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

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13, 23, 30253217, 44, 463022, 266, 11, 12, 4039362, 27, 33, 4816, 30, 3638, 43491, 2, 5, 19, 274221, 3137914, 303639410, 2520, 24, 2918, 28, 45, 4735endocytic vesicle membranecytosollipid dropletGolgi lumen2xPalmC-MyrG-p-S1177-NOS3 CALM1 CAV1 NADP+heme BH4 heme FAD FAD p-T308,S473-AKT1 N-WASPH+NOSTRIN FAD p-T308,S473-AKT1NOSTRIN NOSIP 2xPalmC-MyrG-NOS3CAV1 CALM1 HSP90AA1 NADP+Zn2+ FMN FAD p-S213-SPR DDAH1,2PALM2xPalmC-MyrG-NOS3 heme heme CAV1 NOSTRIN heme CALM1:4xCa2+HSP90AA1 heme CALM1 BH4 LYPLA1 dimerheme Zn2+ eNOS:Caveolin-1:CaM:HSP90Ca2+ eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPDNM2Zn2+ FAD p-S1177-eNOS:CaM:HSP90:p-AKT1FAD Metabolism ofcofactors2xPalmC-MyrG-NOS3 DDAH2 BH4 FMN BH4eNOS:CaM:HSP90WASL FMN CALM1 CAV1 2xPalmC-MyrG-NOS3 heme FAD NADPHFMN FMN eNOS:Caveolin-1HSP90AA1 NADPHheme HSP90AA1 MyrG-NOS3 FAD 2xPalmC-MyrG-p-S1177-NOS3 O2.-DMA2xPalmC-MyrG-p-S1177-NOS3 DNM2 CAV1 NOSIP L-Argp-T308,S473-AKT1 NOSTRIN FAD CYGB dimer:O2FMN Zn2+ Zn2+ NADPHFAD 2xPalmC-MyrG-NOS3 L-Cit2xPalmC-MyrG-NOS3 FMN eNOS:CaM:HSP90:p-AKT1FMN FAD Zn2+ BH4 FMN LYPLA1 BH4 Zn2+ NO3-2xPalmC-MyrG-NOS3 CALM1 Ca2+ NADPHO2myristoylated eNOSdimerFMN Zn2+ heme 2xPalmC-MyrG-NOS3 p-T308,S473-AKT1 Zn2+ heme HSP90AA1 heme CYGB eNOS:NOSIPNOSTRIN palmitoylated,myristoylated eNOSdimerCa2+ eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPCALM1 Zn2+ H+FAD FMN BH2 heme FMN eNOS:NOSIPNOSTRIN homotrimerZn2+ 2xPalmC-MyrG-NOS3 Zn2+ Zn2+ FAD Ca2+ FAD p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4CALM1 FMN sepiapterinheme PALM-CoACALM1 2xPalmC-MyrG-NOS3 eNOS:Caveolin-1:NOSTRIN:Dynamin-2Ca2+ MyrG-NOS3WASL PIP3 activates AKTsignalingCAV1 CAV1FMN FAD PeroxynitriteFAD Zn2+ eNOS:Caveolin-1:NOSTRIN complexheme CYGB dimerFMN NADP+O2ATPH2OFAD DNM2 heme ADPmyristoylated eNOSdimer2xPalmC-MyrG-NOS3 heme HSP90AA1 CAV1 FMN BH4 eNOS:Caveolin-1:CaMMyrG-NOS3 NADP+Zn2+ p-T308,S473-AKT1 2xPalmC-MyrG-NOS3 Ca2+ HSP90AA1NOSIPDNM2 DDAH1 p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2NOMYS-CoAO2 FMN heme p-SPR dimer2xPalmC-MyrG-NOS3 Ca2+ BH4 CYGB ZDHHC21Zn2+ NOS3Zn2+ heme BH2ADMACa2+ 31531687, 34, 41


Description

Nitric oxide (NO), a multifunctional second messenger, is implicated in physiological processes 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 is controlled at the levels of biosynthesis and local availability. Its 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 cell 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 NH2-terminal oxygenase domain from a COOH-terminal reductase 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>In this Reactome pathway module, details of eNOS activation and regulation are annotated. Originally identified as endothelium-derived relaxing factor, eNOS derived NO is a critical signaling molecule in vascular homeostasis. It regulates blood pressure and vascular tone, and is involved in vascular smooth muscle cell proliferation, platelet aggregation, and leukocyte adhesion. Loss of endothelium derived NO is a key feature of endothelial dysfunction, implicated in the pathogenesis of hypertension and atherosclerosis. The endothelial isoform eNOS is unique among the nitric oxide synthase (NOS) family in that it is co-translationally modified at its amino terminus by myristoylation and is further acylated by palmitoylation (two residues next to the myristoylation site). These modifications target eNOS to the plasma membrane caveolae and lipid rafts. <p>Factors that stimulate eNOS activation and nitric oxide (NO) production include fluid shear stress generated by blood flow, vascular endothelial growth factor (VEGF), bradykinin, estrogen, insulin, and angiopoietin. The activity of eNOS is further regulated by numerous post-translational modifications, including protein-protein interactions, phosphorylation, and subcellular localization. <p>Following activation, eNOS shuttles between caveolae and other subcellular compartments such as the noncaveolar plasma membrane portions, Golgi apparatus, and perinuclear structures. This subcellular distribution is variable depending upon cell type and mode of activation. <p>Subcellular localization of eNOS has a profound effect on its ability to produce NO as the availability of its substrates and cofactors will vary with location. eNOS is primarily particulate, and depending on the cell type, eNOS can be found in several membrane compartments: plasma membrane caveolae, lipid rafts, and intracellular membranes such as the Golgi complex. View original pathway at Reactome.</div>

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Reactome-Converter 
Pathway is converted from Reactome ID: 202131
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Hemish, J

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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
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
2xPalmC-MyrG-NOS3 ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-NOS3ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-p-S1177-NOS3 ProteinP29474 (Uniprot-TrEMBL)
ADMAMetaboliteCHEBI:25682 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
BH2 MetaboliteCHEBI:15375 (ChEBI)
BH2MetaboliteCHEBI:15375 (ChEBI)
BH4 MetaboliteCHEBI:15372 (ChEBI)
BH4MetaboliteCHEBI:15372 (ChEBI)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
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)
DDAH1 ProteinO94760 (Uniprot-TrEMBL)
DDAH1,2ComplexR-HSA-6786641 (Reactome)
DDAH2 ProteinO95865 (Uniprot-TrEMBL)
DMAMetaboliteCHEBI:17170 (ChEBI)
DNM2 ProteinP50570 (Uniprot-TrEMBL)
DNM2ProteinP50570 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FMN MetaboliteCHEBI:17621 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90AA1ProteinP07900 (Uniprot-TrEMBL)
L-ArgMetaboliteCHEBI:32682 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
LYPLA1 ProteinO75608 (Uniprot-TrEMBL)
LYPLA1 dimerComplexR-HSA-203655 (Reactome)
MYS-CoAMetaboliteCHEBI:15532 (ChEBI)
Metabolism of cofactorsPathwayR-HSA-8978934 (Reactome) Many proteins depend for their activity on cofactors, associated ions and small molecules. This module contains annotations of processes involved in the synthesis of cofactors, either de novo or from essential molecules consumed in the diet (vitamins), as well as regeneration of active forms of cofactors (Lipmann 1984).
MyrG-NOS3 ProteinP29474 (Uniprot-TrEMBL)
MyrG-NOS3ProteinP29474 (Uniprot-TrEMBL)
N-WASPProteinO00401 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NO3-MetaboliteCHEBI:17632 (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)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PeroxynitriteMetaboliteCHEBI:25941 (ChEBI)
WASL ProteinO00401 (Uniprot-TrEMBL)
ZDHHC21ProteinQ8IVQ6 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (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-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-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
2xPalmC-MyrG-NOS3ArrowR-HSA-203567 (Reactome)
2xPalmC-MyrG-NOS3R-HSA-203700 (Reactome)
ADMAR-HSA-5693373 (Reactome)
ADMATBarR-HSA-202127 (Reactome)
ADPArrowR-HSA-202111 (Reactome)
ATPR-HSA-202111 (Reactome)
BH2ArrowR-HSA-1497869 (Reactome)
BH2R-HSA-1497796 (Reactome)
BH4ArrowR-HSA-1497796 (Reactome)
BH4R-HSA-1497784 (Reactome)
CALM1:4xCa2+ArrowR-HSA-202129 (Reactome)
CALM1:4xCa2+R-HSA-202110 (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)
DDAH1,2mim-catalysisR-HSA-5693373 (Reactome)
DMAArrowR-HSA-5693373 (Reactome)
DNM2R-HSA-203662 (Reactome)
H+R-HSA-1497869 (Reactome)
H+R-HSA-5340226 (Reactome)
H2OR-HSA-5693373 (Reactome)
HSP90AA1R-HSA-202129 (Reactome)
L-ArgR-HSA-202127 (Reactome)
L-CitArrowR-HSA-202127 (Reactome)
L-CitArrowR-HSA-5693373 (Reactome)
LYPLA1 dimermim-catalysisR-HSA-203613 (Reactome)
MYS-CoAR-HSA-203611 (Reactome)
MyrG-NOS3ArrowR-HSA-203611 (Reactome)
MyrG-NOS3R-HSA-203567 (Reactome)
N-WASPR-HSA-203565 (Reactome)
NADP+ArrowR-HSA-1497810 (Reactome)
NADP+ArrowR-HSA-1497869 (Reactome)
NADP+ArrowR-HSA-202127 (Reactome)
NADP+ArrowR-HSA-5340226 (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)
PeroxynitriteArrowR-HSA-1497878 (Reactome)
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-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-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-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: hemoglobin 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) (Burmester et al. 2002, 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).
ZDHHC21mim-catalysisR-HSA-203567 (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-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 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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