MetaCyc Pathway: L-citrulline biosynthesis
Traceable author statement to experimental support

Pathway diagram: L-citrulline biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: BiosynthesisAmino Acids BiosynthesisOther Amino Acid BiosynthesisL-citrulline Biosynthesis

Some taxa known to possess this pathway include : Bos taurus, Homo sapiens, Mus musculus, Rattus norvegicus

Expected Taxonomic Range: Mammalia

General Background

L-citrulline is a non-standard amino acid that is not normally incorporated into proteins during protein synthesis. The name citrulline was coined in 1930 from Citrullus, the Latin name of the watermelon, from which it was first isolated. Free citrulline is formed mainly by catabolism of amino acids in the small intestine, as an intermediate in the conversion of ammonia to urea in the urea cycle, and as a by-product during the production of nitric oxide (see L-citrulline-nitric oxide cycle). In addition, citrulline is also formed by modification of arginine residues in proteins (see protein citrullination).

About This Pathway

Most of the citrulline circulating in the blood of mammals comes from glutamine conversion in enterocytes, the intetsinal absorptive cells found in the mucosa of the small intestine. Several other amino acids can also act as citrulline precursors, including glutamate, proline, and arginine. In rats, 28% of these metabolized amino acids are converted into citrulline. Two glutamate molecules are required for the synthesis of each citrulline molecule, only one of which can be substituted by another amino acid.

The citrulline that is formed in the intestinal mucosa enters the blood stream, and reaches the kidneys, where it is converted into arginine (see superpathway of L-citrulline metabolism). In adults, this citrulline to arginine conversion provides the body's full arginine requirements [Curis05]. About 83% of the citrulline released from the intestine is metabolized by the kidneys [Windmueller81], and the rest is used for nitric acid production within other tissues.

In newborn mammals, which have a much larger need for arginine, proline is the main source of citrulline synthesis in the gut [Dillon99]. In addition, in new borns conversion of citrulline to arginine is not limited to the kidneys, and occurs in the intestinal mucosa as well.

Inhibition of intestinal citrulline synthesis causes severe growth retardation [Hoogenraad85].

Superpathways: superpathway of L-citrulline metabolism

Created 29-Sep-2005 by Caspi R, SRI International


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

Dillon99: Dillon EL, Knabe DA, Wu G (1999). "Lactate inhibits citrulline and arginine synthesis from proline in pig enterocytes." Am J Physiol 276(5 Pt 1);G1079-86. PMID: 10329997

Hoogenraad85: Hoogenraad N, Totino N, Elmer H, Wraight C, Alewood P, Johns RB (1985). "Inhibition of intestinal citrulline synthesis causes severe growth retardation in rats." Am J Physiol 249(6 Pt 1);G792-9. PMID: 4083357

Windmueller81: Windmueller HG, Spaeth AE (1981). "Source and fate of circulating citrulline." Am J Physiol 241(6);E473-80. PMID: 7325229

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

Aledo00: Aledo JC, Gomez-Fabre PM, Olalla L, Marquez J (2000). "Identification of two human glutaminase loci and tissue-specific expression of the two related genes." Mamm Genome 11(12);1107-10. PMID: 11130979

Aral96: Aral B, Schlenzig JS, Liu G, Kamoun P (1996). "Database cloning human delta 1-pyrroline-5-carboxylate synthetase (P5CS) cDNA: a bifunctional enzyme catalyzing the first 2 steps in proline biosynthesis." C R Acad Sci III 319(3);171-8. PMID: 8761662

Baich69: Baich A (1969). "Proline synthesis in Escherichia coli. A proline-inhibitable glutamic acid kinase." Biochim Biophys Acta 1969;192(3);462-7. PMID: 4904678

Baich71: Baich A (1971). "The biosynthesis of proline in Escherichia coli: phosphate-dependent glutamate -semialdehyde dehydrogenase (NADP), the second enzyme in the pathway." Biochim Biophys Acta 244(1);129-34. PMID: 4399189

Bairoch93a: Bairoch A, Boeckmann B (1993). "The SWISS-PROT protein sequence data bank, recent developments." Nucleic Acids Res. 21:3093-3096. PMID: 8332529

Barrett87: Barrett DJ, Bateman JB, Sparkes RS, Mohandas T, Klisak I, Inana G (1987). "Chromosomal localization of human ornithine aminotransferase gene sequences to 10q26 and Xp11.2." Invest Ophthalmol Vis Sci 28(7);1037-42. PMID: 3596985

Baumgartner00: Baumgartner MR, Hu CA, Almashanu S, Steel G, Obie C, Aral B, Rabier D, Kamoun P, Saudubray JM, Valle D (2000). "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase." Hum Mol Genet 9(19);2853-8. PMID: 11092761

Baumgartner05: Baumgartner MR, Rabier D, Nassogne MC, Dufier JL, Padovani JP, Kamoun P, Valle D, Saudubray JM (2005). "Delta1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline." Eur J Pediatr 164(1);31-6. PMID: 15517380

Baur90: Baur H, Tricot C, Stalon V, Haas D (1990). "Converting catabolic ornithine carbamoyltransferase to an anabolic enzyme." J Biol Chem 265(25);14728-31. PMID: 2118516

Bender05: Bender HU, Almashanu S, Steel G, Hu CA, Lin WW, Willis A, Pulver A, Valle D (2005). "Functional consequences of PRODH missense mutations." Am J Hum Genet 76(3);409-20. PMID: 15662599

Bicknell08: Bicknell LS, Pitt J, Aftimos S, Ramadas R, Maw MA, Robertson SP (2008). "A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome." Eur J Hum Genet 16(10);1176-86. PMID: 18478038

Brandriss79: Brandriss MC, Magasanik B (1979). "Genetics and physiology of proline utilization in Saccharomyces cerevisiae: enzyme induction by proline." J Bacteriol 1979;140(2);498-503. PMID: 387737

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Brown08: Brown G, Singer A, Proudfoot M, Skarina T, Kim Y, Chang C, Dementieva I, Kuznetsova E, Gonzalez CF, Joachimiak A, Savchenko A, Yakunin AF (2008). "Functional and structural characterization of four glutaminases from Escherichia coli and Bacillus subtilis." Biochemistry 47(21);5724-35. PMID: 18459799

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.

Cama03: Cama E, Colleluori DM, Emig FA, Shin H, Kim SW, Kim NN, Traish AM, Ash DE, Christianson DW (2003). "Human arginase II: crystal structure and physiological role in male and female sexual arousal." Biochemistry 42(28);8445-51. PMID: 12859189

Campbell97: Campbell HD, Webb GC, Young IG (1997). "A human homologue of the Drosophila melanogaster sluggish-A (proline oxidase) gene maps to 22q11.2, and is a candidate gene for type-I hyperprolinaemia." Hum Genet 101(1);69-74. PMID: 9385373

Canas08: Canas RA, Villalobos DP, Diaz-Moreno SM, Canovas FM, Canton FR (2008). "Molecular and functional analyses support a role of Ornithine-{delta}-aminotransferase in the provision of glutamate for glutamine biosynthesis during pine germination." Plant Physiol 148(1);77-88. PMID: 18621980

Cederbaum04: Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK (2004). "Arginases I and II: do their functions overlap?." Mol Genet Metab 81 Suppl 1;S38-44. PMID: 15050972

Chen04: Chen H, McCaig BC, Melotto M, He SY, Howe GA (2004). "Regulation of plant arginase by wounding, jasmonate, and the phytotoxin coronatine." J Biol Chem 279(44);45998-6007. PMID: 15322128

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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
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