If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Amino Acids Biosynthesis → Other Amino Acid Biosynthesis → L-citrulline Biosynthesis|
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 (see L-citrulline biosynthesis), 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
Free citrulline metabolism involves three key enzymes: nitric oxide synthase (NOS, EC 220.127.116.11), which catalyzes the production of nitric oxide from arginine, generating citrulline as a by-product, ornithine carbamoyltransferase (OCT, EC 18.104.22.168), which produces citrulline by condensing carbamoyl phosphate and L-ornithine, and argininosuccinate synthase (ASS, EC 22.214.171.124), which converts citrulline into argininosuccinate.
The tissue distribution of these enzymes results in three orthogonal metabolic routes for citrulline in mammals, all of which are depicted in this pathway:
1. In the liver, citrulline is locally synthesized by the combined action of arginase 1, ammonia-dependent carbamoyl-phosphate synthase and ornithine carbamoyltransferase, and metabolized by argininosuccinate synthase and argininosuccinate lyase back to arginine. The main purpose of this cycle is the production of urea, and it is described in greater detail in the pathway urea cycle.
2. In most of the tissues producing NO, citrulline is generated from arginine in a single step by NOS, and then recycled back into arginine via argininosuccinate synthase and argininosuccinate lyase. The main purpose of this cycle is the production of NO, and it is described in greater detail in the pathway L-citrulline-nitric oxide cycle.
3. In the gut citrulline is synthesized from glutamine and other amino acids (such as proline) by the combined action of many enzymes, including glutaminase, kidney isoform, δ-1-pyrroline-5-carboxylate synthase, mitochondrial proline dehydrogenase 1, ornithine aminotransferase and ornithine carbamoyltransferase. Citrulline is then released into the blood, and converted back into arginine in the kidneys by argininosuccinate synthase and argininosuccinate lyase. The main purpose of this pathway is the transport of arginine in the blood, avoiding captation by the liver, and it is described in the pathway L-citrulline biosynthesis.
Citrulline has long been administered in the treatment of inherited urea cycle disorders, and recent studies suggest that it may be used to control the production of NO.
In plants, citrulline has additional roles. It has been shown that in drought-tolerant wild watermelon leaves citrulline functions both as a compatible solute and ahydroxyl radical scavenger [Akashi01, Yokota02].
Unification Links: AraCyc:PWY-5004
Akashi01: Akashi K, Miyake C, Yokota A (2001). "Citrulline, a novel compatible solute in drought-tolerant wild watermelon leaves, is an efficient hydroxyl radical scavenger." FEBS Lett 508(3);438-42. PMID: 11728468
Yokota02: Yokota A, Kawasaki S, Iwano M, Nakamura C, Miyake C, Akashi K (2002). "Citrulline and DRIP-1 protein (ArgE homologue) in drought tolerance of wild watermelon." Ann Bot (Lond) 89 Spec No;825-32. PMID: 12102508
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
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
Barrett87a: 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
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
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
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
Brown59: Brown, G.W., Cohen, P.P. (1959). "Comparative biochemistry of urea synthesis. I. Methods for the quantitative assay of urea cycle enzymes in liver." J Biol Chem 234(7);1769-74. PMID: 13672961
Brown59a: Brown, G.W., Brown, W.R., Cohen, P.P. (1959). "Comparative biochemistry of urea synthesis. II. Levels of urea cycle enzymes in metamorphosing Rana catesbeiana tadpoles." J Biol Chem 234(7);1775-80. PMID: 13672962
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
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