protein yneI respectively. Succinic acid can then be integrated in the TCA cycle.

The metabolism of arginine begins like glutamic acid reacting with acetyl-CoA through a amino-acid acetyltransferase resulting in the release of coenzyme A, hydrogen ion and a N-acetyl-L-glutamate. The latter reacts with an ATP through acetylglutamate kinase resulting in the release of ADP and N-acetylglutamyl-phosphate. The latter then reacts with an NADPH and a Hydrogen ion through a n-acetyl-gamma-glutamyl-phosphate reductase resulting in the release of phosphate, NADP and N-acetyl-L-glutamate 5-semialdehyde. The latter compound reacts with L-glutamate through an acetylornithine transaminase resulting in the release of oxoglutaric acid and N-acetyl-L-ornithine. The latter reacts with Water through a acetylornithine deacetylase resulting in the release of acetate and L-ornithine. Ornithine can also be produced by the acetyl cycle. The acetyl cycle starts with N-acetylglutamic acid being phosphorylated through an acetylglutamate kinase resulting in the release of ADP and N-acetylglutamyl-phosphate. The latter compound reacts with NADPH and a hydrogen ion through a N-acetyl-gamma-glutamyl-phosphate reductase resulting in the release of a phosphate, NADP and N-acetyl-L-glutamic 5-semialdehyde. The latter reacts with L-glutamate through an acetyl ornithine transaminase resulting in the release of oxoglutaric acid and N-acetylornithine. The latter compound reacts with L-glutamic acid resulting in the release of L-ornithine and N-acetylglutamate. The latter compound starts the cycle over again. Ornithine reacts with carbomoyl phosphate through an OTC resulting in the release of phosphate, hydrogen ion and L-citrulline. The latter compound reacts with ATP, and L-aspartate through a argininosuccinate synthase resulting in the release of AMP, diphosphate, hydrogen ion and L-arginino-succinate. The latter compound reacts with argininosuccinate lyase resulting in the release of fumarate and l-arginine. Arginine reacts with water through arginase resulting in the release of urea and l-ornithine. Ornithine reacts with oxoglutaric acid through an ornithine aminotransferase resulting in the release of glutamic acid and l-glutamate 5- semialdehyde which can spontaneously react to produce S-pyrroline-5-carboxylate. The latter reacts with pyrroline 5-carboxylate reductase resulting in the release of proline. Arginine eacts with water through arginase resulting in the release of urea and l-ornithine. Ornithine reacts with oxoglutaric acid through an ornithine aminotransferase resulting in the release of glutamic acid and l-glutamate 5- semialdehyde react with pyrroline 5 carboxylate dehydrogenase resulting in the release of glutamic acid.

The metabolism of L-arginine starts with the acetylation of L-glutamic acid resulting in a N-acetylglutamic acid while releasing a coenzyme A and a hydrogen ion. N-acetylglutamic acid is then phosphorylated via an ATP driven acetylglutamate kinase which yields a N-acetyl-L-glutamyl 5-phosphate. This compound undergoes a NDPH dependent reduction resulting in N-acetyl-L-glutamate 5-semialdehyde, which then reacts with L-glutamic acid through a acetylornithine aminotransferase / N-succinyldiaminopimelate aminotransferase to produce an N-acetylornithine. Next N-acetylornithine is deacetylated through a acetylornithine deacetylase yielding an ornithine. L-glutamine is used to synthesize carbamoyl phosphate through the interaction of L-glutamine, water, ATP, and hydrogen carbonate. This reaction yields ADP, L-glutamic acid, phosphate, and hydrogen ion. Carbamoyl phosphate and ornithine are used to catalyze the production of citrulline through an ornithine carbamoyltransferase. Citrulline reacts with L-aspartic acid through an ATP dependent enzyme, argininosuccinate synthase to produce pyrophosphate, AMP and argininosuccinic acid. Argininosussinic acid is then lyase to produce L-arginine and fumaric acid. L-arginine can be metabolized into succinic acid by two different sets of reactions: 1. Arginine reacts with succinyl-CoA through a arginine N-succinyltransferase resulting in N2-succinyl-L-arginine while releasing CoA and Hydrogen Ion. N2-succinyl-L-arginine is then dihydrolase to produce a N2-succinyl-L-ornithine through a N-succinylarginine dihydrolase which in turn reacts with oxoglutaric acid through succinylornithine transaminase resulting in L-glutamic acid and N2-succinyl-L-glutamic acid 5-semialdehyde. Next N2-succinyl-L-glutamic acid 5-semialdehyde reacts with a NAD dependent dehydrogenase resulting in N2-succinylglutamate and releases NADH and hydrogen ion. Finally, N2-succinylglutamate reacts with water through a succinylglutamate desuccinylase resulting in L-glutamic acid and a succinic acid. The succinic acid is then incorporated in the TCA cycle 2. Argine reacts with carbon dioxide and a hydrogen ion through a biodegradative arginine decarboxylase, resulting in Agmatine. Agmatine is transformed into putrescine by reacting with water and an agmatinase, and releasing urea. Putrescine can be metabolized by reaction with either l-glutamic acid or oxoglutaric acid. If putrescine reacts with L-glutamic acid, it reacts through an ATP mediated gamma-glutamylputrescine producing a hydrogen ion, ADP, phosphate and gamma-glutamyl-L-putrescine. Gamma-glutamyl-L-putrescine is reduced via interactions with oxygen, water and a gamma-glutamylputrescine oxidoreductase resulting in ammonium, hydrogen peroxide and 4-gamma-glutamylamino butanal. Dehydrogenated through a NADP mediated reaction lead by gamma-glutamyl-gamma-aminobutaryaldehyde dehydrogenase, 4-gamma-glutamylamino butanal is converted into hydrogen ions, NADPH and 4-glutamylamino butanoate. In turn, the latter compound reacts with water through a gamma-glutamyl-gamma-aminobutyrate hydrolase resulting in L-glutamic acid and Gamma aminobutyric acid. On the other hand, if putrescine reacts with oxoglutaric acid through a putrescine aminotransferase, it results in L-glutamic acid, and a 4-aminobutyraldehyde, which continues and reacts with water through a NAD dependent gamma aminobutyraldehyde dehydrogenase resulting in hydrogen ion, NADH and gamma-aminobutyric acid. Gamma Aaminobutyric acid reacts with oxoglutaric acid through 4-aminobutyrate aminotransferase resulting in L-glutamic acid and succinic acid semialdehyde. Succinic acid semialdehyde then reacts with either NADP or NAD to produce succinic acid through succinate-semialdehyde dehydrogenase or aldehyde dehydrogenase-like protein yneI respectively. Succinic acid can then be integrated in the TCA cycle.

Alanine is one of the 21 amino acids necessary for synthesis of proteins. To begin the synthesis of arginine, oxoglutaric acid is obtained from the citric acid cycle. The oxoglutaric acid is then either processed by aspartate aminotransferase in the mitochondrion, or alanine transaminase elsewhere in the cell, in order to produce L-glutamic acid. L-glutamic acid can then be convereted to N-acetyl-L-glutamic acid by an amino acid N-acetyltransferase, which is a potential end product for this pathway. Otherwise, it can be converted reversibly by a glutamate dehydrogenase into oxoglutaric acid once again, as well as ammonia, which then becomes the product of interest. Ammonia can be converted into L-glutamine by glutamine synthetase with the addition of L-glutamic acid, and L-glutamine can be converted back to ammonia by glutaminase a. Ammonia can also be converted into carbamoyl phosphate by carbamoyl-phosphate synthase 1 in the mitochondrion, and carbamoyl phosphate can both come from and be used in both nitrogen metabolism and pyrimidine metabolism. In addition to those, it can be converted, along with ornithine, by ornithine carbamoyltransferase, also in the mitochondrion, to citrulline. Citruline, along with L-aspartic acid from the aspartate metabolism pathway, are converted by argininosuccinate synthase to argininosuccinic acid. The argininosuccinic acid is then converted by argininosuccinate lyase to fumaric adic, and L-arginine, the main product of this pathway. The fumaric acid produced can be used in the citrate cycle, while the L-arginine can be used in arginine metabolism, or can be converted by arginase to both urea and ornithine. Urea is then moved through a urea transporter out of the cell and excreted, while ornithine is used in the previously mentioned reaction to produce citrulline. Finally citrulline can be directly converted to and from L-arginine by nitric oxide synthase, and L-arginine along with ornithine can be used in D-arginine and D-ornithine metabolism.

arginine

Alanine is one of the 21 amino acids necessary for synthesis of proteins. To begin the synthesis of arginine, oxoglutaric acid is obtained from the citric acid cycle. The oxoglutaric acid is then either processed by aspartate aminotransferase in the mitochondrion, or alanine transaminase elsewhere in the cell, in order to produce L-glutamic acid. L-glutamic acid can then be convereted to N-acetyl-L-glutamic acid by an amino acid N-acetyltransferase, which is a potential end product for this pathway. Otherwise, it can be converted reversibly by a glutamate dehydrogenase into oxoglutaric acid once again, as well as ammonia, which then becomes the product of interest. Ammonia can be converted into L-glutamine by glutamine synthetase with the addition of L-glutamic acid, and L-glutamine can be converted back to ammonia by glutaminase a. Ammonia can also be converted into carbamoyl phosphate by carbamoyl-phosphate synthase 1 in the mitochondrion, and carbamoyl phosphate can both come from and be used in both nitrogen metabolism and pyrimidine metabolism. In addition to those, it can be converted, along with ornithine, by ornithine carbamoyltransferase, also in the mitochondrion, to citrulline. Citruline, along with L-aspartic acid from the aspartate metabolism pathway, are converted by argininosuccinate synthase to argininosuccinic acid. The argininosuccinic acid is then converted by argininosuccinate lyase to fumaric adic, and L-arginine, the main product of this pathway. The fumaric acid produced can be used in the citrate cycle, while the L-arginine can be used in arginine metabolism, or can be converted by arginase to both urea and ornithine. Urea is then moved through a urea transporter out of the cell and excreted, while ornithine is used in the previously mentioned reaction to produce citrulline. Finally citrulline can be directly converted to and from L-arginine by nitric oxide synthase, and L-arginine along with ornithine can be used in D-arginine and D-ornithine metabolism.

The arginine and proline metabolism pathway illustrates the biosynthesis and metabolism of several amino acids including arginine, ornithine, proline, citrulline, and glutamate in mammals. In adult mammals, the synthesis of arginine takes place primarily through the intestinal-renal axis (PMID: 19030957). In particular, the amino acid citrulline is first synthesized from several other amino acids (glutamine, glutamate, and proline) in the mitochondria of the intestinal enterocytes (PMID: 9806879). The mitochondrial synthesis of citrulline starts with the deamination of glutamine to glutamate via mitochondrial glutaminase. The resulting mitochondrial glutamate is converted into 1-pyrroline-5-carboxylate via pyrroline-5-carboxylate synthase (P5CS). Alternately, the 1-pyrroline-5-carboxylate can be generated from mitochondrial proline via proline oxidase (PO). Ornithine aminotransferase (OAT) then converts the mitochondrial 1-pyrroline-5-carboxylate into ornithine and the enzyme ornithine carbamoyltransferase (OCT -- using carbamoyl phosphate) converts the ornithine to citrulline (PMID: 19030957). After this, the mitochondrial citrulline is released from the small intestine enterocytes and into the bloodstream where it is taken up by the kidneys for arginine production. Once the citrulline enters the kidney cells, the cytosolic enzyme argininosuccinate synthetase (ASS) will combine citrulline with aspartic acid to generate argininosuccinic acid. After this step, the enzyme argininosuccinate lyase (ASL) will remove fumarate from argininosuccinic acid to generate arginine. The resulting arginine can either stay in the cytosol where it is converted to ornithine via arginase I (resulting in the production of urea) or it can be transported into the mitochondria where it is decomposed into ornithine and urea via arginase II. The resulting mitochondrial ornithine can then be acted on by the enzyme ornithine amino transferase (OAT), which combines alpha-ketoglutarate with ornithine to produce glutamate and 1-pyrroline-5-carboxylate. The mitochondrial enzyme pyrroline-5-carboxylate dehydrogenase (P5CD) acts on the resulting 1-pyrroline-5-carboxylate (using NADPH as a cofactor) to generate glutamate. Alternately, the mitochondrial 1-pyrroline-5-carboxylate can be exported into the kidney cell’s cytosol where the enzyme pyrroline-5-carboxylate reductase (P5CR) can convert it to proline. While citrulline-to-arginine production primarily occurs in the kidney, citrulline is readily converted into arginine in other cell types, including adipocytes, endothelial cells, myocytes, macrophages, and neurons. Interestingly, chickens and cats cannot produce citrulline via glutamine/glutamate due to a lack of a functional pyrroline-5-carboxylate synthase (P5CS) in their enterocytes (PMID: 19030957).