Citrulline (T3D4295)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (13)XML
Targets (13)
Record Information
Version2.0
Creation Date2014-08-29 06:16:39 UTC
Update Date2014-12-24 20:26:45 UTC
Accession NumberT3D4295
Identification
Common NameCitrulline
ClassSmall Molecule
DescriptionCitrulline is an amino acid. It 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 by-product of the reaction catalyzed by NOS family. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated.
Compound Type
  • Amide
  • Amine
  • Animal Toxin
  • Dietary Supplement
  • Drug
  • Food Toxin
  • Metabolite
  • Micronutrient
  • Natural Compound
  • Non-Essential Amino Acid
  • Nutraceutical
  • Organic Compound
  • Supplement
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
(2S)-2-amino-5-(carbamoylamino)pentanoate
(2S)-2-amino-5-(carbamoylamino)pentanoic acid
(S)-2-amino-5-(aminocarbonyl)aminopentanoate
(S)-2-amino-5-(aminocarbonyl)aminopentanoic acid
(S)-2-Amino-5-ureidopentanoate
(S)-2-Amino-5-ureidopentanoic acid
2-Amino-5-uredovalerate
2-Amino-5-uredovaleric acid
2-Amino-5-ureidovalerate
2-Amino-5-ureidovaleric acid
A-Amino-D-ureidovalerate
A-Amino-D-ureidovaleric acid
alpha-Amino-delta-ureidovalerate
alpha-Amino-delta-ureidovaleric acid
alpha-Amino-gamma-ureidovalerate
alpha-Amino-gamma-ureidovaleric acid
Amino-ureidovalerate
Amino-ureidovaleric acid
CIR
CIT
Cytrulline
D-Ureidonorvaline
delta-Ureidonorvaline
DL-citrulline
Gammaureidonorvaline
H-Cit-oh
L(+)-2-Amino-5-ureidovalerate
L(+)-2-Amino-5-ureidovaleric acid
L(+)-Citrulline
L-2-Amino-5-ureido-valerate
L-2-Amino-5-ureido-valeric acid
L-2-Amino-5-ureidovalerate
L-2-Amino-5-ureidovaleric acid
L-Citrulline
L-Cytrulline
L-N5-carbamoyl-Ornithine
N()-Carbamylornithine
N(5)-(Aminocarbonyl)-DL-Ornithine
N(5)-(Aminocarbonyl)-L-ornithine
N(delta)-Carbamylornithine
N-Carbamylornithine
N5-(Aminocarbonyl)-L-ornithine
N5-(aminocarbonyl)-Ornithine
N5-(Aminocarbonyl)ornithine
N5-Carbamoyl-L-ornithine
N5-carbamoylornithine
N5-carbamylornithine
N<SUP>5</SUP>-(aminocarbonyl)ornithine
ND-carbamylornithine
Ndelta-carbamy-ornithine
Ndelta-carbamylornithine
Ngamma-carbamylornithine
Sitrulline
Ureidonorvaline
Ureidovalerate
Ureidovaleric acid
α-amino-δ-ureidovaleric acid
δ-ureidonorvaline
Chemical FormulaC6H13N3O3
Average Molecular Mass175.186 g/mol
Monoisotopic Mass175.096 g/mol
CAS Registry Number372-75-8
IUPAC Name(2S)-2-amino-5-(carbamoylamino)pentanoic acid
Traditional NameL-citrulline
SMILES[H][C@](N)(CCCNC(O)=N)C(O)=O
InChI IdentifierInChI=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)/t4-/m0/s1
InChI KeyInChIKey=RHGKLRLOHDJJDR-BYPYZUCNSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as l-alpha-amino acids. These are alpha amino acids which have the L-configuration of the alpha-carbon atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentL-alpha-amino acids
Alternative Parents
Substituents
  • L-alpha-amino acid
  • Fatty acid
  • Isourea
  • Amino acid
  • Carboximidic acid derivative
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Carboximidamide
  • Amine
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxide
  • Primary aliphatic amine
  • Organopnictogen compound
  • Imine
  • Organic oxygen compound
  • Organic nitrogen compound
  • Carbonyl group
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Membrane
  • Mitochondria
Biofluid LocationsNot Available
Tissue Locations
  • Bladder
  • Epidermis
  • Fibroblasts
  • Intestine
  • Kidney
  • Liver
  • Myelin
  • Nerve Cells
  • Neuron
  • Placenta
  • Platelet
  • Prostate
Pathways
NameSMPDB LinkKEGG Link
Arginine and Proline MetabolismSMP00020 map00330
Aspartate MetabolismSMP00067 map00250
Urea CycleSMP00059 Not Available
Argininosuccinic AciduriaSMP00003 Not Available
Citrullinemia Type ISMP00001 Not Available
Pyruvate Carboxylase DeficiencySMP00350 Not Available
Saccharopinuria/Hyperlysinemia IISMP00239 Not Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point235.5°C
Boiling PointNot Available
Solubility200 g/L (at 20°C)
LogP-3.19
Predicted Properties
PropertyValueSource
Water Solubility21.8 g/LALOGPS
logP-3.3ALOGPS
logP-3.9ChemAxon
logS-0.9ALOGPS
pKa (Strongest Acidic)2.27ChemAxon
pKa (Strongest Basic)9.23ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area118.44 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity41.33 m³·mol⁻¹ChemAxon
Polarizability17.35 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-0a4i-0920000000-2d92b63cd5d9648023b82014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-MS (3 TMS)splash10-00di-9610000000-2e7cd23afc2adcef35a32014-06-16View Spectrum
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0a4i-0920000000-2d92b63cd5d9648023b82017-09-12View Spectrum
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-00di-9610000000-2e7cd23afc2adcef35a32017-09-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-007o-9100000000-1f8dd2c6648b104639c72016-09-22View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-00dl-9410000000-37909012a777213f85662017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, PositiveNot Available2021-11-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_3) - 70eV, PositiveNot Available2021-11-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_4) - 70eV, PositiveNot Available2021-11-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, PositiveNot Available2021-11-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_2) - 70eV, PositiveNot Available2021-11-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_3) - 70eV, PositiveNot Available2021-11-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_4) - 70eV, PositiveNot Available2021-11-06View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0a4i-0900000000-4c1d7af748a47e4899492012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-00di-9000000000-988fced362fc0da157c92012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-00di-9000000000-0818e0e8bcee126924982012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-004j-0900000000-5fa8a338dcd2f2a6bdd22012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-004i-0900000000-16763200aa07f7629ad42012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-03di-3900000000-d9cfc5187aa799f6f9782012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-0a4i-0900000000-10ee9a593e13550bec1c2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-004i-0900000000-45d272576af34c9512a32012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-014i-3900000000-6177a284fdea5a3f13062012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-0a4i-0900000000-d9456d45e2dbd7a3df102012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Positivesplash10-004i-0900000000-ada57cdc73bda93be4832012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Negativesplash10-008a-0904000000-23fbe48f82e515087d682012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Negativesplash10-03di-5900000000-78afcbaf8b8b3eabf1742012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Negativesplash10-001i-0900000000-8fb191d4c20fd54b92822012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , Negativesplash10-00di-0900000000-da484f0362a8dca5127e2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negativesplash10-00e9-0900000000-46229b4f77feabb3f8572012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negativesplash10-001i-0900000000-4aca1022c393602a297d2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negativesplash10-001i-0900000000-3bc2eff2e907b7734cc82012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negativesplash10-001i-3900000000-2613bf40e3be814da86f2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negativesplash10-0006-9300000000-e83287bbc060eb9cf6f32012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Positivesplash10-056r-0900000000-694a8872bdfd7eec1f2b2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Positivesplash10-08fr-2900000000-15b4711991ea9985fb2b2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Positivesplash10-00di-9300000000-915fbb73e0b728420e4a2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Positivesplash10-00di-9000000000-67e60567f5c0627283502012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Positivesplash10-00di-9000000000-25140713431edd7c5eea2012-08-31View Spectrum
1D NMR13C NMR Spectrum (1D, 125 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
1D NMR1H NMR Spectrum (1D, D2O, experimental)Not Available2016-10-22View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-24View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, H2O, experimental)Not Available2021-10-10View Spectrum
2D NMR[1H, 1H]-TOCSY. Unexported temporarily by An Chi on Oct 15, 2021 until json or nmrML file is generated. 2D NMR Spectrum (experimental)Not Available2012-12-04View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, H2O, experimental)Not Available2012-12-05View Spectrum
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityL-citrulline is converted to L-arginine by argininosuccinate synthase. L-arginine is in turn responsible for citrulline's therapeutic affects. Many of L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3',5' -cyclic guanylate or cyclic GMP. NO activates the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. Cyclic GMP is converted to guanylic acid via the enzyme cyclic GMP phosphodiesterase.

NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The form of NOS induced by immunological or inflammatory stimuli is known as iNOS. iNOS may be expressed constitutively in select tissues such as lung epithelium.

All the nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O2) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin. eNOS and nNOS synthesize NO in response to an increased concentration of calcium ions or in some cases in response to calcium-independent stimuli, such as shear stress. In vitro studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate. In other words, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid would make any difference with regard to NO production. The reaction would appear to have reached its maximum level. However, in vivo studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, L-arginine could enhance endothelial-dependent vasodilation and NO production.
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed for nutritional supplementation, also for treating dietary shortage or imbalance.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00155
HMDB IDHMDB00904
PubChem Compound ID9750
ChEMBL IDCHEMBL444814
ChemSpider ID9367
KEGG IDC00327
UniProt IDNot Available
OMIM ID
ChEBI ID16349
BioCyc IDL-CITRULLINE
CTD IDNot Available
Stitch IDNot Available
PDB IDCIR
ACToR IDNot Available
Wikipedia LinkCitrulline
References
Synthesis Reference

Hua Bai, Peijie Yang, Zhengjie Chen, Chongyan Xu, Zhaorul Li, Zigang Zhao, Luyan Jiang, Zongyi Yang, Jiang Li, “PROCESSES FOR THE PRODUCTION OF L-CITRULLINE.” U.S. Patent US20090142813, issued June 04, 2009.

MSDSLink
General References
  1. DeLong GR, Glick TH: Ammonia metabolism in Reye syndrome and the effect of citrulline. Ann Neurol. 1982 Jan;11(1):53-8. [7059128 ]
  2. Jianfeng G, Weiming Z, Ning L, Fangnan L, Li T, Nan L, Jieshou L: Serum citrulline is a simple quantitative marker for small intestinal enterocytes mass and absorption function in short bowel patients. J Surg Res. 2005 Aug;127(2):177-82. [15921697 ]
  3. Cynober LA: Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition. 2002 Sep;18(9):761-6. [12297216 ]
  4. Liappis N, Pohl B, Weber HP, el-Karkani H: [Free amino acids in the saliva of children with phenylketonuria]. Klin Padiatr. 1986 Jan-Feb;198(1):25-8. [3959486 ]
  5. Rainesalo S, Keranen T, Palmio J, Peltola J, Oja SS, Saransaari P: Plasma and cerebrospinal fluid amino acids in epileptic patients. Neurochem Res. 2004 Jan;29(1):319-24. [14992292 ]
  6. Fleisher LD, Harris CJ, Mitchell DA, Nadler HL: Citrullinemia: prenatal diagnosis of an affected fetus. Am J Hum Genet. 1983 Jan;35(1):85-90. [6823975 ]
  7. Potter MA, Zeesman S, Brennan B, Kobayashi K, Gao HZ, Tabata A, Saheki T, Whelan DT: Pregnancy in a healthy woman with untreated citrullinemia. Am J Med Genet A. 2004 Aug 15;129A(1):77-82. [15266621 ]
  8. Wheatley DN, Kilfeather R, Stitt A, Campbell E: Integrity and stability of the citrulline-arginine pathway in normal and tumour cell lines. Cancer Lett. 2005 Sep 28;227(2):141-52. [16112417 ]
  9. Melis GC, Boelens PG, van der Sijp JR, Popovici T, De Bandt JP, Cynober L, van Leeuwen PA: The feeding route (enteral or parenteral) affects the plasma response of the dipetide Ala-Gln and the amino acids glutamine, citrulline and arginine, with the administration of Ala-Gln in preoperative patients. Br J Nutr. 2005 Jul;94(1):19-26. [16115328 ]
  10. Reparon-Schuijt CC, van Esch WJ, van Kooten C, Schellekens GA, de Jong BA, van Venrooij WJ, Breedveld FC, Verweij CL: Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum. 2001 Jan;44(1):41-7. [11212174 ]
  11. Maruyama H, Ogawa M, Nishio T, Kobayashi K, Saheki T, Sunohara N: Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels. J Neurol Sci. 2001 Jan 1;182(2):167-70. [11137523 ]
  12. McLaurin J, Moscarello MA: The preparation of antibodies reactive against citrulline-containing charge isomers of myelin basic protein but not against the arginine-containing charge isomers. Anal Biochem. 1990 Dec;191(2):272-7. [1707596 ]
  13. Facchinetti F, Longo M, Piccinini F, Neri I, Volpe A: L-arginine infusion reduces blood pressure in preeclamptic women through nitric oxide release. J Soc Gynecol Investig. 1999 Jul-Aug;6(4):202-7. [10486782 ]
  14. Origuchi Y, Ushijima T, Sakaguchi M, Akaboshi I, Matsuda I: Citrullinemia presenting as uncontrollable epilepsy. Brain Dev. 1984;6(3):328-31. [6486381 ]
  15. Booth FA, Haworth JC, Dilling LA, Perry TL, Greenberg CR, Seargeant LE, Penn AM, Rhead WJ: Mitochondrial encephalomyopathy with associated aminoacidopathy in a male sibship. J Pediatr. 1989 Jul;115(1):81-8. [2738799 ]
  16. Engelborghs S, Marescau B, De Deyn PP: Amino acids and biogenic amines in cerebrospinal fluid of patients with Parkinson's disease. Neurochem Res. 2003 Aug;28(8):1145-50. [12834252 ]
  17. Le Boucher J, Charret C, Coudray-Lucas C, Giboudeau J, Cynober L: Amino acid determination in biological fluids by automated ion-exchange chromatography: performance of Hitachi L-8500A. Clin Chem. 1997 Aug;43(8 Pt 1):1421-8. [9267323 ]
  18. Crenn P, Coudray-Lucas C, Thuillier F, Cynober L, Messing B: Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology. 2000 Dec;119(6):1496-505. [11113071 ]
  19. Hagenfeldt L, Bjerkenstedt L, Edman G, Sedvall G, Wiesel FA: Amino acids in plasma and CSF and monoamine metabolites in CSF: interrelationship in healthy subjects. J Neurochem. 1984 Mar;42(3):833-7. [6198473 ]
  20. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4. doi: 10.1038/nature07762. [19212411 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Argininosuccinate synthase
General Function:
Toxic substance binding
Specific Function:
Is indirectly involved in the control of blood pressure.
Gene Name:
ASS1
Uniprot ID:
P00966
Molecular Weight:
46530.055 Da
References
  1. Braissant O, Honegger P, Loup M, Iwase K, Takiguchi M, Bachmann C: Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate lyase genes in aggregating cell cultures of fetal rat brain. Neurosci Lett. 1999 May 7;266(2):89-92. [10353334 ]
  2. Braissant O, Gotoh T, Loup M, Mori M, Bachmann C: L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an in situ hybridization study. Brain Res Mol Brain Res. 1999 Jul 5;70(2):231-41. [10407171 ]
  3. Keilhoff G, Reiser M, Stanarius A, Aoki E, Wolf G: Citrulline immunohistochemistry for demonstration of NOS activity in vivo and in vitro. Nitric Oxide. 2000 Aug;4(4):343-53. [10944418 ]
  4. Zhang B, Cao GL, Domachowske J, Jackson MJ, Porasuphatana S, Rosen GM: Stable expression of varied levels of inducible nitric oxide synthase in primary cultures of endothelial cells. Anal Biochem. 2000 Nov 15;286(2):198-205. [11067741 ]
  5. Zhang WY, Gotoh T, Oyadomari S, Mori M: 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. 2000 Nov 10;83(1-2):1-8. [11072090 ]
Target Details
2. Argininosuccinate synthetase, isoform CRA_a
General Function:
Toxic substance binding
Specific Function:
Not Available
Gene Name:
ASS
Uniprot ID:
Q5T6L4
Molecular Weight:
46530.055 Da
References
  1. Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A: Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. Eur J Biochem. 2003 May;270(9):1887-99. [12709047 ]
  2. Hammermann R, Bliesener N, Mossner J, Klasen S, Wiesinger H, Wessler I, Racke K: Inability of rat alveolar macrophages to recycle L-citrulline to L-arginine despite induction of argininosuccinate synthetase mRNA and protein, and inhibition of nitric oxide synthesis by exogenous L-citrulline. Naunyn Schmiedebergs Arch Pharmacol. 1998 Dec;358(6):601-7. [9879717 ]
  3. Van Geldre LA, Timmermans JP, Lefebvre RA: L-citrulline recycling by argininosuccinate synthetase and lyase in rat gastric fundus. Eur J Pharmacol. 2002 Nov 29;455(2-3):149-60. [12445581 ]
  4. Zandvliet MM, Rothuizen J: Transient hyperammonemia due to urea cycle enzyme deficiency in Irish wolfhounds. J Vet Intern Med. 2007 Mar-Apr;21(2):215-8. [17427379 ]
  5. Takahashi H, Kagawa T, Kobayashi K, Hirabayashi H, Yui M, Begum L, Mine T, Takagi S, Saheki T, Shinohara Y: A case of adult-onset type II citrullinemia--deterioration of clinical course after infusion of hyperosmotic and high sugar solutions. Med Sci Monit. 2006 Feb;12(2):CS13-5. Epub 2006 Jan 26. [16449956 ]
Target Details
3. Nitric oxide synthase, brain
General Function:
Tetrahydrobiopterin binding
Specific Function:
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.
Gene Name:
NOS1
Uniprot ID:
P29475
Molecular Weight:
160969.095 Da
References
  1. Kominami S, Yamazaki T, Koga T, Hori H: EPR studies on the photo-induced intermediates of ferric NO complexes of rat neuronal nitric oxide synthase trapped at low temperature. J Biochem. 1999 Oct;126(4):756-61. [10502685 ]
  2. Giraldi-Guimaraes A, Tenorio F, Bruning G, Mayer B, Mendez-Otero R, Cavalcante LA: Nitric oxide synthase expression in the opossum superior colliculus: a histochemical, immunohistochemical and biochemical study. Brain Behav Evol. 1999 Dec;54(6):303-13. [10681601 ]
  3. Perry JM, Zhao Y, Marletta MA: Cu2+ and Zn2+ inhibit nitric-oxide synthase through an interaction with the reductase domain. J Biol Chem. 2000 May 12;275(19):14070-6. [10799481 ]
  4. Adak S, Wang Q, Stuehr DJ: Arginine conversion to nitroxide by tetrahydrobiopterin-free neuronal nitric-oxide synthase. Implications for mechanism. J Biol Chem. 2000 Oct 27;275(43):33554-61. [10945985 ]
  5. Yu W, Juang S, Lee J, Liu T, Cheng J: Decrease of neuronal nitric oxide synthase in the cerebellum of aged rats. Neurosci Lett. 2000 Sep 8;291(1):37-40. [10962148 ]
Target Details
4. Nitric oxide synthase, endothelial
General Function:
Tetrahydrobiopterin binding
Specific Function:
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.
Gene Name:
NOS3
Uniprot ID:
P29474
Molecular Weight:
133287.62 Da
References
  1. Hayakawa H, Raij L: Relationship between hypercholesterolaemia, endothelial dysfunction and hypertension. J Hypertens. 1999 May;17(5):611-9. [10403604 ]
  2. Trovati M, Massucco P, Mattiello L, Costamagna C, Aldieri E, Cavalot F, Anfossi G, Bosia A, Ghigo D: Human vascular smooth muscle cells express a constitutive nitric oxide synthase that insulin rapidly activates, thus increasing guanosine 3':5'-cyclic monophosphate and adenosine 3':5'-cyclic monophosphate concentrations. Diabetologia. 1999 Jul;42(7):831-9. [10440125 ]
  3. McDuffie JE, Coaxum SD, Maleque MA: 5-hydroxytryptamine evokes endothelial nitric oxide synthase activation in bovine aortic endothelial cell cultures. Proc Soc Exp Biol Med. 1999 Sep;221(4):386-90. [10460702 ]
  4. Tan E, Gurjar MV, Sharma RV, Bhalla RC: Estrogen receptor-alpha gene transfer into bovine aortic endothelial cells induces eNOS gene expression and inhibits cell migration. Cardiovasc Res. 1999 Aug 15;43(3):788-97. [10690351 ]
  5. Abu-Soud HM, Ichimori K, Presta A, Stuehr DJ: Electron transfer, oxygen binding, and nitric oxide feedback inhibition in endothelial nitric-oxide synthase. J Biol Chem. 2000 Jun 9;275(23):17349-57. [10749853 ]
Target Details
5. Nitric oxide synthase, inducible
General Function:
Tetrahydrobiopterin binding
Specific Function:
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such COX2. As component of the iNOS-S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH on 'Cys-247' implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM.
Gene Name:
NOS2
Uniprot ID:
P35228
Molecular Weight:
131116.3 Da
References
  1. Cunningham JM, Rayne RC: Radiochemical measurement of NOS activity by conversion of [14C]L-arginine to citrulline using HPLC separation. Methods Mol Biol. 1998;100:75-81. [10906995 ]
  2. Keilhoff G, Reiser M, Stanarius A, Aoki E, Wolf G: Citrulline immunohistochemistry for demonstration of NOS activity in vivo and in vitro. Nitric Oxide. 2000 Aug;4(4):343-53. [10944418 ]
  3. Conrad KP, Powers RW, Davis AK, Novak J: Citrulline is not the major product using the standard "NOS activity" assay on renal cortical homogenates. Am J Physiol Regul Integr Comp Physiol. 2002 Jan;282(1):R303-10. [11742852 ]
  4. Knowles RG, Salter M: Measurement of NOS activity by conversion of radiolabeled arginine to citrulline using ion-exchange separation. Methods Mol Biol. 1998;100:67-73. [10906994 ]
  5. Yi GB, McClendon D, Desaiah D, Goddard J, Lister A, Moffitt J, Meer RK, deShazo R, Lee KS, Rockhold RW: Fire ant venom alkaloid, isosolenopsin A, a potent and selective inhibitor of neuronal nitric oxide synthase. Int J Toxicol. 2003 Mar-Apr;22(2):81-6. [12745988 ]
Target Details
6. Protein-arginine deiminase type-4
General Function:
Protein-arginine deiminase activity
Specific Function:
Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance. Citrullinates histone H1 at 'Arg-54' (to form H1R54ci), histone H3 at 'Arg-2', 'Arg-8', 'Arg-17' and/or 'Arg-26' (to form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at 'Arg-3' (to form H4R3ci). Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1: citrullination of 'Arg-54' of histone H1 (H1R54ci) results in H1 displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci. Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.
Gene Name:
PADI4
Uniprot ID:
Q9UM07
Molecular Weight:
74078.65 Da
References
  1. Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA: Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 2004 Oct 8;306(5694):279-83. Epub 2004 Sep 2. [15345777 ]
  2. Wysocka J, Allis CD, Coonrod S: Histone arginine methylation and its dynamic regulation. Front Biosci. 2006 Jan 1;11:344-55. [16146736 ]
  3. Yamamoto K, Yamada R: Genome-wide single nucleotide polymorphism analyses of rheumatoid arthritis. J Autoimmun. 2005;25 Suppl:12-5. Epub 2005 Nov 2. [16271291 ]
  4. Chang X, Han J: Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog. 2006 Mar;45(3):183-96. [16355400 ]
  5. Okazaki Y, Suzuki A, Sawada T, Ohtake-Yamanaka M, Inoue T, Hasebe T, Yamada R, Yamamoto K: Identification of citrullinated eukaryotic translation initiation factor 4G1 as novel autoantigen in rheumatoid arthritis. Biochem Biophys Res Commun. 2006 Mar 3;341(1):94-100. Epub 2006 Jan 6. [16412378 ]
Target Details
7. N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
General Function:
Metal ion binding
Specific Function:
Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation.
Gene Name:
DDAH1
Uniprot ID:
O94760
Molecular Weight:
31121.5 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory3700 uMNot AvailableBindingDB 92903
References
  1. Mishima T, Hamada T, Ui-Tei K, Takahashi F, Miyata Y, Imaki J, Suzuki H, Yamashita K: Expression of DDAH1 in chick and rat embryos. Brain Res Dev Brain Res. 2004 Feb 20;148(2):223-32. [14766200 ]
  2. Tran CT, Fox MF, Vallance P, Leiper JM: Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics. 2000 Aug 15;68(1):101-5. [10950934 ]
  3. Arrigoni FI, Vallance P, Haworth SG, Leiper JM: Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation. 2003 Mar 4;107(8):1195-201. [12615801 ]
  4. Wang Y, Monzingo AF, Hu S, Schaller TH, Robertus JD, Fast W: Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide. Biochemistry. 2009 Sep 15;48(36):8624-35. doi: 10.1021/bi9007098. [19663506 ]
Target Details
8. Protein-arginine deiminase type-3
General Function:
Protein-arginine deiminase activity
Specific Function:
Catalyzes the deimination of arginine residues of proteins.
Gene Name:
PADI3
Uniprot ID:
Q9ULW8
Molecular Weight:
74742.705 Da
References
  1. Dong S, Kanno T, Yamaki A, Kojima T, Shiraiwa M, Kawada A, Mechin MC, Chavanas S, Serre G, Simon M, Takahara H: NF-Y and Sp1/Sp3 are involved in the transcriptional regulation of the peptidylarginine deiminase type III gene (PADI3) in human keratinocytes. Biochem J. 2006 Aug 1;397(3):449-59. [16671893 ]
  2. Iida A, Nakamura Y: Identification of 45 novel SNPs in the 83-kb region containing peptidylarginine deiminase types 1 and 3 loci on chromosomal band 1p36.13. J Hum Genet. 2004;49(7):387-90. Epub 2004 May 19. [15150696 ]
  3. Kanno T, Kawada A, Yamanouchi J, Yosida-Noro C, Yoshiki A, Shiraiwa M, Kusakabe M, Manabe M, Tezuka T, Takahara H: Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin. J Invest Dermatol. 2000 Nov;115(5):813-23. [11069618 ]
Target Details
9. N(G),N(G)-dimethylarginine dimethylaminohydrolase 2
General Function:
Dimethylargininase activity
Specific Function:
Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation.
Gene Name:
DDAH2
Uniprot ID:
O95865
Molecular Weight:
29643.54 Da
References
  1. Tran CT, Fox MF, Vallance P, Leiper JM: Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics. 2000 Aug 15;68(1):101-5. [10950934 ]
  2. Tain YL, Baylis C: Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Kidney Int. 2007 Oct;72(7):886-9. Epub 2007 Jul 25. [17653133 ]
Target Details
10. Ornithine carbamoyltransferase, mitochondrial
General Function:
Phospholipid binding
Specific Function:
Not Available
Gene Name:
OTC
Uniprot ID:
P00480
Molecular Weight:
39934.775 Da
References
  1. Quintero MJ, Muro-Pastor AM, Herrero A, Flores E: Arginine catabolism in the cyanobacterium Synechocystis sp. Strain PCC 6803 involves the urea cycle and arginase pathway. J Bacteriol. 2000 Feb;182(4):1008-15. [10648527 ]
  2. Morizono H, Cabrera-Luque J, Shi D, Gallegos R, Yamaguchi S, Yu X, Allewell NM, Malamy MH, Tuchman M: Acetylornithine transcarbamylase: a novel enzyme in arginine biosynthesis. J Bacteriol. 2006 Apr;188(8):2974-82. [16585758 ]
Target Details
11. Protein-arginine deiminase type-6
General Function:
Protein-arginine deiminase activity
Specific Function:
Catalyzes the deimination of arginine residues of proteins. May be involved in cytoskeletal reorganization in the egg and early embryo (By similarity).
Gene Name:
PADI6
Uniprot ID:
Q6TGC4
Molecular Weight:
77726.735 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Target Details
12. Protein-arginine deiminase type-1
General Function:
Protein-arginine deiminase activity
Specific Function:
Catalyzes the deimination of arginine residues of proteins.
Gene Name:
PADI1
Uniprot ID:
Q9ULC6
Molecular Weight:
74664.97 Da
References
  1. Iida A, Nakamura Y: Identification of 45 novel SNPs in the 83-kb region containing peptidylarginine deiminase types 1 and 3 loci on chromosomal band 1p36.13. J Hum Genet. 2004;49(7):387-90. Epub 2004 May 19. [15150696 ]
Target Details
13. Protein-arginine deiminase type-2
General Function:
Protein-arginine deiminase activity
Specific Function:
Catalyzes the deimination of arginine residues of proteins.
Gene Name:
PADI2
Uniprot ID:
Q9Y2J8
Molecular Weight:
75563.35 Da
References
  1. Dong S, Kojima T, Shiraiwa M, Mechin MC, Chavanas S, Serre G, Simon M, Kawada A, Takahara H: Regulation of the expression of peptidylarginine deiminase type II gene (PADI2) in human keratinocytes involves Sp1 and Sp3 transcription factors. J Invest Dermatol. 2005 May;124(5):1026-33. [15854045 ]