This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: L-citrulline-NO cycle, nitric oxide biosynthesis II
|Superclasses:||Biosynthesis → Amino Acids Biosynthesis → Proteinogenic Amino Acids Biosynthesis → L-arginine Biosynthesis|
|Biosynthesis → Metabolic Regulators Biosynthesis → Nitric Oxide Biosynthesis|
|Degradation/Utilization/Assimilation → Amino Acids Degradation → Proteinogenic Amino Acids Degradation → L-arginine Degradation|
Some taxa known to possess this pathway include : Homo sapiens
Expected Taxonomic Range: Metazoa
Nitric oxide (NO) plays an important role in cell signaling in the nervous system, and is implicated in synaptic plasticity. It also participates in the immunologic response to infection. In the vasculature NO relaxes smooth muscle and inhibits platelet and leukocyte adhesion.
NO is synthesized from arginine by nitric oxide synthase (NOS), generating L-citrulline as a by-product. NO production is absolutely dependent on arginine availability. Arginine can be provided either by exogenous sources (via blood circulation) or by the citrulline-NO cycle. In this cycle, arginine is used by NOS forming NO and citrulline, and then regenerated from citrulline by the combined action of the enzymes argininosuccinate synthase and argininosuccinate lyase.
The citrulline-NO cycle functions in many different types of cells. It has been demonstrated in endothelial cells [Hecker90], macrophages [Wu92a], and the peripheral nervous system, including canine enteric neurons [Shuttleworth95], opossum internal anal sphincter [Rattan97] and canine esophageal sphincter [Salapatek98].
The different enzymes of this cycle are coregulated. Coregulation of iNOS and argininosuccinate synthase has been shown in activated murine macrophage-like cells [Nussler94], in vascular smooth muscle cells [Hattori94], in in vivo-activated rat and mouse macrophages [Nagasaki96, Salimuddin99], and in rodent and human pancreatic β-cells [Flodstrom95]. In addition, a coinduction of iNOS, argininosuccinate synthase and argininosuccinate lyase has been demonstrated PC12 cells [Zhang00a].
Superpathways: superpathway of L-citrulline metabolism
Variants: L-arginine biosynthesis I (via L-ornithine), L-arginine biosynthesis II (acetyl cycle), L-arginine biosynthesis III (via N-acetyl-L-citrulline), L-arginine biosynthesis IV (archaebacteria), L-arginine degradation I (arginase pathway), L-arginine degradation II (AST pathway), L-arginine degradation III (arginine decarboxylase/agmatinase pathway), L-arginine degradation IV (arginine decarboxylase/agmatine deiminase pathway), L-arginine degradation V (arginine deiminase pathway), L-arginine degradation VI (arginase 2 pathway), L-arginine degradation VII (arginase 3 pathway), L-arginine degradation VIII (arginine oxidase pathway), L-arginine degradation IX (arginine:pyruvate transaminase pathway), L-arginine degradation X (arginine monooxygenase pathway), L-arginine degradation XI, L-arginine degradation XII, nitric oxide biosynthesis (plants), superpathway of L-arginine and L-ornithine degradation, superpathway of L-arginine, putrescine, and 4-aminobutanoate degradation
Flodstrom95: Flodstrom M, Niemann A, Bedoya FJ, Morris SM, Eizirik DL (1995). "Expression of the citrulline-nitric oxide cycle in rodent and human pancreatic beta-cells: induction of argininosuccinate synthetase by cytokines." Endocrinology 136(8);3200-6. PMID: 7628352
Hattori94: Hattori Y, Campbell EB, Gross SS (1994). "Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle. Role in the regeneration or arginine for nitric oxide synthesis." J Biol Chem 269(13);9405-8. PMID: 7511585
Hecker90: Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR (1990). "The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine." Proc Natl Acad Sci U S A 87(21);8612-6. PMID: 2236071
Nagasaki96: Nagasaki A, Gotoh T, Takeya M, Yu Y, Takiguchi M, Matsuzaki H, Takatsuki K, Mori M (1996). "Coinduction of nitric oxide synthase, argininosuccinate synthetase, and argininosuccinate lyase in lipopolysaccharide-treated rats. RNA blot, immunoblot, and immunohistochemical analyses." J Biol Chem 271(5);2658-62. PMID: 8576237
Nussler94: Nussler AK, Billiar TR, Liu ZZ, Morris SM (1994). "Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line. Implications for regulation of nitric oxide production." J Biol Chem 269(2);1257-61. PMID: 7507106
Rattan97: Rattan S, Chakder S (1997). "L-citrulline recycling in opossum internal anal sphincter relaxation by nonadrenergic, noncholinergic nerve stimulation." Gastroenterology 112(4);1250-9. PMID: 9098009
Salapatek98: Salapatek AM, Wang YF, Mao YK, Mori M, Daniel EE (1998). "Myogenic NOS in canine lower esophageal sphincter: enzyme activation, substrate recycling, and product actions." Am J Physiol 274(4 Pt 1);C1145-57. PMID: 9575812
Salimuddin99: Salimuddin , Nagasaki A, Gotoh T, Isobe H, Mori M (1999). "Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide." Am J Physiol 277(1 Pt 1);E110-7. PMID: 10409134
Shuttleworth95: Shuttleworth CW, Burns AJ, Ward SM, O'Brien WE, Sanders KM (1995). "Recycling of L-citrulline to sustain nitric oxide-dependent enteric neurotransmission." Neuroscience 68(4);1295-304. PMID: 8545001
Zhang00a: Zhang WY, Gotoh T, Oyadomari S, Mori M (2000). "Coinduction of inducible nitric oxide synthase and arginine recycling enzymes in cytokine-stimulated PC12 cells and high output production of nitric oxide." Brain Res Mol Brain Res 83(1-2);1-8. PMID: 11072090
Bhaumik04: Bhaumik P, Koski MK, Bergmann U, Wierenga RK (2004). "Structure determination and refinement at 2.44 A resolution of argininosuccinate lyase from Escherichia coli." Acta Crystallogr D Biol Crystallogr 60(Pt 11);1964-70. PMID: 15502303
BSUB93: "Bacillus subtilis and Other Gram-Positive Bacteria: Biochemistry, Physiology, and Molecular Genetics." (1993). Editors: Sonenshein, A.L., Hoch, J.A., Losick, R. American Society For Microbiology, Washington, DC.
Calaycay96: Calaycay JR, Kelly TM, MacNaul KL, McCauley ED, Qi H, Grant SK, Griffin PR, Klatt T, Raju SM, Nussler AK, Shah S, Weidner JR, Williams HR, Wolfe GC, Geller DA, Billiar TR, MacCoss M, Mumford RA, Tocci MJ, Schmidt JA, Wong KK, Hutchinson NI (1996). "Expression and immunoaffinity purification of human inducible nitric-oxide synthase. Inhibition studies with 2-amino-5,6-dihydro-4H-1,3-thiazine." J Biol Chem 271(45);28212-9. PMID: 8910438
Forstermann94: Forstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H (1994). "Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions." Hypertension 23(6 Pt 2);1121-31. PMID: 7515853
Garvey94: Garvey EP, Tuttle JV, Covington K, Merrill BM, Wood ER, Baylis SA, Charles IG (1994). "Purification and characterization of the constitutive nitric oxide synthase from human placenta." Arch Biochem Biophys 311(2);235-41. PMID: 7515611
Geller93: Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR (1993). "Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes." Proc Natl Acad Sci U S A 90(8);3491-5. PMID: 7682706
Hall94: Hall AV, Antoniou H, Wang Y, Cheung AH, Arbus AM, Olson SL, Lu WC, Kau CL, Marsden PA (1994). "Structural organization of the human neuronal nitric oxide synthase gene (NOS1)." J Biol Chem 269(52);33082-90. PMID: 7528745
Husson03: Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A (2003). "Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle." Eur J Biochem 270(9);1887-99. PMID: 12709047
Janssens92: Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD (1992). "Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase." J Biol Chem 267(21);14519-22. PMID: 1378832
Jin11: Jin CW, Du ST, Shamsi IH, Luo BF, Lin XY (2011). "NO synthase-generated NO acts downstream of auxin in regulating Fe-deficiency-induced root branching that enhances Fe-deficiency tolerance in tomato plants." J Exp Bot 62(11);3875-84. PMID: 21511908
Jinno85: Jinno Y, Nomiyama H, Matuo S, Shimada K, Matsuda I, Saheki T (1985). "Structure of the 5' end region of the human argininosuccinate synthetase gene." J Inherit Metab Dis 8(3);157-9. PMID: 3027451
Karlberg08: Karlberg T, Collins R, van den Berg S, Flores A, Hammarstrom M, Hogbom M, Holmberg Schiavone L, Uppenberg J (2008). "Structure of human argininosuccinate synthetase." Acta Crystallogr D Biol Crystallogr 64(Pt 3);279-86. PMID: 18323623
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