View source for Citrulline

{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 443676645
| ImageFile = L-Citrullin2.svg
| ImageSize = 230
| ImageFile_Ref = {{chemboximage|correct|??}}
| ImageFile1 = L-Citrulline zwitterion ball from xtal.png
| ImageSize1 = 230
| ImageName1 = Ball and stick model of zwitterionic citrulline
| IUPACName = 2-Amino-5-(carbamoylamino)pentanoic acid<ref>{{cite web|title=Citrulline - Compound Summary|url=https://pubchem.ncbi.nlm.nih.gov/compound/833|work=PubChem Compound|publisher=National Center for Biotechnology Information|access-date=1 May 2012|location=USA|date=16 September 2004|at=Identification}}</ref>
|Section1={{Chembox Identifiers
| CASNo = 627-77-0
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo1 = 13594-51-9
| CASNo1_Ref = {{cascite|correct|CAS}}
| CASNo1_Comment = (<small>''D''</small>)
| CASNo2 = 372-75-8
| CASNo2_Ref = {{cascite|correct|CAS}}
| CASNo2_Comment = (<small>''L''</small>)
| PubChem = 833
| PubChem1 = 637599
| PubChem1_Comment = <small>''D''</small>
| PubChem2 = 9750
| PubChem2_Comment = <small>''L''</small>
| ChemSpiderID = 810
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID1 = 553200
| ChemSpiderID1_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID1_Comment = <small>''D''</small>
| ChemSpiderID2 = 9367
| ChemSpiderID2_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID2_Comment = <small>''L''</small>

| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1OYO2NV4NM
| UNII1_Ref = {{fdacite|correct|FDA}}
| UNII1 = KNS2VUH6P2
| UNII1_Comment = (''D'')
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = 29VT07BGDA
| UNII2_Comment = (''L'')

| EINECS = 211-012-2
| DrugBank = DB00155
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| KEGG = D07706
| KEGG_Ref = {{keggcite|correct|kegg}}
| MeSHName = Citrulline
| ChEBI = 18211
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 444814
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| IUPHAR_ligand = 722
| Beilstein = 1725417, 1725415 <small>''D''</small>, 1725416 <small>''L''</small>
| Gmelin = 774677 <small>''L''</small>
| 3DMet = B01217
| SMILES = NC(CCCNC(N)=O)C(O)=O
| StdInChI = 1S/C6H13N3O3/c7-4(5(10)11)2-1-3-9-6(8)12/h4H,1-3,7H2,(H,10,11)(H3,8,9,12)
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = RHGKLRLOHDJJDR-UHFFFAOYSA-N
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
}}
|Section2={{Chembox Properties
| C=6 | H=13 | N=3 | O=3 
| Appearance = White crystals
| Odor = Odourless
| LogP = −1.373
| pKa = 2.508
| pKb = 11.489
}}
|Section3={{Chembox Thermochemistry
| Entropy = 254.4 J K<sup>−1</sup> mol<sup>−1</sup>
| HeatCapacity = 232.80 J K<sup>−1</sup> mol<sup>−1</sup>
}}
|Section4={{Chembox Related
| OtherFunction_label = alkanoic acids
| OtherFunction = {{unbulleted list|[[n-Acetylaspartic acid|''N''-Acetylaspartic acid]]|[[Aceglutamide]]|[[n-Acetylglutamic acid|''N''-Acetylglutamic acid]]|[[Pivagabine]]}}
| OtherCompounds = {{unbulleted list|[[Bromisoval]]|[[Carbromal]]}}
}}
}}
The [[organic compound]] '''citrulline''' is an α-[[amino acid]].<ref name=":0">{{Citation|last=Banerjee|first=Aryamitra|title=Chapter 15 - Gastrointestinal toxicity biomarkers|date=2014-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780124046306000154|work=Biomarkers in Toxicology|pages=269–277|editor-last=Gupta|editor-first=Ramesh C.|place=Boston|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-404630-6.00015-4|isbn=978-0-12-404630-6|s2cid=88798984 |access-date=2020-11-10|url-access=subscription}}</ref> Its name is derived from ''[[citrullus]]'', the [[Latin]] word for [[watermelon]]. Although named and described by [[gastroenterology|gastroenterologists]] since the late 19th century, it was first isolated from watermelon in 1914 by [[Japan]]ese researchers Yatarō Koga (古賀彌太郎) and Ryō Ōtake (大嶽了)<ref name="Koga1914">{{cite journal
 | last1 = Koga
 | first1 = Yatarō
 | last2 = Ōtake
 | first2 = Ryō
 | title = Study report on the constituents of squeezed watermelon
 | journal = Tokyo Kagaku Kaishi [Journal of the Tokyo Chemical Society]
 | volume = 35
 | number = 5
 | pages = 519–528
 | doi = 10.1246/nikkashi1880.35.519
 | year = 1914
| doi-access = free
 }}</ref><ref name="Fragkos2011">{{cite journal
 |last1 = Fragkos
 |first1 = Konstantinos C.
 |last2 = Forbes
 |first2 = Alastair
 | title = Was citrulline first a laxative substance? The truth about modern citrulline and its isolation
 | journal = Nihon Ishigaku Zasshi [Journal of the Japanese Society for the History of Medicine]
 | volume = 57
 | number = 3
 | pages = 275–292
 | url = http://jshm.or.jp/journal/57-3/57-3_275.pdf
 | pmid = 22397107
 | year = 2011
}}</ref> and further codified by Mitsunori Wada of [[Tokyo Imperial University]] in 1930.<ref name="Wada1930a">{{cite journal
 | last = Wada
 | first = Mitsunori
 | title = On the occurrence of a new amino acid in watermelon. Citrullus vulgaris, Schrad.
 | journal = Proceedings of the Imperial Academy
 | volume = 6
 | number = 1
 | pages = 15–17
 | doi = 10.2183/pjab1912.6.15
 | year = 1930
| doi-access = free
 }}</ref><ref name="Wada1930b">{{cite journal
 | last = Wada
 | first = Mitsunori
 | title = On the occurrence of a new amino acid in watermelon, Citrullus vulgaris, Schrad.
 | journal = Bulletin of the Agricultural Chemical Society of Japan
 | volume = 6
 | number = 1–5
 | pages = 32–34
 | doi = 10.1271/bbb1924.6.32
 | year = 1930
| doi-access = free
 }}</ref><ref name="Wada1930c">{{cite journal
 | author = Wada, Mitsunori
 | title = Über Citrullin, eine neue Aminosäure im Preßsaft der Wassermelone, Citrullus vulgaris, Schrad.
 | journal = Biochemische Zeitschrift
 | volume = 224
 | pages = 420–429
 | year = 1930
 | language = de
}}</ref>
It has the [[chemical formula|formula]] H<sub>2</sub>NC(O)NH(CH<sub>2</sub>)<sub>3</sub>CH(NH<sub>2</sub>)CO<sub>2</sub>H.  It is a key intermediate in the [[urea cycle]], the pathway by which mammals excrete [[ammonia]] by converting it into [[urea]]. Citrulline is also produced as a byproduct of the [[enzyme|enzymatic]] production of [[nitric oxide]] from the amino acid [[arginine]], catalyzed by [[nitric oxide synthase]].<ref>{{cite web|title=Nos2 - Nitric Oxide Synthase|url=https://www.uniprot.org/uniprot/P29477|website=Uniprot.org|publisher=Uniprot Consortium|access-date=10 February 2015}}</ref>

==Biosynthesis==
Citrulline can be derived from:
* from arginine via [[nitric oxide synthase]], as a byproduct of the production of nitric oxide for [[Second messenger system|signaling]] purposes
* from [[ornithine]] through the breakdown of [[proline]] or [[glutamine]]/[[glutamate]]
* from [[asymmetric dimethylarginine]] via DDAH

Citrulline is made from [[ornithine]] and [[carbamoyl phosphate]] in one of the central reactions in the urea cycle. It is also produced from [[arginine]] as a byproduct of the reaction catalyzed by [[nitric oxide synthase|NOS]] family (NOS; [https://enzyme.expasy.org/EC/1.14.13.39 EC 1.14.13.39]).<ref>{{cite book |vauthors=Cox M, Lehninger AL, Nelson DR |title=Lehninger principles of biochemistry |publisher=Worth Publishers |location=New York |year=2000 |page= [https://archive.org/details/lehningerprincip01lehn/page/449 449] |isbn=978-1-57259-153-0 |edition=3rd |access-date= 13 March 2020 |url=https://archive.org/details/lehningerprincip01lehn }}</ref> It is also prevalent in [[TCHH|trichohyalin]] at the inner root [[Root sheath (hair)|sheath]] and medulla of hair follicles, where it is synthesized from arginine.<ref>{{Cite journal 
| last1 = Rogers | first1 = G. E. 
| last2 = Rothnagel | first2 = J. A. 
| title = A sensitive assay for the enzyme activity in hair follicles and epidermis that catalyses the peptidyl-arginine-citrulline post-translational modification 
| journal = Current Problems in Dermatology 
| volume = 11 
| pages = 171–184 
| year = 1983 
| pmid = 6653155
| doi = 10.1159/000408673 
| isbn = 978-3-8055-3752-0 
}}</ref> [[Arginine]] is first oxidized into ''N''-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide.

Citrulline is also made by [[enterocytes]] of the small intestine.<ref name=":0" /><ref>{{Citation|last=DeLegge|first=Mark H.|title=Chapter 7 - Enteral Access and Enteral Nutrition in Patients With Short Bowel Syndrome|date=2019-01-01|url=http://www.sciencedirect.com/science/article/pii/B978012814330800007X|work=Adult Short Bowel Syndrome|pages=81–96|editor-last=Corrigan|editor-first=Mandy L.|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-814330-8.00007-x|isbn=978-0-12-814330-8|s2cid=81295089|access-date=2020-11-10|editor2-last=Roberts|editor2-first=Kristen|editor3-last=Steiger|editor3-first=Ezra|url-access=subscription}}</ref>

==Function==
Citrulline is a metabolic intermediate within the [[urea cycle]], which is the pathway by which mammals excrete ammonia by converting it into urea. Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase. In the yeast species Saccharomyces cerevisiae, citrulline is a metabolic intermediate in the latter, cytosolic half of the arginine biosynthesis pathway.<ref>{{cite web | url=https://pathway.yeastgenome.org/YEAST/new-image?object=CITRUL-BIO2-PWY | title=Saccharomyces cerevisiae citrulline biosynthesis }}</ref>

Several proteins contain citrulline as a result of a [[post-translational modification]]. These citrulline residues are generated by a family of enzymes called [[peptidylarginine deiminase]]s (PADs), which convert arginine into citrulline in a process called [[citrullination]] or deimination with the help of calcium ions. Proteins that normally contain citrulline residues include [[myelin basic protein]] (MBP), [[filaggrin]], and several [[histone]] proteins, whereas other proteins, such as [[fibrin]] and [[vimentin]] are susceptible to citrullination during cell death and tissue [[inflammation]].

Circulating citrulline concentration is a [[biomarker]] of intestinal functionality.<ref>{{Cite journal|last1=Fragkos|first1=Konstantinos C.|last2=Forbes|first2=Alastair|date=2017-10-12|title=Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis|journal=United European Gastroenterology Journal|volume=6|issue=2|pages=181–191|language=en|doi=10.1177/2050640617737632|pmid=29511548|pmc=5833233}}</ref><ref>{{cite journal | last1 = Crenn | first1 = P. | display-authors = etal   | year = 2000 | title = Post-absorptive plasma citrulline concentration is a marker of intestinal failure in short bowel syndrome patients | journal = Gastroenterology | volume = 119 | issue = 6| pages = 1496–505 | doi=10.1053/gast.2000.20227| pmid = 11113071 | doi-access = free }}</ref>

==Commercial use==
L-citrulline is sold as a [[dietary supplement]], usually in powder form. Advocates suggest that since L-citrulline boosts nitric oxide production, helping arterial function and thus blood flow throughout the body, this might be helpful in treating or preventing various ailments. 
*Lowering [[blood pressure]] in people with elevated blood pressure.<ref>{{cite journal | pmc=6369322 | date=2019 | last1=Barkhidarian | first1=B. | last2=Khorshidi | first2=M. | last3=Shab-Bidar | first3=S. | last4=Hashemi | first4=B. | title=Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysis | journal=Avicenna Journal of Phytomedicine | volume=9 | issue=1 | pages=10–20 | pmid=30788274 }}</ref>
*Easing symptoms of mild-to-moderate [[erectile dysfunction]], with fewer risks than [[Viagra]].
*Ameliorating circulatory problems such as slow wound healing due to [[diabetes]].
*Raising muscle protein levels, preventing malnourishment in the elderly and possibly improving athletic performance.
*Treating intestinal problems, including [[short bowel syndrome]], [[celiac disease]] and radiation-caused [[small bowel]] damage
*Various genetic disorders and health conditions such as liver disease, [[Parkinson's disease]] and certain [[dementia]]s.

Some of these assertions are based on animal studies, and like most dietary supplement claims have not been endorsed by the [[Food and Drugs Administration]].<ref>{{cite web |last1=Miller |first1=Kelli |title=L-citrulline |url=https://www.webmd.com/vitamins-and-supplements/l-citrulline-uses-and-risks |website=WebMD |publisher=WebMD LLC |access-date=16 December 2024}}</ref>

L-citrulline is added to certain [[energy drink]]s such as [[Reign (drink)|Reign]] and touted for its [[thermogenics|thermogenic]] effects.<ref>Label on Reign Inferno Watermelon Overlord can; Reign Beverage Company: Los Angeles, 2020</ref>

==See also==
* [[Citrullinemia]]

==References==
{{reflist|20em}}

{{Non-proteinogenic amino acids}}
{{Amino acid metabolism intermediates}}

[[Category:Alpha-Amino acids]]
[[Category:Ureas]]
[[Category:Urea cycle]]
[[Category:Non-proteinogenic amino acids]]
[[Category:Biomarkers]]