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NO synthase-1 (calmodulin NO synthase, NADPH diaphorase, neuronal NO synthase, nNOS)

Function: - produces nitric oxide (NO), a messenger molecule with diverse functions throughout the body - in brain & peripheral nervous system, NO displays many properties of a neurotransmitter - stimulated by Ca+2/calmodulin - interacts with DLG4; the interaction possibly being prevented by the association between NOS1 & CAPON - forms a ternary complex with CAPON & RASD1 - forms a ternary complex with CAPON & SYN1 - interacts with ZDHHC23 - interacts with NOSIPwhich may impair its synaptic location - interacts with HTR4 (putative) L-arginine + n NADPH + m O2 citrulline + nitric oxide + n NADP+ Cofactor: - heme group - binds 1 FAD - binds 1 FMN - betrahydrobiopterin (BH4) Kinetics: - half maximal activity at Ca+2 of 160 nM - intraneuronal Ca+2 is typically 100 nM Structure: - homodimer - PDZ domain in the N-terminal part of the neuronal isoform participates in protein-protein interaction, & is responsible for targeting NOS1 to synaptic membranes in muscles - belongs to the NOS family - contains 1 flavodoxin-like domain - contains 1 PDZ (DHR) domain Compartment: - cell membrane, sarcolemma - cell projection, dendritic spine - in skeletal muscle, localized beneath the sarcolemma of fast-twitch muscle fiber by associating with the dystrophin glycoprotein complex - in neurons, enriched in dendritic spines (putative) Alternative splicing: named isoforms=4 Expression: - isoform 1 is ubiquitously expressed: a) detected in skeletal muscle & brain, also in testis, lung & kidney b) low levels in heart, adrenal gland & retina c) not detected in the platelets - isoform 3 is expressed only in testis - isoform 4 a) detected in testis, skeletal muscle, lung, & kidney b) low levels in the brain, c) not detected in heart or adrenal gland Notes: - inhibited by n-Nos-inhibiting protein (PIN) which may prevent the dimerization of the protein - inhibited by NOSIP Pathology: - genetic variations in NOS1 gene are associated with susceptibility to infantile hypertrophic pyloric stenosis type 1

Interactions

molecular events

Related

calmodulin nitric oxide (NO, endothelium derived relaxation factor {EDRF})

General

diaphorase nitric oxide [NO] synthase

Properties

CONFIGURATION: dimer SIZE: entity length = 1434 aa MW = 161 kD MOTIF: NOSIP interaction {1-205} MOTIF: PDZ domain NAME: PDZ domain SITE: 17-99 PIN (nNOS-inhibiting protein) binding {163-245} Iron [Fe]-binding site SITE: 420-420 binding site SITE: 730-750 FOR-BINDING-OF: calmodulin binding site SITE: 755-774 FOR-BINDING-OF: 5,6,7-8-tetrahydrobiopterin Flavodoxin-like {760-940} cofactor-binding site [1032-1043] COFACTOR-BOUND: flavin adenine dinucleotide cofactor-binding site [1175-1185] COFACTOR-BOUND: flavin adenine dinucleotide cofactor-binding site [1250-1268] COFACTOR-BOUND: NADP cofactor-binding site [1348-1363] COFACTOR-BOUND: NADP

Database Correlations

OMIM correlations UniProt P29475 PFAM correlations Kegg hsa:4842 ENZYME 1.14.13.39

References

  1. Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990 Jan;87(2):682-5. PMID: 1689048
  2. Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci. 1991 Feb;14(2):60-7. Review. PMID: 1708538
  3. Snyder SH, Bredt DS. Nitric oxide as a neuronal messenger. Trends Pharmacol Sci. 1991 Apr;12(4):125-8. Review. PMID: 1712138
  4. Crossin KL. Nitric oxide (NO): a versatile second messenger in brain. Trends Biochem Sci. 1991 Mar;16(3):81-2. PMID: 1711724
  5. Vincent SR, Hope BT. Neurons that say NO. Trends Neurosci. 1992 Mar;15(3):108-13. Review. PMID: 1373918
  6. Prince RC, Gunson DE. Rising interest in nitric oxide synthase. Trends Biochem Sci. 1993 Feb;18(2):35-6. Review. PMID: 7683828
  7. UniProt :accession P29475

Component-of

dystrophin associated protein complex (DPC)