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

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475439, 4934, 4835203253, 5514, 521450501815312, 1124646449, 21, 29, 33506, 12, 16, 3841, 5122547, 25, 4319, 23, 3040, 452, 36, 465, 8, 28192710, 17, 31, 37, 424p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2[plasma membrane]eNOS:Caveolin-1:CaM:HSP90[plasma membrane]GCH1 decamer[cytosol]palmitoylated,myristoylated eNOSdimer [plasmamembrane]palmitoylated,myristoylated eNOSdimer [plasmamembrane]palmitoylated,myristoylated eNOSdimer [plasmamembrane]NOSTRIN homotrimer[endocytic vesiclemembrane]Active Calmodulin[plasma membrane]GCHFR pentamer[cytosol]Active Calmodulin[plasma membrane]palmitoylated,myristoylated eNOSdimer [endocyticvesicle membrane]myristoylated eNOSdimer [cytosol]GCH1 dimer [cytosol]eNOS:CaM:HSP90[plasma membrane]endocytic vesicle membraneAPT1 homodimer[cytosol]eNOS:Caveolin-1[plasma membrane]GCH1 decamer[cytosol]PTPS hexamer[cytosol]eNOS:Caveolin-1[plasma membrane]NOSTRIN homotrimer[plasma membrane]palmitoylated,myristoylated eNOSdimer [plasmamembrane]eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASP[endocytic vesiclemembrane]eNOS:Caveolin-1[endocytic vesiclemembrane]palmitoylated,myristoylated eNOSdimer [plasmamembrane]Active Calmodulin[cytosol]p-S1177-eNOS dimer[plasma membrane]eNOS:Caveolin-1[plasma membrane]p-S1177-eNOS dimer[plasma membrane]palmitoylated,myristoylated eNOSdimer [plasmamembrane]eNOS:Caveolin-1:CaM[plasma membrane]SPR dimer [cytosol]eNOS:Caveolin-1:NOSTRINcomplex [plasmamembrane]eNOS:NOSIP [Golgimembrane]palmitoylated,myristoylated eNOSdimer [plasmamembrane]eNOS:Caveolin-1[plasma membrane]NOSTRIN homotrimer[plasma membrane]eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASP[plasma membrane]NOSTRIN homotrimer[plasma membrane]eNOS:CaM:HSP90:p-AKT1[plasma membrane]p-S1177-eNOS:CaM:HSP90:p-AKT1[plasma membrane]DHFR dimer [cytosol]GCH1 dimer [cytosol]Active Calmodulin[cytosol]palmitoylated,myristoylated eNOSdimer [plasmamembrane]palmitoylated,myristoylated eNOSdimer [plasmamembrane]NOSTRIN homotrimer[plasma membrane]Active Calmodulin[plasma membrane]eNOS:CaM:HSP90[plasma membrane]p-PTPS hexamer[cytosol]p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4[plasma membrane]p-S1177-eNOS dimer[plasma membrane]lipid particlep-SPR dimer[cytosol]2GCHFR:GCH1[cytosol]palmitoylated,myristoylated eNOSdimer [plasmamembrane]palmitoylated,myristoylated eNOSdimer [Golgimembrane]eNOS:Caveolin-1:NOSTRIN:Dynamin-2[plasma membrane]eNOS:NOSIP [plasmamembrane]Active Calmodulin[cytosol]Golgi lumencytosolmyristoylated eNOSdimer [Golgimembrane]Active Calmodulin[plasma membrane]Active Calmodulin[cytosol]GCHFR pentamer[cytosol]CAV1 [plasmamembrane]O2HSP90AA1 [plasmamembrane]MYS-CoAFMN [cytosol]Ca2+ [plasmamembrane]CAV1 [endocyticvesicle membrane]heme [cytosol]Zn2+ [cytosol]heme [cytosol]L-Argp-T308,S473-AKT1[cytosol]heme [cytosol]2xPalmC-MyrG-p-S1177-NOS3(2-1203)[plasma membrane]heme [cytosol]eNOS:NOSIPFAD [cytosol]PALMCAV1 [plasmamembrane]H+DNM2 [endocyticvesicle membrane]BH4 [cytosol]eNOS:NOSIPeNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPBH4 [cytosol]PPPheme [cytosol]NADP+NOS3(2-1203)Zn2+ [cytosol]MyrG-NOS3(2-1203)ADPNADP+PRKG2heme [cytosol]PALM-CoAheme [cytosol]Ca2+ [cytosol]APT1 homodimerFAD [cytosol]2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]NOSIP [Golgimembrane]2GCHFR:GCH1FAD [cytosol]Zn2+ [cytosol]heme [cytosol]FMN [cytosol]Zn2+ [cytosol]VitCATPZn2+ [cytosol]Zn2+ [cytosol]e-Zn2+ [cytosol]Ascorbate radicalFAD [cytosol]Zn2+ [cytosol]FMN [cytosol]ZDHHC21heme [cytosol]MyrG-NOS3(2-1203)[Golgi membrane]GCH1 [cytosol]FMN [cytosol]HSP90AA1 [plasmamembrane]ADPBH4 [cytosol]GCH1 [cytosol]HSP90AA1SPR dimerheme [cytosol]p-S213-SPR [cytosol]FMN [cytosol]L-CitBH4 [cytosol]eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPBH4ATPNADP+GCHFR [cytosol]2xPalmC-MyrG-p-S1177-NOS3(2-1203)[plasma membrane]heme [cytosol]p-S1177-eNOS:CaM:HSP90:p-AKT1Ca2+ [cytosol]Fe3+NOSTRIN [plasmamembrane]Ca2+ [cytosol]PTHPZn2+ [cytosol]DNM2 [plasmamembrane]eNOS:CaM:HSP90:p-AKT1PeroxynitriteFMN [cytosol]FAD [cytosol]NOSIPFAD [cytosol]FMN [cytosol]FMN [cytosol]2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]CAV1 [plasmamembrane]heme [cytosol]FMN [cytosol]p-T308,S473-AKT1CALM1 [plasmamembrane]NADP+p-S19-PTS [cytosol]GTPFMN [cytosol]eNOS:Caveolin-1:CaMPTPS hexamerBH2O2NOSTRIN homotrimerBH4 [cytosol]FAD [cytosol]FAD [cytosol]WASLeNOS:CaM:HSP90FAD [cytosol]p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ATPFAD [cytosol]CALM1 [plasmamembrane]heme [cytosol]Zn2+ [cytosol]p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2HSP90AA1 [cytosol]eNOS:Caveolin-1:CaM:HSP90eNOS:Caveolin-12xPalmC-MyrG-NOS3(2-1203)[plasma membrane]2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]NADPHFAD [cytosol]p-T308,S473-AKT1[plasma membrane]FMN [cytosol]NOSIP [cytosol]CALM1 [cytosol]GCHFR pentamerZn2+ [cytosol]Zn2+ [cytosol]2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]FMN [cytosol]DHFR dimer2xPalmC-MyrG-NOS3(2-1203)FMN [cytosol]Active CalmodulinDNM2FAD [cytosol]BH4 [cytosol]DHNTPpalmitoylated,myristoylated eNOSdimerFMN [cytosol]CALM1 [cytosol]heme [cytosol]FMN [cytosol]2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]BH2 [cytosol]myristoylated eNOSdimerFMN [cytosol]Ca2+ [cytosol]Ca2+ [plasmamembrane]NADPHCAV1 [plasmamembrane]Zn2+ [cytosol]2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]BH4 [cytosol]p-T308,S473-AKT1[cytosol]HSP90AA1 [plasmamembrane]WASL [endocyticvesicle membrane]DNM2 [plasmamembrane]eNOS:Caveolin-1:NOSTRIN:Dynamin-22xPalmC-MyrG-NOS3(2-1203)[endocytic vesiclemembrane]Ca2+ [plasmamembrane]GCH1 decamerNOSTRIN [plasmamembrane]Zn2+ [cytosol]Fe2+HSP90AA1 [cytosol]heme [cytosol]FAD [cytosol]WASL [plasmamembrane]Zn2+ [cytosol]2xPalmC-MyrG-NOS3(2-1203)[Golgi membrane]BH3.2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]HSP90AA1 [cytosol]Zn2+ [cytosol]p-SPR dimerADPH2O2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]NOSTRIN [plasmamembrane]NADP+2xPalmC-MyrG-p-S1177-NOS3(2-1203)[plasma membrane]Zn2+ [cytosol]L-PheCALM1 [cytosol]FMN [cytosol]NOSTRIN [plasmamembrane]DHFR [cytosol]p-PTPS hexamerCAV1 [plasmamembrane]heme [cytosol]CAV1 [plasmamembrane]p-T308,S473-AKT1[cytosol]CAV1MyrG-NOS3(2-1203)[cytosol]FAD [cytosol]GCHFR [cytosol]LYPLA1 [cytosol]CALM1 [cytosol]PTS [cytosol]FAD [cytosol]NOHCOOHFAD [cytosol]O2.-sepiapterin2xPalmC-MyrG-NOS3(2-1203)[plasma membrane]Zn2+ [cytosol]SPR [cytosol]Ca2+ [plasmamembrane]myristoylated eNOSdimerNOSTRIN [endocyticvesicle membrane]eNOS:Caveolin-1:NOSTRINcomplexheme [cytosol]CALM1 [plasmamembrane]FAD [cytosol]CALM1 [plasmamembrane]NADPHNADPH241, 3, 13263626


Description

Nitric oxide (NO), a multifunctional second messenger, is implicated in physiological functions in mammals that range from immune response and potentiation of synaptic transmission to dilation of blood vessels and muscle relaxation. 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. 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 (Pacher et al. 2007).

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.<p>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).<p>The molecular details of eNOS function are annotated here.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=202131</div>

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History

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114629view16:09, 25 January 2021ReactomeTeamReactome version 75
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99395view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99089view12:39, 31 October 2018ReactomeTeamreactome version 62
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93432view11:23, 9 August 2017ReactomeTeamreactome version 61
86524view09:20, 11 July 2016ReactomeTeamreactome version 56
83235view10:27, 18 November 2015ReactomeTeamVersion54
81634view13:10, 21 August 2015ReactomeTeamVersion53
77097view08:39, 17 July 2014ReactomeTeamFixed remaining interactions
76803view12:18, 16 July 2014ReactomeTeamFixed remaining interactions
76126view10:19, 11 June 2014ReactomeTeamRe-fixing comment source
75838view11:40, 10 June 2014ReactomeTeamReactome 48 Update
75197view09:43, 9 May 2014AnweshaFixing comment source for displaying WikiPathways description
74846view10:07, 30 April 2014ReactomeTeamReactome46
70998view15:37, 22 September 2013EgonwImproved the layout, so that references and text are better readable in the current PV.
68887view17:27, 8 July 2013MaintBotUpdated to 2013 gpml schema
44897view10:20, 6 October 2011MartijnVanIerselOntology Term : 'classic metabolic pathway' added !
42166view23:32, 4 March 2011MaintBotModified categories
42068view21:54, 4 March 2011MaintBotAutomatic update
39876view05:54, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2GCHFR:GCH1ComplexREACT_111854 (Reactome)
2xPalmC-MyrG-NOS3(2-1203) [Golgi membrane]ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-NOS3(2-1203)

[endocytic vesicle

membrane]		ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-NOS3(2-1203) [plasma membrane]ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-NOS3(2-1203)ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-p-S1177-NOS3(2-1203) [plasma membrane]ProteinP29474 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
APT1 homodimerComplexREACT_13023 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active CalmodulinComplexREACT_3178 (Reactome)
Ascorbate radicalMetaboliteCHEBI:59513 (ChEBI)
BH2 [cytosol]MetaboliteCHEBI:15375 (ChEBI)
BH2MetaboliteCHEBI:15375 (ChEBI)
BH3.MetaboliteCHEBI:62772 (ChEBI)
BH4 [cytosol]MetaboliteCHEBI:15372 (ChEBI)
BH4MetaboliteCHEBI:15372 (ChEBI)
CALM1 [cytosol]ProteinP62158 (Uniprot-TrEMBL)
CALM1 [plasma membrane]ProteinP62158 (Uniprot-TrEMBL)
CAV1 [endocytic vesicle membrane]ProteinQ03135 (Uniprot-TrEMBL)
CAV1 [plasma membrane]ProteinQ03135 (Uniprot-TrEMBL)
CAV1ProteinQ03135 (Uniprot-TrEMBL)
Ca2+ [cytosol]MetaboliteCHEBI:29108 (ChEBI)
Ca2+ [plasma membrane]MetaboliteCHEBI:29108 (ChEBI)
DHFR [cytosol]ProteinP00374 (Uniprot-TrEMBL)
DHFR dimerComplexREACT_111516 (Reactome)
DHNTPMetaboliteCHEBI:18372 (ChEBI)
DNM2 [endocytic vesicle membrane]ProteinP50570 (Uniprot-TrEMBL)
DNM2 [plasma membrane]ProteinP50570 (Uniprot-TrEMBL)
DNM2ProteinP50570 (Uniprot-TrEMBL)
FAD [cytosol]MetaboliteCHEBI:16238 (ChEBI)
FMN [cytosol]MetaboliteCHEBI:17621 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
Fe3+MetaboliteCHEBI:29034 (ChEBI)
GCH1 [cytosol]ProteinP30793 (Uniprot-TrEMBL)
GCH1 decamerComplexREACT_111358 (Reactome)
GCHFR [cytosol]ProteinP30047 (Uniprot-TrEMBL)
GCHFR pentamerComplexREACT_111549 (Reactome)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCOOHMetaboliteCHEBI:30751 (ChEBI)
HSP90AA1 [cytosol]ProteinP07900 (Uniprot-TrEMBL)
HSP90AA1 [plasma membrane]ProteinP07900 (Uniprot-TrEMBL)
HSP90AA1ProteinP07900 (Uniprot-TrEMBL)
L-ArgMetaboliteCHEBI:16467 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
L-PheMetaboliteCHEBI:17295 (ChEBI)
LYPLA1 [cytosol]ProteinO75608 (Uniprot-TrEMBL)
MYS-CoAMetaboliteCHEBI:15532 (ChEBI)
MyrG-NOS3(2-1203) [Golgi membrane]ProteinP29474 (Uniprot-TrEMBL)
MyrG-NOS3(2-1203) [cytosol]ProteinP29474 (Uniprot-TrEMBL)
MyrG-NOS3(2-1203)ProteinP29474 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NOMetaboliteCHEBI:16480 (ChEBI)
NOS3(2-1203)ProteinP29474 (Uniprot-TrEMBL)
NOSIP [Golgi membrane]ProteinQ9Y314 (Uniprot-TrEMBL)
NOSIP [cytosol]ProteinQ9Y314 (Uniprot-TrEMBL)
NOSIPProteinQ9Y314 (Uniprot-TrEMBL)
NOSTRIN [endocytic vesicle membrane]ProteinQ8IVI9 (Uniprot-TrEMBL)
NOSTRIN [plasma membrane]ProteinQ8IVI9 (Uniprot-TrEMBL)
NOSTRIN homotrimerComplexREACT_12963 (Reactome)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PALM-CoAMetaboliteCHEBI:15525 (ChEBI)
PALMMetaboliteCHEBI:15756 (ChEBI)
PPPMetaboliteCHEBI:15266 (ChEBI)
PRKG2ProteinQ13237 (Uniprot-TrEMBL)
PTHPMetaboliteCHEBI:17804 (ChEBI)
PTPS hexamerComplexREACT_111768 (Reactome)
PTS [cytosol]ProteinQ03393 (Uniprot-TrEMBL)
PeroxynitriteMetaboliteCHEBI:25941 (ChEBI)
SPR [cytosol]ProteinP35270 (Uniprot-TrEMBL)
SPR dimerComplexREACT_111821 (Reactome)
VitCMetaboliteCHEBI:29073 (ChEBI)
WASL [endocytic vesicle membrane]ProteinO00401 (Uniprot-TrEMBL)
WASL [plasma membrane]ProteinO00401 (Uniprot-TrEMBL)
WASLProteinO00401 (Uniprot-TrEMBL)
ZDHHC21ProteinQ8IVQ6 (Uniprot-TrEMBL)
Zn2+ [cytosol]MetaboliteCHEBI:29105 (ChEBI)
e-MetaboliteCHEBI:10545 (ChEBI)
eNOS:CaM:HSP90:p-AKT1ComplexREACT_12902 (Reactome)
eNOS:CaM:HSP90ComplexREACT_12871 (Reactome)
eNOS:Caveolin-1:CaM:HSP90ComplexREACT_12971 (Reactome)
eNOS:Caveolin-1:CaMComplexREACT_12757 (Reactome)
eNOS:Caveolin-1:NOSTRIN complexComplexREACT_13185 (Reactome)
eNOS:Caveolin-1:NOSTRIN:Dynamin-2ComplexREACT_12737 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPComplexREACT_12814 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPComplexREACT_13117 (Reactome)
eNOS:Caveolin-1ComplexREACT_12997 (Reactome)
eNOS:NOSIPComplexREACT_12699 (Reactome)
eNOS:NOSIPComplexREACT_13282 (Reactome)
heme [cytosol]MetaboliteCHEBI:17627 (ChEBI)
myristoylated eNOS dimerComplexREACT_12833 (Reactome)
myristoylated eNOS dimerComplexREACT_13272 (Reactome)
p-PTPS hexamerComplexREACT_111591 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2ComplexREACT_111290 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ComplexREACT_111579 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1ComplexREACT_12662 (Reactome)
p-S19-PTS [cytosol]ProteinQ03393 (Uniprot-TrEMBL)
p-S213-SPR [cytosol]ProteinP35270 (Uniprot-TrEMBL)
p-SPR dimerComplexREACT_111842 (Reactome)
p-T308,S473-AKT1 [cytosol]ProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1 [plasma membrane]ProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)
palmitoylated,

myristoylated eNOS

dimer		ComplexREACT_13093 (Reactome)
sepiapterinMetaboliteCHEBI:16095 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2GCHFR:GCH1ArrowREACT_111115 (Reactome)
2GCHFR:GCH1TBarREACT_111143 (Reactome)
2xPalmC-MyrG-NOS3(2-1203)ArrowREACT_12530 (Reactome)
2xPalmC-MyrG-NOS3(2-1203)REACT_12492 (Reactome)
ADPArrowREACT_111129 (Reactome)
ADPArrowREACT_111245 (Reactome)
ADPArrowREACT_12415 (Reactome)
APT1 homodimermim-catalysisREACT_12463 (Reactome)
ATPREACT_111129 (Reactome)
ATPREACT_111245 (Reactome)
ATPREACT_12415 (Reactome)
Active CalmodulinArrowREACT_12426 (Reactome)
Active CalmodulinREACT_12620 (Reactome)
Ascorbate radicalArrowREACT_111191 (Reactome)
BH2ArrowREACT_111165 (Reactome)
BH2ArrowREACT_111234 (Reactome)
BH2REACT_111041 (Reactome)
BH2REACT_111106 (Reactome)
BH3.ArrowREACT_111060 (Reactome)
BH3.ArrowREACT_111062 (Reactome)
BH3.REACT_111125 (Reactome)
BH3.REACT_111165 (Reactome)
BH3.REACT_111191 (Reactome)
BH4ArrowREACT_111041 (Reactome)
BH4ArrowREACT_111093 (Reactome)
BH4ArrowREACT_111106 (Reactome)
BH4ArrowREACT_111125 (Reactome)
BH4ArrowREACT_111191 (Reactome)
BH4REACT_111060 (Reactome)
BH4REACT_111062 (Reactome)
BH4REACT_111175 (Reactome)
BH4TBarREACT_111143 (Reactome)
CAV1ArrowREACT_12459 (Reactome)
CAV1REACT_12499 (Reactome)
DHFR dimermim-catalysisREACT_111041 (Reactome)
DHNTPArrowREACT_111143 (Reactome)
DHNTPREACT_111082 (Reactome)
DNM2REACT_12512 (Reactome)
Fe2+REACT_111125 (Reactome)
Fe3+ArrowREACT_111125 (Reactome)
GCH1 decamerREACT_111115 (Reactome)
GCH1 decamermim-catalysisREACT_111143 (Reactome)
GCHFR pentamerREACT_111115 (Reactome)
GTPREACT_111143 (Reactome)
H+REACT_111041 (Reactome)
H+REACT_111234 (Reactome)
H2OREACT_111143 (Reactome)
HCOOHArrowREACT_111143 (Reactome)
HSP90AA1REACT_12426 (Reactome)
L-ArgREACT_12443 (Reactome)
L-CitArrowREACT_12443 (Reactome)
L-PheArrowREACT_111143 (Reactome)
MYS-CoAREACT_12474 (Reactome)
MyrG-NOS3(2-1203)ArrowREACT_12474 (Reactome)
MyrG-NOS3(2-1203)REACT_12530 (Reactome)
NADP+ArrowREACT_111041 (Reactome)
NADP+ArrowREACT_111093 (Reactome)
NADP+ArrowREACT_111234 (Reactome)
NADP+ArrowREACT_111249 (Reactome)
NADP+ArrowREACT_12443 (Reactome)
NADPHREACT_111041 (Reactome)
NADPHREACT_111093 (Reactome)
NADPHREACT_111234 (Reactome)
NADPHREACT_111249 (Reactome)
NADPHREACT_12443 (Reactome)
NOArrowREACT_12443 (Reactome)
NOREACT_111092 (Reactome)
NOS3(2-1203)REACT_12474 (Reactome)
NOSIPREACT_12589 (Reactome)
NOSTRIN homotrimerREACT_12427 (Reactome)
O2.-ArrowREACT_111249 (Reactome)
O2.-REACT_111092 (Reactome)
O2REACT_111249 (Reactome)
O2REACT_12443 (Reactome)
PALM-CoAREACT_12530 (Reactome)
PALMArrowREACT_12463 (Reactome)
PPPArrowREACT_111082 (Reactome)
PRKG2mim-catalysisREACT_111129 (Reactome)
PRKG2mim-catalysisREACT_111245 (Reactome)
PTHPArrowREACT_111082 (Reactome)
PTHPREACT_111093 (Reactome)
PTPS hexamerREACT_111245 (Reactome)
PeroxynitriteArrowREACT_111092 (Reactome)
PeroxynitriteREACT_111062 (Reactome)
REACT_111041 (Reactome) In the second salvage step, dihydrofolate reductase (DHFR) can regenerate BH4 from BH2, a process which increases the BH4:BH2 ratio providing BH4 for coupled eNOS production of NO. In mice cell lines, DHFR inhibition or knockdown diminishes the BH4:BH2 ratio and exacerbates eNOS uncoupling (Crabtree et al. 2009).
REACT_111060 (Reactome) BH4 donates an electron to the eNOS catalytic cycle and is oxidised to the BH3 radical (BH3.-) (Berka et al. 2004).
REACT_111062 (Reactome) Peroxynitrite can oxidise BH4 to the BH3 radical, further reducing BH4 availability to couple eNOS activity and compounding the production of superoxide through uncoupled eNOS activity (Kuzkaya et al. 2003).
REACT_111082 (Reactome) 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) (Takikawa et al. 1986) catalyses the second step in BH4 biosynthesis, the dephosphorylation of DHNTP to 6-pyruvoyl-tetrahydropterin (PTHP). PTPS is believed to function as a homohexamer (Nar et al. 1994, Bürgisser et al. 1994) and has a requirement for Zn2+ (one Zn2+ ion bound per subunit) and Mg2+ ions for activity (Bürgisser et al. 1995). The phosphorylation of Ser-19 is an essential modification for enzyme activity (Scherer-Oppliger et al. 1999).
REACT_111092 (Reactome) Superoxide (O2.-) formed from an uncoupled eNOS action, together with nitric oxide (NO) formed from a coupled eNOS action, readily react together to fom peroxynitrite (ONOO-) (Jourd'heuil et al. 2001, Reiter et al. 2000).
REACT_111093 (Reactome) Sepiapterin reductase (SPR) (Ichinose et al. 1991) reduces DHNTP to tetrahydrobiopterin (BH4).
REACT_111106 (Reactome) The oxidation product of BH4, 7,8-dihydrobiopterin (BH2), can compete with BH4 for binding to eNOS. This can lead to the uncoupling of eNOS and can result in the formation of reactive oxygen species (Vasquez-Vivar et al. 2002).
REACT_111115 (Reactome) High levels of the end product, BH4, negatively regulates GCH1. It does this via GTP cyclohydrolase 1 feedback regulatory protein (GCHFR). BH4-dependant GCHFR in the form of a homopentamer complexes with the decameric GCH1 enzyme in the ratio 2:1 to inactivate it. L-phenylalanine reverses this inhibition. These regulatory steps control the biosynthesis of BH4. (Swick & Kapatos 2006, Chavan et al. 2006, Harada et al. 1993).
REACT_111125 (Reactome) Heme iron from the oxygenase domain of eNOS can reduce the BH3 radical back to BH4, with itself being oxidised from the ferrous (Fe2+) back to the ferric (Fe3+) form (Berka et al. 2004).
REACT_111129 (Reactome) To become active, sepiapterin reductase (SPR) must first be phosphorylated (serine 213 in humans) by Ca2+/calmodulin-dependent protein kinase II (Fujimoto et al. 2002, Katoh et al. 1994).
REACT_111143 (Reactome) The first and rate-limiting enzyme in tetrahydrobiopterin de novo biosynthesis is GTP cyclohydrolase I (GCH1, GTPCHI). Three different isoforms are produced but only isoform 1 is functionally active (Gütlich et al. 1994). GCH1 is functional as a homodecamer. First, a monomer of GCH1 forms a dimer. Then five dimers arrange into a ring-like structure to form the homodecamer (Nar et al. 1995).
REACT_111165 (Reactome) BH4 oxidation results in the radical BH3. which decays to 7,8-dihydrobiopterin (BH2) (Milstien & Katusic, 1999).
REACT_111175 (Reactome) The cofactor tetrahydrobiopterin (BH4) ensures endothelial nitric oxide synthase (eNOS) couples electron transfer to L-arginine oxidation (Berka et al. 2004). During catalysis, electrons derived from NADPH transfer to the flavins FAD and FMN in the reductase domain of eNOS and then on to the ferric heme in the oxygenase domain of eNOS. BH4 can donate an electron to intermediates in this electron transfer and is oxidised in the process, forming the BH3 radical. This radical can be reduced back to BH4 by iron, completing the cycle and forming ferrous iron again. Heme reduction enables O2 binding and L-arginine oxidation to occur within the oxygenase domain (Stuehr et al. 2009).
REACT_111191 (Reactome) Ascorbate (vitamin C) can reduce the BH3 radical back to BH4, thereby maintaining BH4 levels (Baker et al. 2001, Patel et al. 2002, Kuzkaya et al. 2003).
REACT_111234 (Reactome) In the first of two salvage steps to maintain BH4 levels in the cell, sepiapterin is taken up by the cell and reduced by sepiapterin reductase (SRP) to form BH2 (Sawabe et al. 2008).
REACT_111245 (Reactome) 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) requires phosphorylation on Ser-19 for enzyme activity (Scherer-Oppliger et al. 1999).
REACT_111249 (Reactome) BH2 may compete with BH4 to bind eNOS, uncoupling eNOS leading to the formation of superoxide rather than nitric oxide. BH2, the oxidised form of BH4, cannot contribute electrons to heme in the reductase domain of eNOS, thereby uncoupling it from arginine oxidation and producing superoxide from oxygen instead (Vasquez-Vivar et al. 2002).
REACT_12382 (Reactome) AKT1 is recruited to the M domain of HSP90.
REACT_12415 (Reactome) HSP90 serves as a scaffold to promote productive interaction between AKT1 and eNOS. Due to the proximity of these proteins once complexed with HSP90, AKT1 phosphorylates eNOS at Ser1177. When Ser1177 is phosphorylated, the level of NO production is elevated two- to three-fold above basal level.


REACT_12426 (Reactome) HSP90 interacts with the amino terminus of eNOS (amino acids 442-600) and facilitates displacement of caveolin by calmodulin (CaM).
REACT_12427 (Reactome) eNOS interacts with the SH3 domain of NOSTRIN (positions 434-506). Caveolin-1 also binds directly to NOSTRIN (residues 323-434), thus allowing formation of a ternary complex.
REACT_12443 (Reactome) Nitric oxide (NO) is produced from L-arginine by the family of nitric oxide synthases (NOS) enzymes, forming the free radical NO and citrulline as byproduct. The cofactor tetrahydrobiopterin (BH4) is an essential requirement for the delivery of an electron to the intermediate in the catalytic cycle of NOS.
REACT_12459 (Reactome) HSP90 facilitates the CaM-induced displacement of caveolin from eNOS.
REACT_12463 (Reactome) Increases in intracellular calcium and calmodulin stimulate depalmitoylation of eNOS by acyl protein thioesterase 1, which displaces eNOS from the membrane. This might be a mechanism to downregulate NO production following intense stimuli.
REACT_12474 (Reactome) A glycine residue (Gly2) at the N-terminus of eNOS is myristoylated, providing membrane localization.
REACT_12488 (Reactome) Once depalmitoylated, it's proposed that eNOS is displaced from the plasma membrane and redistributed to other intracellular membranes, including the Golgi, where re-palmitoylation occurs. The mechanism of transport from the plasma membrane is still unknown.
REACT_12492 (Reactome) Palymitoylated, myristoylated eNOS forms a dimer and is transported from the Golgi to the plasma membrane. Transport is thought to be mediated by intracellular vesicles, but the details remain unknown.
REACT_12499 (Reactome) Caveolin-1 is the primary negative regulatory protein for eNOS. Caveolin-1 binding to eNOS compromises its ability to bind Calmodulin (CaM), thereby inhibiting enzyme activity. The major binding region of caveolin-1 for eNOS is within amino acids 60-101 and to a lesser extent, amino acids 135-178.
REACT_12512 (Reactome) NOSTRIN binds to dynamin via its SH3 domain.
REACT_12530 (Reactome) DHHC-21 is a Golgi-localized acyl transferase that palmitoylates eNOS, which targets eNOS to plasmalemmal caveolae. Localization to this microdomain is likely to optimize eNOS activation and the extracellular release of nitric oxide.
REACT_12589 (Reactome) NOSIP (eNOS interacting protein) binds to the carboxyl-terminal region of the eNOS oxygenase domain. Note that the eNOS binding sites for caveolin and NOSIP overlap.
REACT_12590 (Reactome) NOSIP promotes translocation of eNOS from the plasma membrane to intracellular sites, thereby uncoupling eNOS from plasma membrane caveolae and inhibiting NO synthesis. eNOS appears to be shifted to intracellular sites that colocalize with Golgi and/or cytoskeletal marker proteins.
REACT_12611 (Reactome) NOSTRIN interacts with the actin nucleation promoting factor N-WASP by means of its SH3 domain.
REACT_12620 (Reactome) Caveolin inhibition of eNOS is relieved by calmodulin, which causes dissociation of eNOS from caveolin.
REACT_12634 (Reactome) NOSTRIN translocates eNOS from the plasma membrane to intracellular vesicular structures. NOSTRIN internalization of eNOS is proposed to occur via vesicle fission and caveolar transport through cooperation with dynamin and N-WASP.
SPR dimerREACT_111129 (Reactome)
VitCREACT_111191 (Reactome)
WASLREACT_12611 (Reactome)
ZDHHC21mim-catalysisREACT_12530 (Reactome)
e-ArrowREACT_111060 (Reactome)
eNOS:CaM:HSP90:p-AKT1ArrowREACT_12382 (Reactome)
eNOS:CaM:HSP90:p-AKT1REACT_12415 (Reactome)
eNOS:CaM:HSP90ArrowREACT_12459 (Reactome)
eNOS:CaM:HSP90REACT_12382 (Reactome)
eNOS:Caveolin-1:CaM:HSP90ArrowREACT_12426 (Reactome)
eNOS:Caveolin-1:CaM:HSP90REACT_12459 (Reactome)
eNOS:Caveolin-1:CaMArrowREACT_12620 (Reactome)
eNOS:Caveolin-1:CaMREACT_12426 (Reactome)
eNOS:Caveolin-1:NOSTRIN complexArrowREACT_12427 (Reactome)
eNOS:Caveolin-1:NOSTRIN complexREACT_12512 (Reactome)
eNOS:Caveolin-1:NOSTRIN:Dynamin-2ArrowREACT_12512 (Reactome)
eNOS:Caveolin-1:NOSTRIN:Dynamin-2REACT_12611 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPArrowREACT_12611 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPArrowREACT_12634 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPREACT_12634 (Reactome)
eNOS:Caveolin-1ArrowREACT_12499 (Reactome)
eNOS:Caveolin-1REACT_12427 (Reactome)
eNOS:Caveolin-1REACT_12620 (Reactome)
eNOS:NOSIPArrowREACT_12589 (Reactome)
eNOS:NOSIPArrowREACT_12590 (Reactome)
eNOS:NOSIPREACT_12590 (Reactome)
myristoylated eNOS dimerArrowREACT_12463 (Reactome)
myristoylated eNOS dimerArrowREACT_12488 (Reactome)
myristoylated eNOS dimerREACT_12488 (Reactome)
p-PTPS hexamerArrowREACT_111245 (Reactome)
p-PTPS hexamermim-catalysisREACT_111082 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2ArrowREACT_111106 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2mim-catalysisREACT_111249 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ArrowREACT_111175 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4REACT_111106 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4mim-catalysisREACT_12443 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1ArrowREACT_12415 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1REACT_111175 (Reactome)
p-SPR dimerArrowREACT_111129 (Reactome)
p-SPR dimermim-catalysisREACT_111093 (Reactome)
p-SPR dimermim-catalysisREACT_111234 (Reactome)
p-T308,S473-AKT1REACT_12382 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		ArrowREACT_12492 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		REACT_12463 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		REACT_12499 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		REACT_12589 (Reactome)
sepiapterinREACT_111234 (Reactome)

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