L-Citrulline

Identification

Name
L-Citrulline
Accession Number
DB00155  (NUTR00021)
Type
Small Molecule
Groups
Approved, Nutraceutical
Description

Citrulline 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.

Structure
Thumb
Synonyms
  • (S)-2-Amino-5-ureidopentanoic acid
  • 2-Amino-5-ureidovaleric acid
  • alpha-amino-delta-Ureidovaleric acid
  • Cit
  • Citrulline
  • delta-Ureidonorvaline
  • L-2-Amino-5-ureidovaleric acid
  • L-Citrulline
  • N(5)-(Aminocarbonyl)-L-ornithine
  • N(delta)-Carbamylornithine
  • N5-(Aminocarbonyl)ornithine
  • N5-Carbamoyl-L-ornithine
  • N5-carbamoylornithine
  • α-amino-δ-ureidovaleric acid
  • δ-ureidonorvaline
Categories
UNII
29VT07BGDA
CAS number
372-75-8
Weight
Average: 175.1857
Monoisotopic: 175.095691297
Chemical Formula
C6H13N3O3
InChI Key
RHGKLRLOHDJJDR-BYPYZUCNSA-N
InChI
InChI=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
IUPAC Name
(2S)-2-amino-5-(carbamoylamino)pentanoic acid
SMILES
N[[email protected]@H](CCCNC(N)=O)C(O)=O

Pharmacology

Indication

Used for nutritional supplementation, also for treating dietary shortage or imbalance.

Structured Indications
Not Available
Pharmacodynamics

A non-essential amino acid and a precursor of arginine. Citrulline supplements have been claimed to promote energy levels, stimulate the immune system and help detoxify ammonia (a cell toxin). L-citrulline is made from L-ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from L-arginine as a by-product of the reaction catalyzed by the enzyme NO synthase. L-citrulline, while being an amino acid, is not involved in protein synthesis and is not one of the amino acids coded for by DNA. Although citrulline cannot be incorporated in proteins during protein synthesis, several proteins are known to contain citrulline as an amino acid. These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert the amino acid arginine into citrulline. Proteins that contain citrulline residues include myelin basic protein (MBP), fillagrin and several histone proteins.

Mechanism of action

L-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.

TargetActionsOrganism
UNitric oxide synthase, endothelialNot AvailableHuman
UArgininosuccinate synthaseNot AvailableHuman
UN(G),N(G)-dimethylarginine dimethylaminohydrolase 2Not AvailableHuman
UArgininosuccinate synthetase, isoform CRA_aNot AvailableHuman
UN(G),N(G)-dimethylarginine dimethylaminohydrolase 1Not AvailableHuman
UOrnithine carbamoyltransferase, mitochondrialNot AvailableHuman
UNitric oxide synthase, brainNot AvailableHuman
UNitric oxide synthase, inducibleNot AvailableHuman
UProtein-arginine deiminase type-4Not AvailableHuman
UProtein-arginine deiminase type-6Not AvailableHuman
UProtein-arginine deiminase type-1Not AvailableHuman
UProtein-arginine deiminase type-3Not AvailableHuman
UProtein-arginine deiminase type-2Not AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Argininosuccinic AciduriaDisease
Prolidase Deficiency (PD)Disease
HypoacetylaspartiaDisease
ArgininemiaDisease
Citrullinemia Type IDisease
Carbamoyl Phosphate Synthetase DeficiencyDisease
Aspartate MetabolismMetabolic
Ornithine Aminotransferase Deficiency (OAT Deficiency)Disease
Arginine and Proline MetabolismMetabolic
Urea CycleMetabolic
Canavan DiseaseDisease
Ornithine Transcarbamylase Deficiency (OTC Deficiency)Disease
Prolinemia Type IIDisease
Hyperprolinemia Type IDisease
Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency)Disease
Hyperprolinemia Type IIDisease
Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency)Disease
Creatine deficiency, guanidinoacetate methyltransferase deficiencyDisease
Hyperornithinemia with gyrate atrophy (HOGA)Disease
Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome]Disease
L-arginine:glycine amidinotransferase deficiencyDisease
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

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.

US20090142813
General References
Not Available
External Links
Human Metabolome Database
HMDB00904
KEGG Compound
C00327
PubChem Compound
9750
PubChem Substance
46506583
ChemSpider
9367
BindingDB
92903
ChEBI
16349
ChEMBL
CHEMBL444814
PharmGKB
PA164747225
IUPHAR
722
Guide to Pharmacology
GtP Drug Page
HET
CIR
PDB Entries
1h70 / 1j1z / 1j21 / 1k97 / 1kod / 1kp3 / 1lxy / 1ol1 / 1qr3 / 2c6z
show 28 more
MSDS
Download (72.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceBlood Pressures1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentSickle Cell Disorders1
1RecruitingDiagnosticSickle Cell Disorders1
1RecruitingTreatmentSickle Cell Disorders1
1Unknown StatusTreatmentSickle Cell Disorders1
1WithdrawnTreatmentChronic Lung Disease of Prematurity1
1, 2CompletedPreventionAtrial Septal Defect (ASD) / Atrioventricular Septal Defects / Ventricular Septal Defects1
1, 2CompletedTreatmentCardiovascular Disease (CVD) / Heart Defects,Congenital / Heart Diseases1
2CompletedPreventionAcute Lung Injury (ALI) / Severe Sepsis1
2CompletedPreventionCancers1
2CompletedTreatmentBecker's Muscular Dystrophy (BMD)1
2Unknown StatusTreatmentIntermittent Claudication / Peripheral Arterial Disease (PAD)1
2, 3RecruitingTreatmentPregnancy / Prophylaxis of preeclampsia1
3Active Not RecruitingTreatmentPost-Polio Syndrome1
3CompletedPreventionHeart Defects,Congenital / Pulmonary Hypertension (PH)1
3CompletedTreatmentIntestinal Failure1
3RecruitingPreventionAcute Lung Injury (ALI)1
Not AvailableRecruitingTreatmentVascular Diseases1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Dosage forms
Not Available
Prices
Unit descriptionCostUnit
L-citrulline powder1.01USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)235.5 °CPhysProp
water solubility200 g/L (at 20 °C)Not Available
logP-3.19SANGSTER (1994)
pKa2.43 (at 25 °C)KORTUM,G ET AL (1961)
Predicted Properties
PropertyValueSource
Water Solubility21.8 mg/mLALOGPS
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 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity41.33 m3·mol-1ChemAxon
Polarizability17.35 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6863
Blood Brain Barrier+0.8961
Caco-2 permeable-0.813
P-glycoprotein substrateNon-substrate0.616
P-glycoprotein inhibitor INon-inhibitor0.9782
P-glycoprotein inhibitor IINon-inhibitor0.982
Renal organic cation transporterNon-inhibitor0.9331
CYP450 2C9 substrateNon-substrate0.7522
CYP450 2D6 substrateNon-substrate0.7828
CYP450 3A4 substrateNon-substrate0.8127
CYP450 1A2 substrateNon-inhibitor0.9415
CYP450 2C9 inhibitorNon-inhibitor0.9149
CYP450 2D6 inhibitorNon-inhibitor0.97
CYP450 2C19 inhibitorNon-inhibitor0.9018
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9896
Ames testNon AMES toxic0.5916
CarcinogenicityNon-carcinogens0.9113
BiodegradationReady biodegradable0.9247
Rat acute toxicity1.3397 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.972
hERG inhibition (predictor II)Non-inhibitor0.9716
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies)GC-MSsplash10-0a4i-0920000000-2d92b63cd5d9648023b8
GC-MS Spectrum - GC-MS (3 TMS)GC-MSsplash10-00di-9610000000-2e7cd23afc2adcef35a3
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-0a4i-0920000000-2d92b63cd5d9648023b8
GC-MS Spectrum - GC-MSGC-MSsplash10-00di-9610000000-2e7cd23afc2adcef35a3
MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)LC-MS/MSsplash10-0a4i-0900000000-4c1d7af748a47e489949
MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)LC-MS/MSsplash10-00di-9000000000-988fced362fc0da157c9
MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)LC-MS/MSsplash10-00di-9000000000-0818e0e8bcee12692498
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-004j-0900000000-5fa8a338dcd2f2a6bdd2
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-004i-0900000000-16763200aa07f7629ad4
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-03di-3900000000-d9cfc5187aa799f6f978
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-0a4i-0900000000-10ee9a593e13550bec1c
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-004i-0900000000-45d272576af34c9512a3
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-014i-3900000000-6177a284fdea5a3f1306
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-0a4i-0900000000-d9456d45e2dbd7a3df10
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , PositiveLC-MS/MSsplash10-004i-0900000000-ada57cdc73bda93be483
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , NegativeLC-MS/MSsplash10-008a-0904000000-23fbe48f82e515087d68
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , NegativeLC-MS/MSsplash10-03di-5900000000-78afcbaf8b8b3eabf174
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , NegativeLC-MS/MSsplash10-001i-0900000000-8fb191d4c20fd54b9282
LC-MS/MS Spectrum - LC-ESI-ITFT (LTQ Orbitrap XL, Thermo Scientfic) , NegativeLC-MS/MSsplash10-00di-0900000000-da484f0362a8dca5127e
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, NegativeLC-MS/MSsplash10-00e9-0900000000-46229b4f77feabb3f857
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, NegativeLC-MS/MSsplash10-001i-0900000000-4aca1022c393602a297d
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, NegativeLC-MS/MSsplash10-001i-0900000000-3bc2eff2e907b7734cc8
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, NegativeLC-MS/MSsplash10-001i-3900000000-2613bf40e3be814da86f
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, NegativeLC-MS/MSsplash10-0006-9300000000-e83287bbc060eb9cf6f3
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, PositiveLC-MS/MSsplash10-056r-0900000000-694a8872bdfd7eec1f2b
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, PositiveLC-MS/MSsplash10-08fr-2900000000-15b4711991ea9985fb2b
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, PositiveLC-MS/MSsplash10-00di-9300000000-915fbb73e0b728420e4a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, PositiveLC-MS/MSsplash10-00di-9000000000-67e60567f5c062728350
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, PositiveLC-MS/MSsplash10-00di-9000000000-25140713431edd7c5eea
LC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , PositiveLC-MS/MSsplash10-074i-5900000000-bf58ae40ccbbcae3b59e
LC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , NegativeLC-MS/MSsplash10-001i-0900000000-daf5b8d935c6f60c6df7
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-00e9-0900000000-46229b4f77feabb3f857
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-001i-0900000000-4aca1022c393602a297d
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-001i-0900000000-322d7f0082e7d5c6ebee
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-001i-3900000000-2613bf40e3be814da86f
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0006-9300000000-e83287bbc060eb9cf6f3
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-03di-5900000000-78afcbaf8b8b3eabf174
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-001i-0900000000-8fb191d4c20fd54b9282
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-00di-0900000000-da484f0362a8dca5127e
LC-MS/MS Spectrum - LC-ESI-QTOF , negativeLC-MS/MSsplash10-001i-0900000000-daf5b8d935c6f60c6df7
MS/MS Spectrum - Linear Ion Trap , negativeLC-MS/MSsplash10-001i-0900000000-20fe8593ca8d8303d73a
MS/MS Spectrum - Linear Ion Trap , negativeLC-MS/MSsplash10-001i-0900000000-a2851fcef80bb0d9b984
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-056r-0900000000-694a8872bdfd7eec1f2b
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-08fr-2900000000-15b4711991ea9985fb2b
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00di-9300000000-915fbb73e0b728420e4a
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00di-9000000000-67e60567f5c062728350
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00di-9000000000-603badf565140abcd117
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-03di-3900000000-d9cfc5187aa799f6f978
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0900000000-10ee9a593e13550bec1c
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-014i-3900000000-6177a284fdea5a3f1306
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0900000000-d9456d45e2dbd7a3df10
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-004i-0900000000-ada57cdc73bda93be483
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-074i-5900000000-bf58ae40ccbbcae3b59e
MS/MS Spectrum - Linear Ion Trap , positiveLC-MS/MSsplash10-0002-0900000000-9e195f6724ee47655efb
MS/MS Spectrum - Linear Ion Trap , positiveLC-MS/MSsplash10-0a4i-0900000000-1742c58acfb2cc3f3944
13C NMR Spectrum1D NMRNot Applicable
1H NMR Spectrum1D NMRNot Applicable
1H NMR Spectrum1D NMRNot Applicable
[1H,1H] 2D NMR Spectrum2D NMRNot Applicable
[1H,13C] 2D NMR Spectrum2D NMRNot Applicable

Taxonomy

Description
This compound 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.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
L-alpha-amino acids
Alternative Parents
Fatty acids and conjugates / Isoureas / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Carboximidamides / Organopnictogen compounds / Organic oxides / Monoalkylamines / Imines
show 2 more
Substituents
L-alpha-amino acid / Fatty acid / Isourea / Amino acid / Carboximidic acid derivative / Carboxylic acid / Monocarboxylic acid or derivatives / Carboximidamide / Amine / Hydrocarbon derivative
show 11 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
citrulline (CHEBI:16349) / Other amino acids (C00327)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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)-induce...
Gene Name
NOS3
Uniprot ID
P29474
Uniprot Name
Nitric oxide synthase, endothelial
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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:10749853]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Is indirectly involved in the control of blood pressure.
Gene Name
ASS1
Uniprot ID
P00966
Uniprot Name
Argininosuccinate synthase
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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:11072090]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Uniprot Name
N(G),N(G)-dimethylarginine dimethylaminohydrolase 2
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. [PubMed: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. [PubMed:17653133]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Not Available
Gene Name
ASS
Uniprot ID
Q5T6L4
Uniprot Name
Argininosuccinate synthetase, isoform CRA_a
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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:16449956]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Uniprot Name
N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
Molecular Weight
31121.5 Da
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. [PubMed: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. [PubMed: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. [PubMed:12615801]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Phospholipid binding
Specific Function
Not Available
Gene Name
OTC
Uniprot ID
P00480
Uniprot Name
Ornithine carbamoyltransferase, mitochondrial
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. [PubMed: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. [PubMed:16585758]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. P...
Gene Name
NOS1
Uniprot ID
P29475
Uniprot Name
Nitric oxide synthase, brain
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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:10962148]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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 ...
Gene Name
NOS2
Uniprot ID
P35228
Uniprot Name
Nitric oxide synthase, inducible
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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:12745988]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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...
Gene Name
PADI4
Uniprot ID
Q9UM07
Uniprot Name
Protein-arginine deiminase type-4
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. [PubMed:15345777]
  2. Wysocka J, Allis CD, Coonrod S: Histone arginine methylation and its dynamic regulation. Front Biosci. 2006 Jan 1;11:344-55. [PubMed: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. [PubMed:16271291]
  4. Chang X, Han J: Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog. 2006 Mar;45(3):183-96. [PubMed: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. [PubMed:16412378]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Uniprot Name
Protein-arginine deiminase type-6
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. [PubMed: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. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein-arginine deiminase activity
Specific Function
Catalyzes the deimination of arginine residues of proteins.
Gene Name
PADI1
Uniprot ID
Q9ULC6
Uniprot Name
Protein-arginine deiminase type-1
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. [PubMed:15150696]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein-arginine deiminase activity
Specific Function
Catalyzes the deimination of arginine residues of proteins.
Gene Name
PADI3
Uniprot ID
Q9ULW8
Uniprot Name
Protein-arginine deiminase type-3
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. [PubMed: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. [PubMed: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. [PubMed:11069618]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein-arginine deiminase activity
Specific Function
Catalyzes the deimination of arginine residues of proteins.
Gene Name
PADI2
Uniprot ID
Q9Y2J8
Uniprot Name
Protein-arginine deiminase type-2
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. [PubMed:15854045]

Drug created on June 13, 2005 07:24 / Updated on October 02, 2017 04:32