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>AKT1 phosphorylates eNOSAKT1 phosphorylates eNOSThis 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: 99519051plasma membraneGO0005886eNOS:CaM:HSP90:p-AKT1 [plasma membrane]eNOS:CaM:HSP90:p-AKT1Reactome DB_ID: 99519011eNOS:CaM:HSP90 [plasma membrane]eNOS:CaM:HSP90Reactome DB_ID: 99518951CALM1:4Ca2+ [plasma membrane]CALM1:4Ca2+Reactome DB_ID: 99518931UniProt:J9NWJ7Reactomehttp://www.reactome.orgCanis familiarisNCBI Taxonomy9615UniProtJ9NWJ7Chain Coordinates2EQUAL149EQUALReactome DB_ID: 1406484calcium(2+) [ChEBI:29108]calcium(2+)ChEBI29108Reactome Database ID Release 759951895Database 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=9951895ReactomeR-CFA-5349971Reactome 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-CFA-534997.1Reactome DB_ID: 99518911palmitoylated, myristoylated eNOS dimer [plasma membrane]palmitoylated, myristoylated eNOS dimerReactome DB_ID: 99518892Ghost homologue of 2xPalmC-MyrG-NOS3 [plasma membrane]Ghost homologue of 2xPalmC-MyrG-NOS3Reactome DB_ID: 711852cytosolGO0005829ferroheme b [ChEBI:17627]ferroheme bChEBI17627Reactome DB_ID: 293862FAD [ChEBI:16238]FADFlavin adenine dinucleotideChEBI16238Reactome DB_ID: 735242FMN [ChEBI:17621]FMNFlavin mononucleotideRiboflavin-5-phosphateChEBI17621Reactome DB_ID: 294261zinc(2+) [ChEBI:29105]zinc(2+)ChEBI29105Reactome Database ID Release 759951891Database 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=9951891ReactomeR-CFA-2036391Reactome 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-CFA-203639.1Reactome DB_ID: 99518991UniProt:F1PGY1HSP90AA1UniProtF1PGY12EQUAL732EQUALReactome Database ID Release 759951901Database 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=9951901ReactomeR-CFA-2021051Reactome 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-CFA-202105.1Reactome DB_ID: 99519031UniProt:E2RJX4AKT1UniProtE2RJX4O-phospho-L-threonine at 308 (in Homo sapiens)308EQUALO-phospho-L-threonine [MOD:00047]O-phospho-L-serine at 473 (in Homo sapiens)473EQUALO-phospho-L-serine [MOD:00046]1EQUAL480EQUALReactome Database ID Release 759951905Database 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=9951905ReactomeR-CFA-2021131Reactome 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-CFA-202113.1Reactome DB_ID: 1135921ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 99519131p-S1177-eNOS:CaM:HSP90:p-AKT1 [plasma membrane]p-S1177-eNOS:CaM:HSP90:p-AKT1Reactome DB_ID: 99414141CALM1:4xCa2+ [cytosol]CALM1:4xCa2+Reactome DB_ID: 740164Reactome DB_ID: 993583312EQUAL149EQUALReactome Database ID Release 759941414Database 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=9941414ReactomeR-CFA-742941Reactome 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-CFA-74294.1Reactome DB_ID: 99519111p-S1177-eNOS dimer [plasma membrane]p-S1177-eNOS dimerReactome DB_ID: 711852Reactome DB_ID: 2987025,6,7,8-tetrahydrobiopterin [ChEBI:15372]5,6,7,8-tetrahydrobiopterinChEBI15372Reactome DB_ID: 293862Reactome DB_ID: 735242Reactome DB_ID: 294261Reactome DB_ID: 99519092Ghost homologue of 2xPalmC-MyrG-p-S1177-NOS3 [plasma membrane]Ghost homologue of 2xPalmC-MyrG-p-S1177-NOS3Reactome Database ID Release 759951911Database 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=9951911ReactomeR-CFA-2035641Reactome 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-CFA-203564.1Reactome DB_ID: 995190712EQUAL732EQUALReactome DB_ID: 99503971O-phospho-L-threonine at 308 (in Homo sapiens)308EQUALO-phospho-L-serine at 473 (in Homo sapiens)473EQUAL1EQUAL480EQUALReactome Database ID Release 759951913Database 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=9951913ReactomeR-CFA-2021211Reactome 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-CFA-202121.1Reactome DB_ID: 293701ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216Reactome Database ID Release 759951915Database 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=9951915ReactomeR-CFA-2021111Reactome 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-CFA-202111.1HSP90 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. <br><br>10376603Pubmed1999Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylationDimmeler, SFleming, IFisslthaler, BHermann, CBusse, RZeiher, AMNature 399:601-510469573Pubmed1999The Akt kinase signals directly to endothelial nitric oxide synthaseMichell, BJGriffiths, JEMitchelhill, KIRodriguez-Crespo, ITiganis, TBozinovski, Sde Montellano, PRKemp, BEPearson, RBCurr Biol 9:845-810376602Pubmed1999Regulation of endothelium-derived nitric oxide production by the protein kinase AktFulton, DGratton, JPMcCabe, TJFontana, JFujio, YWalsh, KFranke, TFPapapetropoulos, ASessa, WCNature 399:597-601inferred by electronic annotationIEAGOIEAThe cofactor BH4 is required for electron transfer in the eNOS catalytic cycleThe cofactor BH4 is required for electron transfer in the eNOS catalytic cycleThis 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: 298701Reactome DB_ID: 99519131Reactome DB_ID: 99519171p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4 [plasma membrane]p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4Reactome DB_ID: 298701Reactome DB_ID: 99519131Reactome Database ID Release 759951917Database 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=9951917ReactomeR-CFA-14978301Reactome 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-CFA-1497830.1Reactome Database ID Release 759977069Database 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=9977069ReactomeR-CFA-14977841Reactome 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-CFA-1497784.1The 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).19583767Pubmed2009Structural and mechanistic aspects of flavoproteins: electron transfer through the nitric oxide synthase flavoprotein domainStuehr, DJTejero, JHaque, MMFEBS J 276:3959-7415476407Pubmed2004Redox function of tetrahydrobiopterin and effect of L-arginine on oxygen binding in endothelial nitric oxide synthaseBerka, VYeh, HCGao, DKiran, FTsai, ALBiochemistry 43:13137-48inferred by electronic annotationIEAGOIEA1.14.13.39eNOS synthesizes NOeNOS synthesizes NONO biosynthesisThis 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: 293642NADPH [ChEBI:16474]NADPHTPNHChEBI16474Reactome DB_ID: 294681L-argininium(1+) [ChEBI:32682]L-argininium(1+)ODKSFYDXXFIFQN-BYPYZUCNSA-OInChI=1S/C6H14N4O2/c7-4(5(11)12)2-1-3-10-6(8)9/h4H,1-3,7H2,(H,11,12)(H4,8,9,10)/p+1/t4-/m0/s1L-arginine monocationL-argininiumC6H15N4O2(2S)-2-ammonio-5-guanidiniopentanoate175.20906L-arginineNC(=[NH2+])NCCC[C@H]([NH3+])C([O-])=OChEBI32682Reactome DB_ID: 293681dioxygen [ChEBI:15379]dioxygenChEBI15379Reactome DB_ID: 293662NADP(+) [ChEBI:18009]NADP(+)ChEBI18009Reactome DB_ID: 2021241nitric oxide [ChEBI:16480]nitric oxideChEBI16480Reactome DB_ID: 299681L-citrulline [ChEBI:16349]L-citrullineChEBI16349PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9951917GO0004517GO molecular functionReactome Database ID Release 759951918Database 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=9951918Reactome Database ID Release 759951920Database 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=9951920ReactomeR-CFA-2021271Reactome 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-CFA-202127.1Nitric 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.8782602Pubmed1996Determination of nitric oxide synthase cofactors: heme, FAD, FMN, and tetrahydrobiopterinKlatt, PSchmidt, KWerner, ERMayer, BMethods Enzymol 268:358-657526779Pubmed1994Nitric oxide: a physiologic messenger moleculeBredt, DSSnyder, SHAnnu Rev Biochem 63:175-9515467163Pubmed2004Nitric Oxide as a Unique Bioactive Signaling Messenger in Physiology and PathophysiologyTuteja, NChandra, MTuteja, RMisra, MKJ Biomed Biotechnol 2004:227-2379173876Pubmed1997Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerizationList, BMKlosch, BVolker, CGorren, ACSessa, WCWerner, ERKukovetz, WRSchmidt, KMayer, BBiochem J 323:159-65inferred by electronic annotationIEAGOIEAINHIBITIONReactome Database ID Release 756783968Database 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=6783968ReactomeR-HSA-67839681Reactome 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-HSA-6783968.1Reactome DB_ID: 5693375N(omega),N'(omega)-dimethyl-L-arginine [ChEBI:25682]N(omega),N'(omega)-dimethyl-L-arginineChEBI256821.1.1.153Salvage - 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: 293641Reactome DB_ID: 14978111sepiapterin [ChEBI:16095]sepiapterinChEBI16095Reactome DB_ID: 701061hydron [ChEBI:15378]hydronChEBI15378Reactome DB_ID: 293661Reactome DB_ID: 14978571D-erythro-7,8-dihydrobiopterin [ChEBI:15375]D-erythro-7,8-dihydrobiopterinChEBI15375PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9976589p-SPR dimer [cytosol]p-SPR dimerReactome DB_ID: 99765872UniProt:F1PTP2SPRUniProtF1PTP2O-phospho-L-serine at 213 (in Homo sapiens)213EQUAL1EQUAL261EQUALReactome Database ID Release 759976589Database 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=9976589ReactomeR-CFA-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-CFA-1497817.1GO0004757GO molecular functionReactome Database ID Release 759976590Database 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=9976590Reactome Database ID Release 759977084Database 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=9977084ReactomeR-CFA-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-CFA-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 annotationIEAGOIEABH2 binding can lead to eNOS uncouplingBH2 binding can lead to eNOS uncouplingThis 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: 99519171Reactome DB_ID: 14978571Reactome DB_ID: 298701Reactome DB_ID: 99770711p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2 [plasma membrane]p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2Reactome DB_ID: 99414141Reactome DB_ID: 99519111Reactome DB_ID: 14978571Reactome DB_ID: 995190712EQUAL732EQUALReactome DB_ID: 99503971O-phospho-L-threonine at 308 (in Homo sapiens)308EQUALO-phospho-L-serine at 473 (in Homo sapiens)473EQUAL1EQUAL480EQUALReactome Database ID Release 759977071Database 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=9977071ReactomeR-CFA-14978891Reactome 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-CFA-1497889.1Reactome Database ID Release 759977073Database 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=9977073ReactomeR-CFA-14977961Reactome 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-CFA-1497796.1The 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).11879202Pubmed2002The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping studyVásquez-Vivar, JMartasek, PWhitsett, JJoseph, JacobKalyanaraman, BBiochem J 362:733-9inferred 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: 56933751Reactome DB_ID: 293561water [ChEBI:15377]waterChEBI15377Reactome DB_ID: 56934101dimethylamine [ChEBI:17170]dimethylamineChEBI17170Reactome DB_ID: 299681PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 10005174DDAH1,2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDDAH1 [cytosol]DDAH2 [cytosol]UniProtJ9NSU7UniProtF1PBI2GO0016403GO molecular functionReactome Database ID Release 7510005175Database 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=10005175Reactome Database ID Release 7510005177Database 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=10005177ReactomeR-CFA-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-CFA-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 annotationIEAGOIEA1.6.3Uncoupled eNOS favours the formation of superoxideUncoupled eNOS favours the formation of superoxideThis 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: 293641Reactome DB_ID: 293681Reactome DB_ID: 293661Reactome DB_ID: 12224241superoxide [ChEBI:18421]superoxideO2.-O2-ChEBI18421PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9977071GO0016175GO molecular functionReactome Database ID Release 759977074Database 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=9977074Reactome Database ID Release 759977076Database 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=9977076ReactomeR-CFA-14978101Reactome 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-CFA-1497810.1BH2 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).inferred 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: 99963421CYGB dimer [cytosol]CYGB dimerReactome DB_ID: 99963402CYGB:heme [cytosol]CYGB:hemeReactome DB_ID: 99963381UniProt:F1PDN7CYGBUniProtF1PDN71EQUAL190EQUALReactome DB_ID: 711851Reactome Database ID Release 759996340Database 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=9996340ReactomeR-CFA-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-CFA-8981623.1Reactome Database ID Release 759996342Database 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=9996342ReactomeR-CFA-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-CFA-5340240.1Reactome DB_ID: 293682Reactome DB_ID: 99963441CYGB dimer:O2 [cytosol]CYGB dimer:O2Reactome DB_ID: 99963421Reactome DB_ID: 293682Reactome Database ID Release 759996344Database 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=9996344ReactomeR-CFA-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-CFA-5340212.1Reactome Database ID Release 759996346Database 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=9996346ReactomeR-CFA-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-CFA-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: 99963441Reactome DB_ID: 293642Reactome DB_ID: 2021242Reactome DB_ID: 701062Reactome DB_ID: 99963421Reactome DB_ID: 293662Reactome DB_ID: 4320312nitrate [ChEBI:17632]nitrateNO3nitrate(1-)trioxidonitrate(1-)trioxonitrate(1-)[NO3](-)trioxonitrate(V)NO3(-)NITRATE IONChEBI17632PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9996344GO0008941GO molecular functionReactome Database ID Release 759996347Database 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=9996347Reactome Database ID Release 759996349Database 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=9996349ReactomeR-CFA-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-CFA-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 7510027975Database 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=10027975ReactomeR-CFA-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-CFA-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