Pathways

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).

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).

Arginine and proline metabolism demonstrates the co-metabolism of arginine, ornithine, proline, citrulline and glutamate in mitochondria. Argininosuccinate synthase catalyzes citrulline into argininosuccinic acid with ATP and L-Aspartic acid. Argininosuccinic acid is cleaved by argininosuccinate lyase to generate L-arginine (arginine), which also generated fumaric acid for citric acid cycle. Citrulline can be generated from ornithine by the ornithine carbamoyltransferase at mitochondria; and ornithine can be generated by series of metabolism that is associated with proline dehydrogenase 1 (with cofactor FAD) and pyrroline-5-carboxylate reductase 2 at mitochondria. Proline is derived from L-glutamatic acid with conversion of L-glutamatic acid to 1-pyrroline-5-carboxylic acid by delta-1-pyrroline-5-carboxylate dehydrogenase and NAD; then 1-pyrroline-5-carboxylic acid can converted to L-proline via proline dehydrogenase 1 with cofactor FAD.

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).

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).

Argatroban is a synthetic derivate of L-arginine and a direct thrombin inhibitor anticoagulant prescribed to patients with heparin-induced thrombocytopenia. Direct thrombin inhibitors bind plasma and fibrin bound thrombin independently of co-factor antithrombin.The inhibition of thrombin reduces the stability of the clot and promotes clot break down. Argatroban does not effect serine proteases like, trypsin, factor Xa, plasmin, and kallikrein. Argatroban is advantageous, particularly for renal failure patients, due to its short-half life and hepatic clearance.