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MetaCyc Pathway: L-citrulline-nitric oxide cycle
Inferred from experiment

Pathway diagram: L-citrulline-nitric oxide cycle

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: BiosynthesisAmino Acids BiosynthesisProteinogenic Amino Acids BiosynthesisL-arginine Biosynthesis
BiosynthesisMetabolic Regulators BiosynthesisNitric Oxide Biosynthesis
Degradation/Utilization/AssimilationAmino Acids DegradationProteinogenic Amino Acids DegradationL-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

Created 28-Sep-2005 by Caspi R, SRI International


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

Wu92a: Wu GY, Brosnan JT (1992). "Macrophages can convert citrulline into arginine." Biochem J 281 ( Pt 1);45-8. PMID: 1731766

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

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

Bock83: Bock HG, Su TS, O'Brien WE, Beaudet AL (1983). "Sequence for human argininosuccinate synthetase cDNA." Nucleic Acids Res 11(18);6505-12. PMID: 6194510

Bredt90: Bredt DS, Snyder SH (1990). "Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme." Proc Natl Acad Sci U S A 87(2);682-5. PMID: 1689048

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

Curis05: Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Benazeth S, Cynober L (2005). "Almost all about citrulline in mammals." Amino Acids NIL. PMID: 16082501

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

Hsia74: Hsia YE (1974). "Inherited hyperammonemic syndromes." Gastroenterology 67(2);347-74. PMID: 4368001

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

Kimball80: Kimball ME, Jacoby LB (1980). "Purification and properties of argininosuccinate synthetase from normal and canavanine-resistant human lymphoblasts." Biochemistry 19(4);705-9. PMID: 6766737

Kwon89: Kwon NS, Nathan CF, Stuehr DJ (1989). "Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages." J Biol Chem 264(34);20496-501. PMID: 2584226

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Nakane93: Nakane M, Schmidt HH, Pollock JS, Forstermann U, Murad F (1993). "Cloned human brain nitric oxide synthase is highly expressed in skeletal muscle." FEBS Lett 316(2);175-80. PMID: 7678401

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Wed May 4, 2016, biocyc13.