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

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25, 6, 3017173215, 59, 634212, 436020, 25, 26, 6141165842237, 31, 40, 47, 5711, 22, 24, 5351594, 27, 3616, 3310, 12, 421, 4414, 1860136450, 5260468, 47, 5719, 34, 39, 45, 6229, 49, 5528, 541235349, 56Golgi lumencytosolendocytic vesicle membranelipid particleCa2+ APT1 homodimerMyrG-NOS3FAD Ca2+ myristoylated eNOSdimerCALM1 DMAGCH1 FMN WASL BH4 Ca2+ heme heme ADPNADP+SPR 2xPalmC-MyrG-NOS3 heme p-T308,S473-AKT1Zn2+ GCHFR pentamereNOS:Caveolin-1:NOSTRIN:Dynamin-2GCHFR ADMAPTS NADPH2xPalmC-MyrG-NOS3 H+NADP+2xPalmC-MyrG-NOS3 CAV1 CAV1 L-Citheme 4xCa2+:CaMCa2+ CALM1 e-2xPalmC-MyrG-NOS3 p-T308,S473-AKT1 FAD HSP90AA1 eNOS:Caveolin-1:CaMDDAH1p-S213-SPR HSP90AA1 HSP90AA1 CALM1 FAD PRKG2PALMFAD NADP+Zn2+ Zn2+ Ca2+ H2OeNOS:CaM:HSP90:p-AKT1FAD Zn2+ CAV1 CALM1 FMN ATP2xPalmC-MyrG-NOS3DNM2 2xPalmC-MyrG-NOS3 NOSTRIN homotrimerMYS-CoAheme FMN heme GCHFR FAD p-T308,S473-AKT1 BH2 Zn2+ MyrG-NOS3 eNOS:Caveolin-1:NOSTRIN complexFAD Zn2+ SPR dimer2xPalmC-MyrG-p-S1177-NOS3 CYGB dimer:O2heme BH3.2GCHFR:GCH1LYPLA1 CYGB dimerNADP+Zn2+ L-PheH2OPeroxynitriteDNM2 p-T308,S473-AKT1 NADPHDNM2 Fe3+NOSTRIN heme palmitoylated,myristoylated eNOSdimerp-PTPS hexamerFAD FMN HSP90AA1 GCH1 FAD FMN Zn2+ heme ZDHHC21ADPFMN BH4 FMN N-WASPGTPPPPCa2+ FMN VitCNADP+2xPalmC-MyrG-p-S1177-NOS3 H+BH2BH4 heme DHFR O2.-NOSTRIN NOSTRIN heme MyrG-NOS3 Zn2+ eNOS:Caveolin-1HSP90AA1 FMN O2 DHNTP2xPalmC-MyrG-NOS3 PTPS hexamerFMN FMN 2xPalmC-MyrG-NOS3 Zn2+ Ca2+ Zn2+ NOSIP myristoylated eNOSdimerNOS3Zn2+ NADPHNOATPATPFMN 2xPalmC-MyrG-NOS3 CYGB Zn2+ Fe2+HSP90AA1 PTHPFMN heme p-S19-PTS heme FAD p-S1177-eNOS:CaM:HSP90:p-AKT1WASL FAD NOSIPBH4 NADPHO2eNOS:NOSIPp-S1177-eNOS:CaM:HSP90:p-AKT1:BH2NOSIP CALM1 heme 2xPalmC-MyrG-NOS3 NO3-GCH1 decamerADPheme FAD Zn2+ NADPHFMN CALM1 Ascorbate radicalBH4 FAD CAV1 p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4Zn2+ sepiapterinFMN 2xPalmC-MyrG-NOS3 FAD Zn2+ FMN HSP90AA1CALM1 NOSTRIN BH4CAV1 L-ArgO2NADP+DHFR dimerCALM1 NOSTRIN BH4 DNM2FAD FMN CAV1 Ca2+ heme 2xPalmC-MyrG-NOS3 eNOS:CaM:HSP90eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPeNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPeNOS:Caveolin-1:CaM:HSP90BH4 HCOOHZn2+ FAD Zn2+ CAV1FAD eNOS:NOSIP2xPalmC-MyrG-p-S1177-NOS3 CYGB heme p-SPR dimerp-T308,S473-AKT1 PALM-CoA2xPalmC-MyrG-NOS3 CAV1 103738383, 21, 48


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. View original pathway at:Reactome.</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114629view16:09, 25 January 2021ReactomeTeamReactome version 75
113077view11:13, 2 November 2020ReactomeTeamReactome version 74
112311view15:23, 9 October 2020ReactomeTeamReactome version 73
101210view11:10, 1 November 2018ReactomeTeamreactome version 66
100748view20:35, 31 October 2018ReactomeTeamreactome version 65
100292view19:12, 31 October 2018ReactomeTeamreactome version 64
99838view15:56, 31 October 2018ReactomeTeamreactome version 63
99395view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99089view12:39, 31 October 2018ReactomeTeamreactome version 62
93867view13:41, 16 August 2017ReactomeTeamreactome version 61
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

View all...
NameTypeDatabase referenceComment
2GCHFR:GCH1ComplexR-HSA-1474149 (Reactome)
2xPalmC-MyrG-NOS3 ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-NOS3ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-p-S1177-NOS3 ProteinP29474 (Uniprot-TrEMBL)
4xCa2+:CaMComplexR-HSA-74294 (Reactome)
ADMAMetaboliteCHEBI:25682 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
APT1 homodimerComplexR-HSA-203655 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ascorbate radicalMetaboliteCHEBI:59513 (ChEBI)
BH2 MetaboliteCHEBI:15375 (ChEBI)
BH2MetaboliteCHEBI:15375 (ChEBI)
BH3.MetaboliteCHEBI:62772 (ChEBI)
BH4 MetaboliteCHEBI:15372 (ChEBI)
BH4MetaboliteCHEBI:15372 (ChEBI)
CALM1 ProteinP62158 (Uniprot-TrEMBL)
CAV1 ProteinQ03135 (Uniprot-TrEMBL)
CAV1ProteinQ03135 (Uniprot-TrEMBL)
CYGB ProteinQ8WWM9 (Uniprot-TrEMBL)
CYGB dimer:O2ComplexR-HSA-5340212 (Reactome)
CYGB dimerComplexR-HSA-5340240 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
DDAH1ProteinO94760 (Uniprot-TrEMBL)
DHFR ProteinP00374 (Uniprot-TrEMBL)
DHFR dimerComplexR-HSA-1497822 (Reactome)
DHNTPMetaboliteCHEBI:18372 (ChEBI)
DMAMetaboliteCHEBI:17170 (ChEBI)
DNM2 ProteinP50570 (Uniprot-TrEMBL)
DNM2ProteinP50570 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FMN MetaboliteCHEBI:17621 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
Fe3+MetaboliteCHEBI:29034 (ChEBI)
GCH1 ProteinP30793 (Uniprot-TrEMBL)
GCH1 decamerComplexR-HSA-1474144 (Reactome)
GCHFR ProteinP30047 (Uniprot-TrEMBL)
GCHFR pentamerComplexR-HSA-1474155 (Reactome)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCOOHMetaboliteCHEBI:30751 (ChEBI)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90AA1ProteinP07900 (Uniprot-TrEMBL)
L-ArgMetaboliteCHEBI:16467 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
L-PheMetaboliteCHEBI:17295 (ChEBI)
LYPLA1 ProteinO75608 (Uniprot-TrEMBL)
MYS-CoAMetaboliteCHEBI:15532 (ChEBI)
MyrG-NOS3 ProteinP29474 (Uniprot-TrEMBL)
MyrG-NOS3ProteinP29474 (Uniprot-TrEMBL)
N-WASPProteinO00401 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NO3-MetaboliteCHEBI:48107 (ChEBI)
NOMetaboliteCHEBI:16480 (ChEBI)
NOS3ProteinP29474 (Uniprot-TrEMBL)
NOSIP ProteinQ9Y314 (Uniprot-TrEMBL)
NOSIPProteinQ9Y314 (Uniprot-TrEMBL)
NOSTRIN ProteinQ8IVI9 (Uniprot-TrEMBL)
NOSTRIN homotrimerComplexR-HSA-203678 (Reactome)
O2 MetaboliteCHEBI:15379 (ChEBI)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PALM-CoAMetaboliteCHEBI:15525 (ChEBI)
PALMMetaboliteCHEBI:15756 (ChEBI)
PPPMetaboliteCHEBI:15266 (ChEBI)
PRKG2ProteinQ13237 (Uniprot-TrEMBL)
PTHPMetaboliteCHEBI:17804 (ChEBI)
PTPS hexamerComplexR-HSA-1497879 (Reactome)
PTS ProteinQ03393 (Uniprot-TrEMBL)
PeroxynitriteMetaboliteCHEBI:25941 (ChEBI)
SPR ProteinP35270 (Uniprot-TrEMBL)
SPR dimerComplexR-HSA-1497791 (Reactome)
VitCMetaboliteCHEBI:29073 (ChEBI)
WASL ProteinO00401 (Uniprot-TrEMBL)
ZDHHC21ProteinQ8IVQ6 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
e-MetaboliteCHEBI:10545 (ChEBI)
eNOS:CaM:HSP90:p-AKT1ComplexR-HSA-202113 (Reactome)
eNOS:CaM:HSP90ComplexR-HSA-202105 (Reactome)
eNOS:Caveolin-1:CaM:HSP90ComplexR-HSA-202130 (Reactome)
eNOS:Caveolin-1:CaMComplexR-HSA-202116 (Reactome)
eNOS:Caveolin-1:NOSTRIN complexComplexR-HSA-203758 (Reactome)
eNOS:Caveolin-1:NOSTRIN:Dynamin-2ComplexR-HSA-203696 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPComplexR-HSA-203629 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPComplexR-HSA-203648 (Reactome)
eNOS:Caveolin-1ComplexR-HSA-202128 (Reactome)
eNOS:NOSIPComplexR-HSA-203595 (Reactome)
eNOS:NOSIPComplexR-HSA-203623 (Reactome)
heme MetaboliteCHEBI:17627 (ChEBI)
myristoylated eNOS dimerComplexR-HSA-203619 (Reactome)
myristoylated eNOS dimerComplexR-HSA-203969 (Reactome)
p-PTPS hexamerComplexR-HSA-1475058 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2ComplexR-HSA-1497889 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ComplexR-HSA-1497830 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1ComplexR-HSA-202121 (Reactome)
p-S19-PTS ProteinQ03393 (Uniprot-TrEMBL)
p-S213-SPR ProteinP35270 (Uniprot-TrEMBL)
p-SPR dimerComplexR-HSA-1497817 (Reactome)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)
palmitoylated,

myristoylated eNOS

dimer		ComplexR-HSA-203639 (Reactome)
sepiapterinMetaboliteCHEBI:16095 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2GCHFR:GCH1ArrowR-HSA-1474158 (Reactome)
2GCHFR:GCH1TBarR-HSA-1474146 (Reactome)
2xPalmC-MyrG-NOS3ArrowR-HSA-203567 (Reactome)
2xPalmC-MyrG-NOS3R-HSA-203700 (Reactome)
4xCa2+:CaMArrowR-HSA-202129 (Reactome)
4xCa2+:CaMR-HSA-202110 (Reactome)
ADMAR-HSA-5693373 (Reactome)
ADMATBarR-HSA-202127 (Reactome)
ADPArrowR-HSA-1475422 (Reactome)
ADPArrowR-HSA-1497853 (Reactome)
ADPArrowR-HSA-202111 (Reactome)
APT1 homodimermim-catalysisR-HSA-203613 (Reactome)
ATPR-HSA-1475422 (Reactome)
ATPR-HSA-1497853 (Reactome)
ATPR-HSA-202111 (Reactome)
Ascorbate radicalArrowR-HSA-1497855 (Reactome)
BH2ArrowR-HSA-1497863 (Reactome)
BH2ArrowR-HSA-1497869 (Reactome)
BH2R-HSA-1497794 (Reactome)
BH2R-HSA-1497796 (Reactome)
BH3.ArrowR-HSA-1497824 (Reactome)
BH3.ArrowR-HSA-1497866 (Reactome)
BH3.R-HSA-1497855 (Reactome)
BH3.R-HSA-1497863 (Reactome)
BH3.R-HSA-1497883 (Reactome)
BH4ArrowR-HSA-1475414 (Reactome)
BH4ArrowR-HSA-1497794 (Reactome)
BH4ArrowR-HSA-1497796 (Reactome)
BH4ArrowR-HSA-1497855 (Reactome)
BH4ArrowR-HSA-1497883 (Reactome)
BH4R-HSA-1497784 (Reactome)
BH4R-HSA-1497824 (Reactome)
BH4R-HSA-1497866 (Reactome)
BH4TBarR-HSA-1474146 (Reactome)
CAV1ArrowR-HSA-202144 (Reactome)
CAV1R-HSA-203712 (Reactome)
CYGB dimer:O2ArrowR-HSA-5340214 (Reactome)
CYGB dimer:O2R-HSA-5340226 (Reactome)
CYGB dimer:O2mim-catalysisR-HSA-5340226 (Reactome)
CYGB dimerArrowR-HSA-5340226 (Reactome)
CYGB dimerR-HSA-5340214 (Reactome)
DDAH1mim-catalysisR-HSA-5693373 (Reactome)
DHFR dimermim-catalysisR-HSA-1497794 (Reactome)
DHNTPArrowR-HSA-1474146 (Reactome)
DHNTPR-HSA-1474184 (Reactome)
DMAArrowR-HSA-5693373 (Reactome)
DNM2R-HSA-203662 (Reactome)
Fe2+R-HSA-1497883 (Reactome)
Fe3+ArrowR-HSA-1497883 (Reactome)
GCH1 decamerR-HSA-1474158 (Reactome)
GCH1 decamermim-catalysisR-HSA-1474146 (Reactome)
GCHFR pentamerR-HSA-1474158 (Reactome)
GTPR-HSA-1474146 (Reactome)
H+R-HSA-1497794 (Reactome)
H+R-HSA-1497869 (Reactome)
H+R-HSA-5340226 (Reactome)
H2OR-HSA-1474146 (Reactome)
H2OR-HSA-5693373 (Reactome)
HCOOHArrowR-HSA-1474146 (Reactome)
HSP90AA1R-HSA-202129 (Reactome)
L-ArgR-HSA-202127 (Reactome)
L-CitArrowR-HSA-202127 (Reactome)
L-CitArrowR-HSA-5693373 (Reactome)
L-PheArrowR-HSA-1474146 (Reactome)
MYS-CoAR-HSA-203611 (Reactome)
MyrG-NOS3ArrowR-HSA-203611 (Reactome)
MyrG-NOS3R-HSA-203567 (Reactome)
N-WASPR-HSA-203565 (Reactome)
NADP+ArrowR-HSA-1475414 (Reactome)
NADP+ArrowR-HSA-1497794 (Reactome)
NADP+ArrowR-HSA-1497810 (Reactome)
NADP+ArrowR-HSA-1497869 (Reactome)
NADP+ArrowR-HSA-202127 (Reactome)
NADP+ArrowR-HSA-5340226 (Reactome)
NADPHR-HSA-1475414 (Reactome)
NADPHR-HSA-1497794 (Reactome)
NADPHR-HSA-1497810 (Reactome)
NADPHR-HSA-1497869 (Reactome)
NADPHR-HSA-202127 (Reactome)
NADPHR-HSA-5340226 (Reactome)
NO3-ArrowR-HSA-5340226 (Reactome)
NOArrowR-HSA-202127 (Reactome)
NOR-HSA-1497878 (Reactome)
NOR-HSA-5340226 (Reactome)
NOS3R-HSA-203611 (Reactome)
NOSIPR-HSA-203553 (Reactome)
NOSTRIN homotrimerR-HSA-203716 (Reactome)
O2.-ArrowR-HSA-1497810 (Reactome)
O2.-R-HSA-1497878 (Reactome)
O2R-HSA-1497810 (Reactome)
O2R-HSA-202127 (Reactome)
O2R-HSA-5340214 (Reactome)
PALM-CoAR-HSA-203567 (Reactome)
PALMArrowR-HSA-203613 (Reactome)
PPPArrowR-HSA-1474184 (Reactome)
PRKG2mim-catalysisR-HSA-1475422 (Reactome)
PRKG2mim-catalysisR-HSA-1497853 (Reactome)
PTHPArrowR-HSA-1474184 (Reactome)
PTHPR-HSA-1475414 (Reactome)
PTPS hexamerR-HSA-1475422 (Reactome)
PeroxynitriteArrowR-HSA-1497878 (Reactome)
PeroxynitriteR-HSA-1497866 (Reactome)
R-HSA-1474146 (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).
R-HSA-1474158 (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).
R-HSA-1474184 (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).
R-HSA-1475414 (Reactome) Sepiapterin reductase (SPR) (Ichinose et al. 1991) reduces DHNTP to tetrahydrobiopterin (BH4).
R-HSA-1475422 (Reactome) 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) requires phosphorylation on Ser-19 for enzyme activity (Scherer-Oppliger et al. 1999).
R-HSA-1497784 (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).
R-HSA-1497794 (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).
R-HSA-1497796 (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).
R-HSA-1497810 (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).
R-HSA-1497824 (Reactome) BH4 donates an electron to the eNOS catalytic cycle and is oxidised to the BH3 radical (BH3.-) (Berka et al. 2004).
R-HSA-1497853 (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).
R-HSA-1497855 (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).
R-HSA-1497863 (Reactome) BH4 oxidation results in the radical BH3. which decays to 7,8-dihydrobiopterin (BH2) (Milstien & Katusic, 1999).
R-HSA-1497866 (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).
R-HSA-1497869 (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).
R-HSA-1497878 (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).
R-HSA-1497883 (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).
R-HSA-202110 (Reactome) Caveolin inhibition of eNOS is relieved by calmodulin, which causes dissociation of eNOS from caveolin.
R-HSA-202111 (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.


R-HSA-202127 (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.
R-HSA-202129 (Reactome) HSP90 interacts with the amino terminus of eNOS (amino acids 442-600) and facilitates displacement of caveolin by calmodulin (CaM).
R-HSA-202132 (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.
R-HSA-202137 (Reactome) AKT1 is recruited to the M domain of HSP90.
R-HSA-202144 (Reactome) HSP90 facilitates the CaM-induced displacement of caveolin from eNOS.
R-HSA-203553 (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.
R-HSA-203565 (Reactome) NOSTRIN interacts with the actin nucleation promoting factor N-WASP by means of its SH3 domain.
R-HSA-203567 (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.
R-HSA-203611 (Reactome) A glycine residue (Gly2) at the N-terminus of eNOS is myristoylated, providing membrane localization.
R-HSA-203613 (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.
R-HSA-203625 (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.
R-HSA-203662 (Reactome) NOSTRIN binds to dynamin via its SH3 domain.
R-HSA-203680 (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.
R-HSA-203700 (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.
R-HSA-203712 (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.
R-HSA-203716 (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.
R-HSA-5340214 (Reactome) Vertebrates possess multiple respiratory globins that differ in structure, function, and tissue distribution. Three different globins have been described so far: haemoglobin facilitates oxygen transport in blood, myoglobin mediates oxygen transport and storage in the muscle and neuroglobin has a yet unidentified function in nerve cells. A fourth globin has been identified in mouse, human and zebrafish. It is ubiquitously expressed in human tissue and therefore called cytoglobin (CYGB) (Trent & Hargrove 2002). Unlike the specific expression patterns of Hb and Mb, CYGB is found in vascular smooth muscle, fibroblasts and cardiomyocytes. CYGB functions as a homodimer (Hamdane et al. 2003) and is localised to the cytosol of these cells where its O2 loading and unloading ability within a narrow O2 tension range makes it an ideal protein for O2 storage, especially during hypoxia (Fago et al. 2004).
R-HSA-5340226 (Reactome) Vertebrates possess multiple respiratory globins that differ in structure, function, and tissue distribution. Three different globins have been described so far: haemoglobin facilitates oxygen transport in blood, myoglobin mediates oxygen transport and storage in the muscle and neuroglobin has a yet unidentified function in nerve cells. A fourth globin has been identified in mouse, human and zebrafish. It is ubiquitously expressed in human tissue and therefore called cytoglobin (CYGB) (Trent & Hargrove 2002). Unlike the specific expression patterns of Hb and Mb, CYGB is found in vascular smooth muscle, fibroblasts and cardiomyocytes. CYGB functions as a homodimer (Hamdane et al. 2003) and is localised to the cytosol. As well as oxygen binding capability, CYGB possesses nitric oxide dioxygenase activity (Halligan et al. 2009), a common feature amongst the globin family (Smagghe et al. 2008). CYGB consumes NO through the dioxygenase pathway, which regulates cell respiration and proliferation (Smagghe et al. 2008). O2 binds to the ferric form of CYGB (CYGB-Fe2+:O2). During NO dioxygenation, CYGB is reduced to the ferrous form (CYGB-Fe3+) (Gardner 2005).
R-HSA-5693373 (Reactome) N(G),N(G)-dimethylarginine dimethylaminohydrolases 1 and 2 (DDAH1 and 2) play a role in the regulation of nitric oxide generation. They can hydrolyse an endogenous inhibitor of nitric oxide synthase (NOS), N(omega),N(omega)-dimethyl-L-arginine (ADMA) to dimethylamine (DMA) and L-citrulline (L-Cit) (Forbes et al. 2008, Wang et al. 2009, Cillero-Pastor et al. 2012).
SPR dimerR-HSA-1497853 (Reactome)
VitCR-HSA-1497855 (Reactome)
ZDHHC21mim-catalysisR-HSA-203567 (Reactome)
e-ArrowR-HSA-1497824 (Reactome)
eNOS:CaM:HSP90:p-AKT1ArrowR-HSA-202137 (Reactome)
eNOS:CaM:HSP90:p-AKT1R-HSA-202111 (Reactome)
eNOS:CaM:HSP90ArrowR-HSA-202144 (Reactome)
eNOS:CaM:HSP90R-HSA-202137 (Reactome)
eNOS:Caveolin-1:CaM:HSP90ArrowR-HSA-202129 (Reactome)
eNOS:Caveolin-1:CaM:HSP90R-HSA-202144 (Reactome)
eNOS:Caveolin-1:CaMArrowR-HSA-202110 (Reactome)
eNOS:Caveolin-1:CaMR-HSA-202129 (Reactome)
eNOS:Caveolin-1:NOSTRIN complexArrowR-HSA-203716 (Reactome)
eNOS:Caveolin-1:NOSTRIN complexR-HSA-203662 (Reactome)
eNOS:Caveolin-1:NOSTRIN:Dynamin-2ArrowR-HSA-203662 (Reactome)
eNOS:Caveolin-1:NOSTRIN:Dynamin-2R-HSA-203565 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPArrowR-HSA-203565 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPArrowR-HSA-203625 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPR-HSA-203625 (Reactome)
eNOS:Caveolin-1ArrowR-HSA-203712 (Reactome)
eNOS:Caveolin-1R-HSA-202110 (Reactome)
eNOS:Caveolin-1R-HSA-203716 (Reactome)
eNOS:NOSIPArrowR-HSA-203553 (Reactome)
eNOS:NOSIPArrowR-HSA-203680 (Reactome)
eNOS:NOSIPR-HSA-203680 (Reactome)
myristoylated eNOS dimerArrowR-HSA-202132 (Reactome)
myristoylated eNOS dimerArrowR-HSA-203613 (Reactome)
myristoylated eNOS dimerR-HSA-202132 (Reactome)
p-PTPS hexamerArrowR-HSA-1475422 (Reactome)
p-PTPS hexamermim-catalysisR-HSA-1474184 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2ArrowR-HSA-1497796 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2mim-catalysisR-HSA-1497810 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ArrowR-HSA-1497784 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4R-HSA-1497796 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4mim-catalysisR-HSA-202127 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1ArrowR-HSA-202111 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1R-HSA-1497784 (Reactome)
p-SPR dimerArrowR-HSA-1497853 (Reactome)
p-SPR dimermim-catalysisR-HSA-1475414 (Reactome)
p-SPR dimermim-catalysisR-HSA-1497869 (Reactome)
p-T308,S473-AKT1R-HSA-202137 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		ArrowR-HSA-203700 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		R-HSA-203553 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		R-HSA-203613 (Reactome)
palmitoylated,

myristoylated eNOS

dimer		R-HSA-203712 (Reactome)
sepiapterinR-HSA-1497869 (Reactome)

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