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

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2930, 32, 4326, 41, 45133416, 542749412717, 24, 38, 44403515, 19429, 2638, 28, 36272, 51492654, 12, 33, 35, 553641721, 11, 526, 10, 22, 464820, 5321, 3139, 4723GCH1 decamer p-S1177-eNOSCaMHSP90p-AKT1BH2 NOSTRIN homotrimer p-S1177-eNOS dimer palmitoylated, myristoylated eNOS dimer 2GCHFRGCH1 endocytic vesicle membraneeNOSCaveolin-1 palmitoylated, myristoylated eNOS dimer Active Calmodulin NOSTRIN homotrimer GCH1 decamer palmitoylated, myristoylated eNOS dimer Golgi lumenGCH1 dimer Active Calmodulin Active Calmodulin APT1 homodimer eNOSCaveolin-1NOSTRINdynamin-2N-WASP NOSTRIN homotrimer p-S1177-eNOSCaMHSP90p-AKT1 palmitoylated, myristoylated eNOS dimer palmitoylated, myristoylated eNOS dimer palmitoylated, myristoylated eNOS dimer Active Calmodulin eNOSCaMHSP90p-AKT1 p-PTPS hexamer lipid particlepalmitoylated, myristoylated eNOS dimer Active Calmodulin eNOSCaveolin-1NOSTRINDynamin-2 myristoylated eNOS dimer eNOSCaMHSP90 PTPS hexamer Active Calmodulin p-S1177-eNOSCaMHSP90p-AKT1BH4 SPR dimer palmitoylated, myristoylated eNOS dimer eNOSCaveolin-1CaMHSP90 eNOSCaveolin-1 myristoylated eNOS dimer Active Calmodulin palmitoylated, myristoylated eNOS dimer eNOSNOSIP palmitoylated, myristoylated eNOS dimer palmitoylated, myristoylated eNOS dimer cytosoleNOSCaveolin-1 GCHFR pentamer eNOSCaveolin-1 NOSTRIN homotrimer eNOSCaveolin-1NOSTRIN complex NOSTRIN homotrimer p-S1177-eNOS dimer eNOSCaveolin-1CaM GCHFR pentamer palmitoylated, myristoylated eNOS dimer eNOSCaMHSP90 DHFR dimer eNOSNOSIP p-S1177-eNOS dimer eNOSCaveolin-1 Active Calmodulin GCH1 dimer p-SPR dimer eNOSCaveolin-1NOSTRINdynamin-2N-WASP BH4 2xPalmC-MyrG-NOS3FMN 2xPalmC-MyrG-NOS3p-T308,S473-AKT1 heme Fe2+heme CALM1 FAD CALM1 2xPalmC-MyrG-p-S1177-NOS3CAV1 Fe3+p-PTPS hexamerDHNTPFMN p-T308,S473-AKT1 SPR dimerHSP90AA1 p-T308,S473-AKT1Zn2+ p-S1177-eNOSCaMHSP90p-AKT1BH4DHFR dimerFAD heme FMN NADP+PTS FMN heme FAD Active CalmodulinZn2+ WASL Zn2+ BH4 2xPalmC-MyrG-NOS3GCHFR BH2 NOSTRIN FAD NOSTRIN CAV1 eNOSNOSIPDNM2 NOFMN Ca2+ ATP2xPalmC-MyrG-NOS3NADP+HSP90AA1 Ca2+ MyrG-NOS3Ascorbate radical2xPalmC-MyrG-NOS32xPalmC-MyrG-NOS3FMN O2BH42xPalmC-MyrG-NOS3Zn2+ FMN BH4 BH4 NADP+PALMeNOSCaveolin-1NOSTRINdynamin-2N-WASPFAD CAV1CAV1 Zn2+ Zn2+ eNOSCaveolin-1eNOSCaveolin-1CaMHSP90PeroxynitriteCa2+ CAV1 FAD 2xPalmC-MyrG-NOS3FMN SPR H+LYPLA1 heme eNOSNOSIPHSP90AA1 2xPalmC-MyrG-NOS3BH4 eNOSCaveolin-1NOSTRINDynamin-2PPPp-S19-PTS myristoylated eNOS dimerAPT1 homodimerNOSTRIN NOSIP Zn2+ CALM1 FMN NADPHCALM1 NOSIPNADPHGCHFR pentamerNOSTRIN ADPMyrG-NOS3PALM-CoAADPheme eNOSCaveolin-1NOSTRIN complexHSP90AA1 CALM1 NOSIP p-T308,S473-AKT1 GCH1 2xPalmC-MyrG-NOS3FMN heme p-T308,S473-AKT1 FMN FMN p-S1177-eNOSCaMHSP90p-AKT1ZDHHC21heme 2xPalmC-MyrG-NOS3CALM1 NOSTRIN heme HCOOHZn2+ 2xPalmC-MyrG-NOS3sepiapterinO2.-ATPFMN heme eNOSCaMHSP90Zn2+ FAD PTPS hexamerCALM1 heme WASL BH2FAD Ca2+ MyrG-NOS3ADPGCH1 L-ArgL-CitFAD CALM1 Ca2+ Zn2+ BH4 eNOSCaMHSP90p-AKT1FAD H2OCAV1 p-SPR dimer2GCHFRGCH1NOSTRIN homotrimerBH3.ATPNADPHp-S1177-eNOSCaMHSP90p-AKT1BH2FAD HSP90AA1FMN GCHFR palmitoylated, myristoylated eNOS dimerZn2+ 2xPalmC-MyrG-NOS3heme FAD heme PTHPBH4 GCH1 decamerMYS-CoAheme myristoylated eNOS dimerFMN FAD heme Ca2+ GTPFAD DNM2 CAV1 FAD heme NADP+DHFR FMN Zn2+ p-S213-SPR heme HSP90AA1 CAV1 VitCNADPHFAD DNM2 Ca2+ Zn2+ WASL2xPalmC-MyrG-p-S1177-NOS3O2Ca2+ HSP90AA1 NOS32xPalmC-MyrG-p-S1177-NOS3FAD DNM2Zn2+ eNOSCaveolin-1NOSTRINdynamin-2N-WASPe-Zn2+ PRKG2NADP+FMN eNOSCaveolin-1CaML-PheZn2+ Zn2+ Zn2+ 251814, 37, 504525


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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Bibliography

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History

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114629view16:09, 25 January 2021ReactomeTeamReactome version 75
113077view11:13, 2 November 2020ReactomeTeamReactome version 74
112311view15:23, 9 October 2020ReactomeTeamReactome version 73
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99838view15:56, 31 October 2018ReactomeTeamreactome version 63
99395view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99089view12:39, 31 October 2018ReactomeTeamreactome version 62
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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 GCH1ComplexREACT_111854 (Reactome)
2xPalmC-MyrG-NOS3ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-p-S1177-NOS3ProteinP29474 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
APT1 homodimerComplexREACT_13023 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active CalmodulinComplexREACT_3178 (Reactome)
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)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
DHFR ProteinP00374 (Uniprot-TrEMBL)
DHFR dimerComplexREACT_111516 (Reactome)
DHNTPMetaboliteCHEBI:18372 (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 decamerComplexREACT_111358 (Reactome)
GCHFR ProteinP30047 (Uniprot-TrEMBL)
GCHFR pentamerComplexREACT_111549 (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-NOS3ProteinP29474 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NOMetaboliteCHEBI:16480 (ChEBI)
NOS3ProteinP29474 (Uniprot-TrEMBL)
NOSIP ProteinQ9Y314 (Uniprot-TrEMBL)
NOSIPProteinQ9Y314 (Uniprot-TrEMBL)
NOSTRIN 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 ProteinQ03393 (Uniprot-TrEMBL)
PeroxynitriteMetaboliteCHEBI:25941 (ChEBI)
SPR ProteinP35270 (Uniprot-TrEMBL)
SPR dimerComplexREACT_111821 (Reactome)
VitCMetaboliteCHEBI:29073 (ChEBI)
WASL ProteinO00401 (Uniprot-TrEMBL)
WASLProteinO00401 (Uniprot-TrEMBL)
ZDHHC21ProteinQ8IVQ6 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
e-MetaboliteCHEBI:10545 (ChEBI)
eNOS

CaM HSP90

p-AKT1		ComplexREACT_12902 (Reactome)
eNOS

CaM

HSP90		ComplexREACT_12871 (Reactome)
eNOS

Caveolin-1 CaM

HSP90		ComplexREACT_12971 (Reactome)
eNOS

Caveolin-1

CaM		ComplexREACT_12757 (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

Caveolin-1

NOSTRIN complex		ComplexREACT_13185 (Reactome)
eNOS Caveolin-1ComplexREACT_12997 (Reactome)
eNOS NOSIPComplexREACT_12699 (Reactome)
eNOS NOSIPComplexREACT_13282 (Reactome)
heme 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

BH2		ComplexREACT_111290 (Reactome)
p-S1177-eNOS

CaM HSP90 p-AKT1

BH4		ComplexREACT_111579 (Reactome)
p-S1177-eNOS

CaM HSP90

p-AKT1		ComplexREACT_12662 (Reactome)
p-S19-PTS ProteinQ03393 (Uniprot-TrEMBL)
p-S213-SPR ProteinP35270 (Uniprot-TrEMBL)
p-SPR dimerComplexREACT_111842 (Reactome)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)
palmitoylated, myristoylated eNOS dimerComplexREACT_13093 (Reactome)
sepiapterinMetaboliteCHEBI:16095 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2GCHFR GCH1TBarREACT_111143 (Reactome)
ADPArrowREACT_111129 (Reactome)
ADPArrowREACT_111245 (Reactome)
ADPArrowREACT_12415 (Reactome)
APT1 homodimerREACT_12463 (Reactome)
ATPREACT_111129 (Reactome)
ATPREACT_111245 (Reactome)
ATPREACT_12415 (Reactome)
Active CalmodulinArrowREACT_12426 (Reactome)
Active CalmodulinREACT_12620 (Reactome)
Ascorbate radicalArrowREACT_111191 (Reactome)
BH2ArrowREACT_111234 (Reactome)
BH2REACT_111041 (Reactome)
BH2REACT_111106 (Reactome)
BH3.ArrowREACT_111060 (Reactome)
BH3.REACT_111125 (Reactome)
BH3.REACT_111191 (Reactome)
BH4ArrowREACT_111041 (Reactome)
BH4ArrowREACT_111093 (Reactome)
BH4ArrowREACT_111106 (Reactome)
BH4ArrowREACT_111125 (Reactome)
BH4ArrowREACT_111191 (Reactome)
BH4REACT_111062 (Reactome)
BH4REACT_111175 (Reactome)
BH4TBarREACT_111143 (Reactome)
CAV1ArrowREACT_12459 (Reactome)
CAV1REACT_12499 (Reactome)
DHFR dimerREACT_111041 (Reactome)
DHNTPArrowREACT_111143 (Reactome)
DNM2REACT_12512 (Reactome)
Fe2+REACT_111125 (Reactome)
Fe3+ArrowREACT_111125 (Reactome)
GCH1 decamerREACT_111115 (Reactome)
GCH1 decamerREACT_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-NOS3REACT_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)
NOS3REACT_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)
PRKG2REACT_111129 (Reactome)
PRKG2REACT_111245 (Reactome)
PTHPArrowREACT_111082 (Reactome)
PTHPREACT_111093 (Reactome)
PTPS hexamerREACT_111245 (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)
ZDHHC21REACT_12530 (Reactome)
e-ArrowREACT_111060 (Reactome)
eNOS

CaM HSP90

p-AKT1		REACT_12415 (Reactome)
eNOS

CaM

HSP90		ArrowREACT_12459 (Reactome)
eNOS

CaM

HSP90		REACT_12382 (Reactome)
eNOS

Caveolin-1 CaM

HSP90		ArrowREACT_12426 (Reactome)
eNOS

Caveolin-1

CaM		REACT_12426 (Reactome)
eNOS

Caveolin-1 NOSTRIN

Dynamin-2		REACT_12611 (Reactome)
eNOS

Caveolin-1

NOSTRIN complex		REACT_12512 (Reactome)
eNOS Caveolin-1REACT_12427 (Reactome)
eNOS Caveolin-1REACT_12620 (Reactome)
myristoylated eNOS dimerArrowREACT_12463 (Reactome)
p-PTPS hexamerArrowREACT_111245 (Reactome)
p-PTPS hexamerREACT_111082 (Reactome)
p-S1177-eNOS

CaM HSP90 p-AKT1

BH2		ArrowREACT_111106 (Reactome)
p-S1177-eNOS

CaM HSP90 p-AKT1

BH2		REACT_111249 (Reactome)
p-S1177-eNOS

CaM HSP90 p-AKT1

BH4		REACT_111106 (Reactome)
p-S1177-eNOS

CaM HSP90 p-AKT1

BH4		REACT_12443 (Reactome)
p-S1177-eNOS

CaM HSP90

p-AKT1		ArrowREACT_12415 (Reactome)
p-S1177-eNOS

CaM HSP90

p-AKT1		REACT_111175 (Reactome)
p-SPR dimerArrowREACT_111129 (Reactome)
p-SPR dimerREACT_111093 (Reactome)
p-SPR dimerREACT_111234 (Reactome)
p-T308,S473-AKT1REACT_12382 (Reactome)
palmitoylated, myristoylated eNOS dimerREACT_12499 (Reactome)
palmitoylated, myristoylated eNOS dimerREACT_12589 (Reactome)
sepiapterinREACT_111234 (Reactome)

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