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Record Information
Version3.6
Creation Date2006-08-12 19:53:05 UTC
Update Date2013-05-29 19:38:08 UTC
HMDB IDHMDB03378
Secondary Accession NumbersNone
Metabolite Identification
Common NameNitric oxide
DescriptionThe biologically active molecule nitric oxide (NO) is a simple, membrane-permeable gas with unique chemistry. It is formed by the conversion of L-arginine to L-citrulline, with the release of NO. The enzymatic oxidation of L-arginine to L-citrulline takes place in the presence of oxygen and NADPH using flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, thiol and tetrahydrobiopterin as cofactors. The enzyme responsible for the generation of NO is nitric oxide synthase (E.C. 1.7.99.7; NOS). Three NOS isoforms have been described and shown to be encoded on three distinct genes: Neuronal NOS (nNOS, NOS type I), inducible NOS (NOS type II) and endothelial NOS (eNOS, NOS type III). Two of them are constitutively expressed and dependent on the presence of calcium ions and calmodulin to function (nNOS and eNOS), while iNOS is considered non-constitutive and calcium-independent. However, experience has shown that constitutive expression of nNOS and eNOS is not as rigid as previously thought (i.e., either present or absent), but can be dynamically controlled during development and in response to injury. Functionally, NO may act as a hormone, neurotransmitter, paracrine messenger, mediator, cytoprotective and cytotoxic molecule. NO has multiple cellular molecular targets. It influences the activity of transcription factors, modulates upstream signaling cascades, mRNA stability and translation, and processes the primary gene products. In the brain, many processes are linked to NO. NO activates its receptor, soluble guanylate cyclase by binding to it. The stimulation of this enzyme leads to increased synthesis of the second messenger, cGMP, which in turn activates cGMP-dependent kinases in target cells. NO exerts strong influence on glutamatergic neurotransmission by directly interacting with the N-Methyl-d-Aspartate (NMDA) receptor. Neuronal NOS is connected to NMDA receptors (see below) and sharply increases NO production following activation of this receptor. Thus, the level of endogenously produced NO around NMDA synapses reflects the activity of glutamate-mediated neurotransmission. However, there is recent evidence showing that non-NMDA glutamate receptors (i.e., AMPA and type I metabotropic receptors) also contribute to NO generation. Besides its influence on glutamate, NO is known to have effects on the storage, uptake and/or release of most other neurotransmitters in the CNS (acetylcholine, dopamine, noradrenaline, GABA, and taurine and glycine, as well as of certain neuropeptides. Finally, since NO is a highly diffusible molecule, it may reach extrasynaptic receptors at target cell membranes at some distance from the place of NO synthesis. NO is thus capable of mediating both synaptic and nonsynaptic communication processes. NO is a potent vasodilator (a major endogenous regulator of vascular tone), and an important endothelium-dependent relaxing factor. NO is synthesized by NO synthases (NOS) and NOS are inhibited by asymmetrical dimethylarginine (ADMA). ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) and excreted in the kidneys. Lower ADMA levels in pregnant women compared to non-pregnant controls suggest that ADMA has a role in vascular dilatation and blood pressure changes. Several studies show an increase in ADMA levels in pregnancies complicated with preeclampsia. Elevated ADMA levels in preeclampsia are seen before clinical symptoms have developed; these findings suggest that ADMA has a role in the pathogenesis of preeclampsia. In some pulmonary hypertensive states such as ARDS, the production of endogenous NO may be impaired. Nitric oxide inhalation selectively dilates the pulmonary circulation. Significant systemic vasodilation does not occur because NO is inactivated by rapidly binding to hemoglobin. In an injured lung with pulmonary hypertension, inhaled NO produces local vasodilation of well-ventilated lung units and may "steal" blood flow away from unventilated regions. This reduces intrapulmonary shunting and may improve systemic arterial oxygenation. Nitric oxide is a chemical mediator fundamental in the maintenance of adequate tissue perfusion and effective cardiovascular function. The use of nitrates is well established as pharmacological agents but it is only recently that it has been recognized that they act as a source of nitric oxide. (PMID: 16966108 , 8752507 , 17181668 , 16005189 ).
Structure
Thumb
Synonyms
  1. Mononitrogen monoxide
  2. Nitric oxide
  3. Nitrogen monoxide
  4. Nitrogen oxide
  5. Nitrogen protoxide
  6. Nitrosyl hydride
  7. Nitrosyl radical
  8. Nitroxide radical
  9. Nitroxyl
Chemical FormulaNO
Average Molecular Weight30.0061
Monoisotopic Molecular Weight29.997988627
IUPAC Namehydroxyamine
Traditional Namehydroxyamine
CAS Registry Number10102-43-9
SMILES
N#[O]
InChI Identifier
InChI=1S/NO/c1-2
InChI KeyMWUXSHHQAYIFBG-UHFFFAOYSA-N
Chemical Taxonomy
KingdomInorganic Compounds
Super ClassHomogeneous Non-metal Compounds
ClassOther Non-metal Organides
Sub ClassOther Non-metal Oxides
Other Descriptors
  • inorganic radical(ChEBI)
  • nitrogen oxide(ChEBI)
  • reactive nitrogen species(ChEBI)
  • reactive oxygen species(ChEBI)
Substituents
  • N/A
Direct ParentOther Non-metal Oxides
Ontology
StatusDetected and Quantified
Origin
  • Endogenous
Biofunction
  • Component of Arginine and proline metabolism
ApplicationNot Available
Cellular locations
  • Cytoplasm
  • Extracellular
Physical Properties
StateGas
Experimental Properties
PropertyValueReference
Melting Point-163.6 °CNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
PropertyValueSource
Physiological Charge0ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area23.79 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity26.23 m3·mol-1ChemAxon
Polarizability1.63 Å3ChemAxon
Spectra
SpectraNot Available
Biological Properties
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid Locations
  • Blood
  • Cerebrospinal Fluid (CSF)
Tissue Location
  • Adipose Tissue
  • Adrenal Gland
  • Adrenal Medulla
  • Bladder
  • Brain
  • Fetus
  • Fibroblasts
  • Intestine
  • Kidney
  • Lung
  • Muscle
  • Myelin
  • Nerve Cells
  • Neuron
  • Pancreas
  • Placenta
  • Platelet
  • Prostate
  • Skeletal Muscle
  • Skin
  • Spleen
  • Testes
  • Thyroid Gland
Pathways
NameSMPDB LinkKEGG Link
Arginine and Proline MetabolismSMP00020map00330
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.000012 +/- 0.000006 uMAdult (>18 years old)BothNormal details
Cerebrospinal Fluid (CSF)Detected and Quantified1.05 +/- 0.01 uMAdult (>18 years old)MaleNormal details
Cerebrospinal Fluid (CSF)Detected and Quantified8.66 +/- 1.07 uMNewborn (0-30 days old)Not SpecifiedNormal details
Abnormal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
Cerebrospinal Fluid (CSF)Detected and Quantified8.60 +/- 0.49 uMNewborn (0-30 days old)Not SpecifiedHypoxic-ischemic encephalopathy details
Cerebrospinal Fluid (CSF)Detected and Quantified0.99 +/- 0.01 uMAdult (>18 years old)MaleSubarachnoid hemorrhage details
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDNot Available
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB021825
KNApSAcK IDNot Available
Chemspider ID127983
KEGG Compound IDC00533
BioCyc IDNITRIC-OXIDE
BiGG ID35273
Wikipedia LinkNitric oxide
NuGOwiki LinkHMDB03378
Metagene LinkHMDB03378
METLIN ID6912
PubChem Compound145068
PDB IDNot Available
ChEBI ID16480
References
Synthesis ReferenceMorabito, Paul; Heicklen, Julian. Disproportionation to combination ratios of alkoxy radicals with nitric oxide. Journal of Physical Chemistry (1985), 89(13), 2914-16.
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Kaynar H, Meral M, Turhan H, Keles M, Celik G, Akcay F: Glutathione peroxidase, glutathione-S-transferase, catalase, xanthine oxidase, Cu-Zn superoxide dismutase activities, total glutathione, nitric oxide, and malondialdehyde levels in erythrocytes of patients with small cell and non-small cell lung cancer. Cancer Lett. 2005 Sep 28;227(2):133-9. Epub 2005 Jan 8. Pubmed: 16112416
  2. Noris M, Todeschini M, Cassis P, Pasta F, Cappellini A, Bonazzola S, Macconi D, Maucci R, Porrati F, Benigni A, Picciolo C, Remuzzi G: L-arginine depletion in preeclampsia orients nitric oxide synthase toward oxidant species. Hypertension. 2004 Mar;43(3):614-22. Epub 2004 Jan 26. Pubmed: 14744923
  3. Moon A: Influence of nitric oxide signalling pathways on pre-contracted human detrusor smooth muscle in vitro. BJU Int. 2002 Jun;89(9):942-9. Pubmed: 12010245
  4. Muerkoster S, Wegehenkel K, Arlt A, Witt M, Sipos B, Kruse ML, Sebens T, Kloppel G, Kalthoff H, Folsch UR, Schafer H: Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res. 2004 Feb 15;64(4):1331-7. Pubmed: 14973050
  5. Huledal G, Jonzon B, Malmenas M, Hedman A, Andersson LI, Odlind B, Brater DC: Renal effects of the cyclooxygenase-inhibiting nitric oxide donator AZD3582 compared with rofecoxib and naproxen during normal and low sodium intake. Clin Pharmacol Ther. 2005 May;77(5):437-50. Pubmed: 15900289
  6. Brown DA, Canning MT, Nay SL, Pena AV, Yarosh DB: Bicyclic monoterpene diols stimulate release of nitric oxide from skin cells, increase microcirculation, and elevate skin temperature. Nitric Oxide. 2006 Aug;15(1):70-6. Epub 2006 Apr 19. Pubmed: 16626981
  7. Santoro G, Romeo C, Impellizzeri P, Ientile R, Cutroneo G, Trimarchi F, Pedale S, Turiaco N, Gentile C: Nitric oxide synthase patterns in normal and varicocele testis in adolescents. BJU Int. 2001 Dec;88(9):967-73. Pubmed: 11851622
  8. Browning DD, McShane MP, Marty C, Ye RD: Nitric oxide activation of p38 mitogen-activated protein kinase in 293T fibroblasts requires cGMP-dependent protein kinase. J Biol Chem. 2000 Jan 28;275(4):2811-6. Pubmed: 10644746
  9. Heym C, Colombo-Benckmann M, Mayer B: Immunohistochemical demonstration of the synthesis enzyme for nitric oxide and of comediators in neurons and chromaffin cells of the human adrenal medulla. Ann Anat. 1994 Jan;176(1):11-6. Pubmed: 7508210
  10. Neri S, Signorelli S, Pulvirenti D, Mauceri B, Cilio D, Bordonaro F, Abate G, Interlandi D, Misseri M, Ignaccolo L, Savastano M, Azzolina R, Grillo C, Messina A, Serra A, Tsami A: Oxidative stress, nitric oxide, endothelial dysfunction and tinnitus. Free Radic Res. 2006 Jun;40(6):615-8. Pubmed: 16753839
  11. Atiya A, Cohen G, Ignarro L, Brunicardi FC: Nitric oxide regulates insulin secretion in the isolated perfused human pancreas via a cholinergic mechanism. Surgery. 1996 Aug;120(2):322-7. Pubmed: 8751600
  12. Kim N, Vardi Y, Padma-Nathan H, Daley J, Goldstein I, Saenz de Tejada I: Oxygen tension regulates the nitric oxide pathway. Physiological role in penile erection. J Clin Invest. 1993 Feb;91(2):437-42. Pubmed: 7679408
  13. Nichols K, Staines W, Krantis A: Neural sites of the human colon colocalize nitric oxide synthase-related NADPH diaphorase activity and neuropeptide Y. Gastroenterology. 1994 Oct;107(4):968-75. Pubmed: 7523222
  14. Reitz A, Knapp PA, Muntener M, Schurch B: Oral nitric oxide donors: a new pharmacological approach to detrusor-sphincter dyssynergia in spinal cord injured patients? Eur Urol. 2004 Apr;45(4):516-20. Pubmed: 15041118
  15. Huguenin S, Vacherot F, Fleury-Feith J, Riffaud JP, Chopin DK, Bolla M, Jaurand MC: Evaluation of the antitumoral potential of different nitric oxide-donating non-steroidal anti-inflammatory drugs (NO-NSAIDs) on human urological tumor cell lines. Cancer Lett. 2005 Feb 10;218(2):163-70. Pubmed: 15670893
  16. Stack WA, Filipowicz B, Hawkey CJ: Nitric oxide donating compounds stimulate human colonic ion transport in vitro. Gut. 1996 Jul;39(1):93-9. Pubmed: 8881817
  17. Khanna A, Cowled PA, Fitridge RA: Nitric oxide and skeletal muscle reperfusion injury: current controversies (research review). J Surg Res. 2005 Sep;128(1):98-107. Pubmed: 15961106
  18. Calka J: The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons. Folia Histochem Cytobiol. 2006;44(1):3-12. Pubmed: 16584085
  19. Kublickiene KR, Cockell AP, Nisell H, Poston L: Role of nitric oxide in the regulation of vascular tone in pressurized and perfused resistance myometrial arteries from term pregnant women. Am J Obstet Gynecol. 1997 Nov;177(5):1263-9. Pubmed: 9396927
  20. Ormerod AD, Copeland P, Hay I, Husain A, Ewen SW: The inflammatory and cytotoxic effects of a nitric oxide releasing cream on normal skin. J Invest Dermatol. 1999 Sep;113(3):392-7. Pubmed: 10469339
  21. Slaghekke F, Dekker G, Jeffries B: Endogenous inhibitors of nitric oxide and preeclampsia: a review. J Matern Fetal Neonatal Med. 2006 Aug;19(8):447-52. Pubmed: 16966108
  22. Hurford WE: Current status of nitric oxide inhalation. Nihon Kyobu Shikkan Gakkai Zasshi. 1995 Dec;33 Suppl:199-204. Pubmed: 8752507
  23. Stephens C, Fawcett TN: Nitric oxide and nursing: a review. J Clin Nurs. 2007 Jan;16(1):67-76. Pubmed: 17181668
  24. Bernstein HG, Bogerts B, Keilhoff G: The many faces of nitric oxide in schizophrenia. A review. Schizophr Res. 2005 Oct 1;78(1):69-86. Pubmed: 16005189

Enzymes

General function:
Involved in oxidoreductase activity
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.
Gene Name:
NOS2
Uniprot ID:
P35228
Molecular weight:
131116.3
Reactions
L-Arginine + NADPH + Oxygen → Citrulline + Nitric oxide + NADP + Waterdetails
NADPH + N-(o)-Hydroxyarginine + Oxygen + Hydrogen Ion → NADP + Nitric oxide + Citrulline + Waterdetails
L-Arginine + Oxygen + NADPH + Hydrogen Ion → Nitric oxide + Citrulline + NADP + Waterdetails
General function:
Involved in oxidoreductase activity
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
Reactions
L-Arginine + NADPH + Oxygen → Citrulline + Nitric oxide + NADP + Waterdetails
NADPH + N-(o)-Hydroxyarginine + Oxygen + Hydrogen Ion → NADP + Nitric oxide + Citrulline + Waterdetails
L-Arginine + Oxygen + NADPH + Hydrogen Ion → Nitric oxide + Citrulline + NADP + Waterdetails
General function:
Involved in oxidoreductase activity
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:
133273.59
Reactions
L-Arginine + NADPH + Oxygen → Citrulline + Nitric oxide + NADP + Waterdetails
NADPH + N-(o)-Hydroxyarginine + Oxygen + Hydrogen Ion → NADP + Nitric oxide + Citrulline + Waterdetails
L-Arginine + Oxygen + NADPH + Hydrogen Ion → Nitric oxide + Citrulline + NADP + Waterdetails
General function:
Involved in iron ion binding
Specific function:
LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure
Gene Name:
HBB
Uniprot ID:
P68871
Molecular weight:
15998.3
General function:
Involved in endothelin A receptor binding
Specific function:
Endothelins are endothelium-derived vasoconstrictor peptides
Gene Name:
EDN1
Uniprot ID:
P05305
Molecular weight:
24424.9
General function:
Involved in oxidoreductase activity
Specific function:
Not Available
Gene Name:
NOS1
Uniprot ID:
B3VK56
Molecular weight:
160969.1
General function:
Involved in microtubule-based process
Specific function:
Regulates apoptotic activities of BCL2L11 by sequestering it to microtubules. Upon apoptotic stimuli the BCL2L11-DYNLL1 complex dissociates from cytoplasmic dynein and translocates to mitochondria and sequesters BCL2 thus neutralizing its antiapoptotic activity
Gene Name:
DYNLL1
Uniprot ID:
P63167
Molecular weight:
10365.8