Metabolism of nitric oxide: NOS3 activation and regulation (Homo sapiens)

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12, 2119, 21, 258, 9, 18, 23102023, 11, 132822196, 27177, 1621194, 221, 5, 14, 15endocytic vesicle membraneGolgi lumencytosollipid particleeNOS:Caveolin-1:NOSTRIN:Dynamin-2eNOS:CaM:HSP90:Phospho-AKT1eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPeNOS:NOSIPPalmitateNitric oxide synthase, endothelialPhospho-AKT1 (T308, S473)HSP90eNOS:Caveolin-1:CaMNOSIPDynamin-2eNOS:Caveolin-1:NOSTRIN complexeNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPOxygenADPeNOS:Caveolin-1NADP+eNOS:Caveolin-1:CaM:HSP90NADPHeNOS:CaM:HSP90L-ArgininePhospho-eNOS (S1177):CaM:HSP90:Phospho-Akt1N-myristoylated eNOS (Gly2)myristoylated eNOS dimermyristoyl-CoAmyristoylated eNOS dimerAPT1 homodimerpalmitoylated, myristoylated eNOS dimercaveolin-1L-Citrullinepalmitoyl-CoANitric oxideeNOS:NOSIPDHHC-21N-WASPActive CalmodulinATPNOSTRIN homotrimerpalmitylated, N-myristoylated eNOS26252426


Description

Nitric oxide (NO), a diffusible multifunctional second messenger, is implicated in numerous physiological functions in mammals, ranging from immune response and potentiation of synaptic transmission, to dilation of blood vessels and muscle relaxation. NO is synthesized from L-arginine by a family of nitric oxide synthases (NOS). Three NOS isoforms have been characterized: neuronal NOS (nNOS, NOS1) primarily found in neuronal tissue and skeletal muscle; inducible NOS (iNOS, NOS2) originally isolated from macrophages and later discovered in many other cells types; and endothelial NOS (eNOS, NOS3) present in vascular endothelial cells, cardiac myocytes, and in blood platelets. The enzymatic activity of all three isoforms is dependent on calmodulin, which binds to nNOS and eNOS at elevated intracellular calcium levels, while it is tightly associated with iNOS (even at basal calcium levels). As a result, the enzymatic activity of nNOS and eNOS is modulated by changes in intracellular calcium levels, leading to transient NO production, while iNOS continuously releases NO independent of fluctuations in intracellular calcium levels and is mainly regulated at the gene expression level.

The NOS enzymes share a common basic structural organization and requirement for substrate cofactors for enzymatic activity. A central calmodulin-binding motif separates an oxygenase (NH2-terminal) domain from a reductase (COOH-terminal) domain. Binding sites for cofactors NADPH, FAD, and FMN are located within the reductase domain, while binding sites for tetrahydrobiopterin (BH4) and heme are located within the oxygenase domain. Once calmodulin binds, it facilitates electron transfer from the cofactors in the reductase domain to heme enabling nitric oxide production. Both nNOS and eNOS contain an additional insert (40-50 amino acids) in the middle of the FMN-binding subdomain that serves as autoinhibitory loop, destabilizing calmodulin binding at low calcium levels and inhibiting electron transfer from FMN to the heme in the absence of calmodulin. iNOS does not contain this insert.

Because NOS enzymatic activity is modulated by the presence of its substrates and cofactors within the cell, under certain conditions, NOS may generate superoxide instead of NO, a process referred to as uncoupling (uncoupling of NADPH oxidation and NO synthesis).

NO is a highly active molecule that diffuses across cell membranes and cannot be stored inside the producing cell. Its signaling capacity must be controlled at the levels of biosynthesis and local availability. Indeed, NO production by NO synthases is under complex and tight control, being regulated at transcriptional and translational levels, through co- and posttranslational modifications, and by subcellular localization.

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Bibliography

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External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADP Metabolite16761 (ChEBI)
APT1

homodimer

ComplexREACT_13023 (Reactome)
ATP Metabolite15422 (ChEBI)
Active

Calmodulin

ComplexREACT_3178 (Reactome)
DHHC-21 ProteinQ8IVQ6 (UniProt)
Dynamin-2 ProteinREACT_10524 (Reactome)
HSP90 ProteinP07900 (UniProt)
L-Arginine Metabolite16467 (ChEBI)
L-Citrulline Metabolite16349 (ChEBI)
N-WASP ProteinO00401 (UniProt)
N-myristoylated

eNOS (Gly2)

ProteinP29474 (UniProt)
NADP+ Metabolite18009 (ChEBI)
NADPH Metabolite16474 (ChEBI)
NOSIP ProteinQ9Y314 (UniProt)
NOSTRIN

homotrimer

ComplexREACT_12963 (Reactome)
Nitric oxide Metabolite16480 (ChEBI)
Nitric oxide synthase,

endothelial

ProteinP29474 (UniProt)
Oxygen Metabolite15379 (ChEBI)
Palmitate Metabolite15756 (ChEBI)
Phospho-

AKT1 (T308, S473)

ProteinP31749 (UniProt)
Phospho-eNOS

(S1177):CaM: HSP90:Phospho- Akt1

ComplexREACT_12662 (Reactome)
caveolin-1 ProteinQ03135 (UniProt)
eNOS:

Caveolin-1

ComplexREACT_12997 (Reactome)
eNOS:

Caveolin-1: CaM

ComplexREACT_12757 (Reactome)
eNOS:

Caveolin-1: CaM:HSP90

ComplexREACT_12971 (Reactome)
eNOS:

Caveolin-1: NOSTRIN complex

ComplexREACT_13185 (Reactome)
eNOS:

Caveolin-1: NOSTRIN: Dynamin-2

ComplexREACT_12737 (Reactome)
eNOS:

Caveolin-1: NOSTRIN: dynamin-2: N-WASP

ComplexREACT_12814 (Reactome)
eNOS:

Caveolin-1: NOSTRIN: dynamin-2: N-WASP

ComplexREACT_13117 (Reactome)
eNOS:

NOSIP

ComplexREACT_12699 (Reactome)
eNOS:

NOSIP

ComplexREACT_13282 (Reactome)
eNOS:CaM:

HSP90

ComplexREACT_12871 (Reactome)
eNOS:CaM:

HSP90: Phospho-AKT1

ComplexREACT_12902 (Reactome)
myristoyl-

CoA

Metabolite15532 (ChEBI)
myristoylated

eNOS dimer

ComplexREACT_12833 (Reactome)
myristoylated

eNOS dimer

ComplexREACT_13272 (Reactome)
palmitoyl-CoA Metabolite15525 (ChEBI)
palmitoylated,

myristoylated eNOS dimer

ComplexREACT_13093 (Reactome)
palmitylated, N-

myristoylated eNOS

ProteinP29474 (UniProt)

Annotated Interactions

No annotated interactions

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