BioPAX pathway converted from "eNOS activation" in the Reactome database.eNOS activationeNOS activationThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>1.1.1.153Salvage - Sepiapterin is reduced to BH2Salvage - Sepiapterin is reduced to BH2This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 293641cytosolGO0005829NADPH [ChEBI:16474]NADPHTPNHReactomehttp://www.reactome.orgChEBI16474Reactome DB_ID: 14978111sepiapterin [ChEBI:16095]sepiapterinChEBI16095Reactome DB_ID: 701061hydron [ChEBI:15378]hydronChEBI15378Reactome DB_ID: 293661NADP(+) [ChEBI:18009]NADP(+)ChEBI18009Reactome DB_ID: 14978571D-erythro-7,8-dihydrobiopterin [ChEBI:15375]D-erythro-7,8-dihydrobiopterinChEBI15375PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 10134782p-SPR dimer [cytosol]p-SPR dimerReactome DB_ID: 101347802UniProt:A0A286ZKH3Sus scrofaNCBI Taxonomy9823UniProtA0A286ZKH3O-phospho-L-serine at 213 (in Homo sapiens)213EQUALO-phospho-L-serine [MOD:00046]Chain Coordinates1EQUAL261EQUALReactome Database ID Release 7510134782Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10134782ReactomeR-SSC-14978171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1497817.1GO0004757GO molecular functionReactome Database ID Release 7510134783Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10134783Reactome Database ID Release 7510135279Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10135279ReactomeR-SSC-14978691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1497869.1In 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).18511317Pubmed2008Cellular uptake of sepiapterin and push-pull accumulation of tetrahydrobiopterinSawabe, KYamamoto, KHarada, YOhashi, ASugawara, YMatsuoka, HHasegawa, HMol Genet Metab 94:410-6inferred by electronic annotationIEAGOIEA3.5.3.18DDAH1,2 hydrolyses ADMA to DMA and L-CitDDAH1,2 hydrolyses ADMA to DMA and L-CitThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 56933751N(omega),N'(omega)-dimethyl-L-arginine [ChEBI:25682]N(omega),N'(omega)-dimethyl-L-arginineChEBI25682Reactome DB_ID: 293561water [ChEBI:15377]waterChEBI15377Reactome DB_ID: 56934101dimethylamine [ChEBI:17170]dimethylamineChEBI17170Reactome DB_ID: 299681L-citrulline [ChEBI:16349]L-citrullineChEBI16349PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 10163065DDAH1,2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDDAH1 [cytosol]DDAH2 [cytosol]UniProtA0A287B1T7UniProtA0A287A5S7GO0016403GO molecular functionReactome Database ID Release 7510163066Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10163066Reactome Database ID Release 7510163068Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10163068ReactomeR-SSC-56933731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5693373.1N(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).21898353Pubmed2012Dimethylarginine dimethylaminohydrolase 2, a newly identified mitochondrial protein modulating nitric oxide synthesis in normal human chondrocytesCillero-Pastor, BertaMateos, JesúsFernández-López, CarlosOreiro, NatividadRuiz-Romero, CristinaBlanco, Francisco JArthritis Rheum. 64:204-1219663506Pubmed2009Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxideWang, YunMonzingo, Arthur FHu, ShougangSchaller, Tera HRobertus, Jon DFast, WalterBiochemistry 48:8624-3518171027Pubmed2008Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in no regulationForbes, Scott PDruhan, Lawrence JGuzman, Jorge EParinandi, NarasimhamZhang, LiwenGreen-Church, Kari BCardounel, Arturo JBiochemistry 47:1819-26inferred by electronic annotationIEAGOIEACYGB binds O2CYGB binds O2This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 101546961CYGB dimer [cytosol]CYGB dimerReactome DB_ID: 101546942CYGB:heme [cytosol]CYGB:hemeReactome DB_ID: 711851ferroheme b [ChEBI:17627]ferroheme bChEBI17627Reactome DB_ID: 101546921UniProt:F1RWP3CYGBUniProtF1RWP31EQUAL190EQUALReactome Database ID Release 7510154694Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10154694ReactomeR-SSC-89816231Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8981623.1Reactome Database ID Release 7510154696Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10154696ReactomeR-SSC-53402401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5340240.1Reactome DB_ID: 293682dioxygen [ChEBI:15379]dioxygenChEBI15379Reactome DB_ID: 101546981CYGB dimer:O2 [cytosol]CYGB dimer:O2Reactome DB_ID: 101546961Reactome DB_ID: 293682Reactome Database ID Release 7510154698Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10154698ReactomeR-SSC-53402121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5340212.1Reactome Database ID Release 7510154700Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10154700ReactomeR-SSC-53402141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5340214.1Vertebrates 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).15299006Pubmed2004Allosteric regulation and temperature dependence of oxygen binding in human neuroglobin and cytoglobin. Molecular mechanisms and physiological significanceFago, AngelaHundahl, ChristianDewilde, SylviaGilany, KambizMoens, LucWeber, Roy EJ. Biol. Chem. 279:44417-2614530264Pubmed2003The redox state of the cell regulates the ligand binding affinity of human neuroglobin and cytoglobinHamdane, DjemelKiger, LaurentDewilde, SylviaGreen, Brian NPesce, AlessandraUzan, JulienBurmester, ThorstenHankeln, ThomasBolognesi, MartinoMoens, LucMarden, Michael CJ. Biol. Chem. 278:51713-2111893755Pubmed2002A ubiquitously expressed human hexacoordinate hemoglobinTrent, James THargrove, Mark SJ. Biol. Chem. 277:19538-4511919282Pubmed2002Cytoglobin: a novel globin type ubiquitously expressed in vertebrate tissuesBurmester, ThorstenEbner, BettinaWeich, BettinaHankeln, ThomasMol. Biol. Evol. 19:416-21inferred by electronic annotationIEAGOIEA1.14.12.17CYGB dioxygenates NOCYGB dioxygenates NOThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 293642Reactome DB_ID: 101546981Reactome DB_ID: 2021242nitric oxide [ChEBI:16480]nitric oxideChEBI16480Reactome DB_ID: 701062Reactome DB_ID: 293662Reactome DB_ID: 101546961Reactome DB_ID: 4320312nitrate [ChEBI:17632]nitrateNO3nitrate(1-)trioxidonitrate(1-)trioxonitrate(1-)[NO3](-)trioxonitrate(V)NO3(-)NITRATE IONChEBI17632PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 10154698GO0008941GO molecular functionReactome Database ID Release 7510154701Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10154701Reactome Database ID Release 7510154703Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10154703ReactomeR-SSC-53402261Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5340226.1Vertebrates 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).15598505Pubmed2005Nitric oxide dioxygenase function and mechanism of flavohemoglobin, hemoglobin, myoglobin and their associated reductasesGardner, Paul RJ. Inorg. Biochem. 99:247-6618446211Pubmed2008NO dioxygenase activity in hemoglobins is ubiquitous in vitro, but limited by reduction in vivoSmagghe, BJTrent JT, 3rdHargrove, MSPLoS One 3:e203919147491Pubmed2009Cytoglobin is expressed in the vasculature and regulates cell respiration and proliferation via nitric oxide dioxygenationHalligan, Katharine EJourd'heuil, Frances LJourd'heuil, DavidJ. Biol. Chem. 284:8539-47inferred by electronic annotationIEAGOIEAReactome Database ID Release 7510186773Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10186773ReactomeR-SSC-2036151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-203615.1GO0050999GO biological processeNOS activity is regulated by numerous post-translational modifications including phosphorylation and acylation, which also modulate its interactions with other proteins and its subcellular localization.<p>In general, following myristoylation and palmitoylation, eNOS localizes to caveolae in the plasma membrane, where in resting cells, it is bound to caveolin and remains inactive. Several agonists that raise intracellular calcium concentrations promote calmodulin binding to eNOS and the dissociation of caveolin from the enzyme, leading to an activated eNOS-calmodulin complex.<p>Phosphorylation plays a significant role in regulating eNOS activity, especially the phosphorylation of Ser1177, located within the reductase domain, which increases enzyme activity by enhancing reductase activity and calcium sensitivity. In unstimulated, cultured endothelial cells, Ser1177 is rapidly phosphorylated following a variety of stimuli: fluid shear stress, insulin, estrogen, VEGF, or bradykinin. The kinases involved in this process depend upon the stimuli applied. For instance, shear stress phosphorylates Ser1177 by activating Akt and PKA; insulin activates both Akt and the AMP-activated protein kinase (AMPK); estrogen and VEGF mainly phosphorylate eNOS via Akt; whereas the bradykinin-induced phosphorylation of Ser1177 is mediated by CaMKII. When Ser1177 is phosphorylated, NO production is increased several-fold above basal levels.<p>The phosphorylation of a threonine residue (Thr 495), located in the CaM binding domain, is associated with a decrease in eNOS activity. When this residue is dephosphorylated, substantially more CaM binds to eNOS and elevates enzyme activity. Stimuli associated with dephosphorylation of Thr495 (e.g., bradykinin, histamine, and Ca2+ ionophores) also increase Ca2+ levels resulting in the phosphorylation of Ser1177.<p>Additional phosphorylation sites, such as Ser114 and Ser633, and tyrosine phosphorylation have all been detected, but their functional relevance remains unclear. It is speculated that the tyrosine phosphorylation of eNOS is unlikely to affect enzyme activity directly, but more likely to impact the protein-protein interactions with associated scaffolding and regulatory proteins.16722822Pubmed2006Subcellular targeting and trafficking of nitric oxide synthasesOess, SIcking, AFulton, DGovers, RMuller-Esterl, WBiochem J 396:401-910551886Pubmed1999Depalmitoylation of endothelial nitric-oxide synthase by acyl-protein thioesterase 1 is potentiated by Ca(2+)-calmodulinYeh, DCDuncan, JAYamashita, SMichel, TJ Biol Chem 274:33148-5412482742Pubmed2003Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthaseFleming, IBusse, RAm J Physiol Regul Integr Comp Physiol 284:R1-1211208594Pubmed2001Cellular regulation of endothelial nitric oxide synthaseGovers, RRabelink, TJAm J Physiol Renal Physiol 280:F193-206inferred by electronic annotationIEAGOIEA