Metabolism of nitric oxide (Homo sapiens)

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10935575, 18, 436, 46, 5537, 59153, 4, 23, 5335716, 44, 6155, 623922, 65554330, 32, 4519, 38, 51, 6365912, 21, 25, 4035586426115713, 20, 47, 60, 64271, 3317, 485234, 50, 5614, 2912, 24, 25, 28, 4931, 42lipid particlecytosolendocytic vesicle membraneGolgi lumenheme FMN DHFR NADP+FMN FAD O2 heme SPR dimerHSP90AA1 2xPalmC-MyrG-NOS3 heme H+BH2heme FMN Ca2+ 2xPalmC-MyrG-p-S1177-NOS3 eNOS:CaM:HSP90FMN BH3.Ca2+ CALM1 BH4 Ca2+ Zn2+ e-eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPFAD heme eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPBH4p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2FAD NOSTRIN homotrimerWASL Zn2+ FAD eNOS:Caveolin-1:NOSTRIN:Dynamin-2p-T308,S473-AKT1 NO2xPalmC-MyrG-NOS3 FMN CAV1 p-S19-PTS PPPAscorbate radicalheme PTHPNOSIP HSP90AA1 eNOS:Caveolin-1heme FAD Ca2+ GCH1 MyrG-NOS3 2xPalmC-MyrG-p-S1177-NOS3 WASL BH4 NADPHNADPHZn2+ NOS3CALM1 CAV1 FMN FAD myristoylated eNOSdimer2xPalmC-MyrG-p-S1177-NOS3 Zn2+ PTPS hexamerheme FAD FMN DNM2 DMACALM1 PeroxynitriteL-PheLYPLA1 FAD p-T308,S473-AKT1Ca2+ CALM1 CAV1 NADP+NADPHPALMNOSTRIN GCHFR FMN eNOS:NOSIPPALM-CoAATPL-ArgFMN BH4 BH4 FAD FAD Ca2+ FAD ATPFe3+p-PTPS hexamerFMN NOSIP2xPalmC-MyrG-NOS3 BH2 Zn2+ NOSTRIN DNM2 sepiapterineNOS:NOSIPZn2+ O2.-CALM1 NO3-2xPalmC-MyrG-NOS3 2xPalmC-MyrG-NOS3 ADPNADP+H2OCAV1 MyrG-NOS3FAD heme p-S1177-eNOS:CaM:HSP90:p-AKT1Zn2+ eNOS:Caveolin-1:NOSTRIN complexO22xPalmC-MyrG-NOS3 VitCHSP90AA1 FMN H+CALM1 heme CYGB 2xPalmC-MyrG-NOS3 PTS DDAH1 2xPalmC-MyrG-NOS3GCH1 decamerAPT1 homodimerFMN Zn2+ Zn2+ Ca2+ FAD eNOS:CaM:HSP90:p-AKT1L-CiteNOS:Caveolin-1:CaMDNM2GCHFR NADPHNOSTRIN GTPCALM1:4xCa2+Zn2+ NADP+p-T308,S473-AKT1 eNOS:Caveolin-1:CaM:HSP90ADMAp-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ADPheme Zn2+ Zn2+ Zn2+ ATPFe2+ADPZn2+ N-WASPDHFR dimermyristoylated eNOSdimer2GCHFR:GCH1FAD FMN FAD heme NADPHCYGB dimerheme NADP+GCHFR pentamerZn2+ ZDHHC21CYGB palmitoylated,myristoylated eNOSdimerDHNTPCALM1 NOSTRIN CAV1p-S213-SPR Zn2+ Ca2+ HCOOH2xPalmC-MyrG-NOS3 CYGB dimer:O2O2FMN heme heme 2xPalmC-MyrG-NOS3 DDAH1,2heme CAV1 2xPalmC-MyrG-NOS3 p-SPR dimerBH4 p-T308,S473-AKT1 Zn2+ GCH1 HSP90AA1 DNM2 NOSIP H2OMyrG-NOS3 FMN FAD FMN 2xPalmC-MyrG-NOS3 BH4 HSP90AA1 2xPalmC-MyrG-NOS3 NADP+heme BH4 p-T308,S473-AKT1 CAV1 PRKG2HSP90AA1SPR NOSTRIN FMN CAV1 HSP90AA1 heme Zn2+ CALM1 FAD MYS-CoADDAH2 heme 41468, 26, 543636


Nitric oxide (NO), a multifunctional second messenger, is implicated in physiological functions in mammals that range from immune response and potentiation of synaptic transmission to dilation of blood vessels and muscle relaxation. NO is a highly active molecule that diffuses across cell membranes and cannot be stored inside the producing cell. Its signaling capacity must be controlled at the levels of biosynthesis and local availability. Indeed, NO production by NO synthases is under complex and tight control, being regulated at transcriptional and translational levels, through co- and posttranslational modifications, and by subcellular localization. NO is synthesized from L-arginine by a family of nitric oxide synthases (NOS). Three NOS isoforms have been characterized: neuronal NOS (nNOS, NOS1) primarily found in neuronal tissue and skeletal muscle; inducible NOS (iNOS, NOS2) originally isolated from macrophages and later discovered in many other cells types; and endothelial NOS (eNOS, NOS3) present in vascular endothelial cells, cardiac myocytes, and in blood platelets. The enzymatic activity of all three isoforms is dependent on calmodulin, which binds to nNOS and eNOS at elevated intracellular calcium levels, while it is tightly associated with iNOS even at basal calcium levels. As a result, the enzymatic activity of nNOS and eNOS is modulated by changes in intracellular calcium levels, leading to transient NO production, while iNOS continuously releases NO independent of fluctuations in intracellular calcium levels and is mainly regulated at the gene expression level (Pacher et al. 2007).

The NOS enzymes share a common basic structural organization and requirement for substrate cofactors for enzymatic activity. A central calmodulin-binding motif separates an oxygenase (NH2-terminal) domain from a reductase (COOH-terminal) domain. Binding sites for cofactors NADPH, FAD, and FMN are located within the reductase domain, while binding sites for tetrahydrobiopterin (BH4) and heme are located within the oxygenase domain. Once calmodulin binds, it facilitates electron transfer from the cofactors in the reductase domain to heme enabling nitric oxide production. Both nNOS and eNOS contain an additional insert (40-50 amino acids) in the middle of the FMN-binding subdomain that serves as autoinhibitory loop, destabilizing calmodulin binding at low calcium levels and inhibiting electron transfer from FMN to the heme in the absence of calmodulin. iNOS does not contain this insert.<p>Because NOS enzymatic activity is modulated by the presence of its substrates and cofactors within the cell, under certain conditions, NOS may generate superoxide instead of NO, a process referred to as uncoupling (uncoupling of NADPH oxidation and NO synthesis).<p>The molecular details of eNOS function are annotated here. View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 202131
Reactome version: 61
Reactome Author 
Reactome Author: Hemish, J

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  30. Icking A, Matt S, Opitz N, Wiesenthal A, Müller-Esterl W, Schilling K.; ''NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS.''; PubMed
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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


View all...
NameTypeDatabase referenceComment
2GCHFR:GCH1ComplexR-HSA-1474149 (Reactome)
2xPalmC-MyrG-NOS3 ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-NOS3ProteinP29474 (Uniprot-TrEMBL)
2xPalmC-MyrG-p-S1177-NOS3 ProteinP29474 (Uniprot-TrEMBL)
ADMAMetaboliteCHEBI:25682 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
APT1 homodimerComplexR-HSA-203655 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ascorbate radicalMetaboliteCHEBI:59513 (ChEBI)
BH2 MetaboliteCHEBI:15375 (ChEBI)
BH2MetaboliteCHEBI:15375 (ChEBI)
BH3.MetaboliteCHEBI:62772 (ChEBI)
BH4 MetaboliteCHEBI:15372 (ChEBI)
BH4MetaboliteCHEBI:15372 (ChEBI)
CALM1 ProteinP62158 (Uniprot-TrEMBL)
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)
DHFR ProteinP00374 (Uniprot-TrEMBL)
DHFR dimerComplexR-HSA-1497822 (Reactome)
DHNTPMetaboliteCHEBI:18372 (ChEBI)
DMAMetaboliteCHEBI:17170 (ChEBI)
DNM2 ProteinP50570 (Uniprot-TrEMBL)
DNM2ProteinP50570 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FMN MetaboliteCHEBI:17621 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
Fe3+MetaboliteCHEBI:29034 (ChEBI)
GCH1 ProteinP30793 (Uniprot-TrEMBL)
GCH1 decamerComplexR-HSA-1474144 (Reactome)
GCHFR ProteinP30047 (Uniprot-TrEMBL)
GCHFR pentamerComplexR-HSA-1474155 (Reactome)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCOOHMetaboliteCHEBI:30751 (ChEBI)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90AA1ProteinP07900 (Uniprot-TrEMBL)
L-ArgMetaboliteCHEBI:32682 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
L-PheMetaboliteCHEBI:58095 (ChEBI)
LYPLA1 ProteinO75608 (Uniprot-TrEMBL)
MYS-CoAMetaboliteCHEBI:15532 (ChEBI)
MyrG-NOS3 ProteinP29474 (Uniprot-TrEMBL)
MyrG-NOS3ProteinP29474 (Uniprot-TrEMBL)
N-WASPProteinO00401 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NO3-MetaboliteCHEBI:48107 (ChEBI)
NOMetaboliteCHEBI:16480 (ChEBI)
NOS3ProteinP29474 (Uniprot-TrEMBL)
NOSIP ProteinQ9Y314 (Uniprot-TrEMBL)
NOSIPProteinQ9Y314 (Uniprot-TrEMBL)
NOSTRIN ProteinQ8IVI9 (Uniprot-TrEMBL)
NOSTRIN homotrimerComplexR-HSA-203678 (Reactome)
O2 MetaboliteCHEBI:15379 (ChEBI)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PALM-CoAMetaboliteCHEBI:15525 (ChEBI)
PALMMetaboliteCHEBI:15756 (ChEBI)
PPPMetaboliteCHEBI:15266 (ChEBI)
PRKG2ProteinQ13237 (Uniprot-TrEMBL)
PTHPMetaboliteCHEBI:17804 (ChEBI)
PTPS hexamerComplexR-HSA-1497879 (Reactome)
PTS ProteinQ03393 (Uniprot-TrEMBL)
PeroxynitriteMetaboliteCHEBI:25941 (ChEBI)
SPR ProteinP35270 (Uniprot-TrEMBL)
SPR dimerComplexR-HSA-1497791 (Reactome)
VitCMetaboliteCHEBI:29073 (ChEBI)
WASL ProteinO00401 (Uniprot-TrEMBL)
ZDHHC21ProteinQ8IVQ6 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
e-MetaboliteCHEBI:10545 (ChEBI)
eNOS:CaM:HSP90:p-AKT1ComplexR-HSA-202113 (Reactome)
eNOS:CaM:HSP90ComplexR-HSA-202105 (Reactome)
eNOS:Caveolin-1:CaM:HSP90ComplexR-HSA-202130 (Reactome)
eNOS:Caveolin-1:CaMComplexR-HSA-202116 (Reactome)
eNOS:Caveolin-1:NOSTRIN complexComplexR-HSA-203758 (Reactome)
eNOS:Caveolin-1:NOSTRIN:Dynamin-2ComplexR-HSA-203696 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPComplexR-HSA-203629 (Reactome)
eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASPComplexR-HSA-203648 (Reactome)
eNOS:Caveolin-1ComplexR-HSA-202128 (Reactome)
eNOS:NOSIPComplexR-HSA-203595 (Reactome)
eNOS:NOSIPComplexR-HSA-203623 (Reactome)
heme MetaboliteCHEBI:17627 (ChEBI)
myristoylated eNOS dimerComplexR-HSA-203619 (Reactome)
myristoylated eNOS dimerComplexR-HSA-203969 (Reactome)
p-PTPS hexamerComplexR-HSA-1475058 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2ComplexR-HSA-1497889 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4ComplexR-HSA-1497830 (Reactome)
p-S1177-eNOS:CaM:HSP90:p-AKT1ComplexR-HSA-202121 (Reactome)
p-S19-PTS ProteinQ03393 (Uniprot-TrEMBL)
p-S213-SPR ProteinP35270 (Uniprot-TrEMBL)
p-SPR dimerComplexR-HSA-1497817 (Reactome)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)

myristoylated eNOS

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

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2GCHFR:GCH1ArrowR-HSA-1474158 (Reactome)
2GCHFR:GCH1TBarR-HSA-1474146 (Reactome)
2xPalmC-MyrG-NOS3ArrowR-HSA-203567 (Reactome)
2xPalmC-MyrG-NOS3R-HSA-203700 (Reactome)
ADMAR-HSA-5693373 (Reactome)
ADMATBarR-HSA-202127 (Reactome)
ADPArrowR-HSA-1475422 (Reactome)
ADPArrowR-HSA-1497853 (Reactome)
ADPArrowR-HSA-202111 (Reactome)
APT1 homodimermim-catalysisR-HSA-203613 (Reactome)
ATPR-HSA-1475422 (Reactome)
ATPR-HSA-1497853 (Reactome)
ATPR-HSA-202111 (Reactome)
Ascorbate radicalArrowR-HSA-1497855 (Reactome)
BH2ArrowR-HSA-1497863 (Reactome)
BH2ArrowR-HSA-1497869 (Reactome)
BH2R-HSA-1497794 (Reactome)
BH2R-HSA-1497796 (Reactome)
BH3.ArrowR-HSA-1497824 (Reactome)
BH3.ArrowR-HSA-1497866 (Reactome)
BH3.R-HSA-1497855 (Reactome)
BH3.R-HSA-1497863 (Reactome)
BH3.R-HSA-1497883 (Reactome)
BH4ArrowR-HSA-1475414 (Reactome)
BH4ArrowR-HSA-1497794 (Reactome)
BH4ArrowR-HSA-1497796 (Reactome)
BH4ArrowR-HSA-1497855 (Reactome)
BH4ArrowR-HSA-1497883 (Reactome)
BH4R-HSA-1497784 (Reactome)
BH4R-HSA-1497824 (Reactome)
BH4R-HSA-1497866 (Reactome)
BH4TBarR-HSA-1474146 (Reactome)
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)
DHFR dimermim-catalysisR-HSA-1497794 (Reactome)
DHNTPArrowR-HSA-1474146 (Reactome)
DHNTPR-HSA-1474184 (Reactome)
DMAArrowR-HSA-5693373 (Reactome)
DNM2R-HSA-203662 (Reactome)
Fe2+R-HSA-1497883 (Reactome)
Fe3+ArrowR-HSA-1497883 (Reactome)
GCH1 decamerR-HSA-1474158 (Reactome)
GCH1 decamermim-catalysisR-HSA-1474146 (Reactome)
GCHFR pentamerR-HSA-1474158 (Reactome)
GTPR-HSA-1474146 (Reactome)
H+R-HSA-1497794 (Reactome)
H+R-HSA-1497869 (Reactome)
H+R-HSA-5340226 (Reactome)
H2OR-HSA-1474146 (Reactome)
H2OR-HSA-5693373 (Reactome)
HCOOHArrowR-HSA-1474146 (Reactome)
HSP90AA1R-HSA-202129 (Reactome)
L-ArgR-HSA-202127 (Reactome)
L-CitArrowR-HSA-202127 (Reactome)
L-CitArrowR-HSA-5693373 (Reactome)
L-PheArrowR-HSA-1474146 (Reactome)
MYS-CoAR-HSA-203611 (Reactome)
MyrG-NOS3ArrowR-HSA-203611 (Reactome)
MyrG-NOS3R-HSA-203567 (Reactome)
N-WASPR-HSA-203565 (Reactome)
NADP+ArrowR-HSA-1475414 (Reactome)
NADP+ArrowR-HSA-1497794 (Reactome)
NADP+ArrowR-HSA-1497810 (Reactome)
NADP+ArrowR-HSA-1497869 (Reactome)
NADP+ArrowR-HSA-202127 (Reactome)
NADP+ArrowR-HSA-5340226 (Reactome)
NADPHR-HSA-1475414 (Reactome)
NADPHR-HSA-1497794 (Reactome)
NADPHR-HSA-1497810 (Reactome)
NADPHR-HSA-1497869 (Reactome)
NADPHR-HSA-202127 (Reactome)
NADPHR-HSA-5340226 (Reactome)
NO3-ArrowR-HSA-5340226 (Reactome)
NOArrowR-HSA-202127 (Reactome)
NOR-HSA-1497878 (Reactome)
NOR-HSA-5340226 (Reactome)
NOS3R-HSA-203611 (Reactome)
NOSIPR-HSA-203553 (Reactome)
NOSTRIN homotrimerR-HSA-203716 (Reactome)
O2.-ArrowR-HSA-1497810 (Reactome)
O2.-R-HSA-1497878 (Reactome)
O2R-HSA-1497810 (Reactome)
O2R-HSA-202127 (Reactome)
O2R-HSA-5340214 (Reactome)
PALM-CoAR-HSA-203567 (Reactome)
PALMArrowR-HSA-203613 (Reactome)
PPPArrowR-HSA-1474184 (Reactome)
PRKG2mim-catalysisR-HSA-1475422 (Reactome)
PRKG2mim-catalysisR-HSA-1497853 (Reactome)
PTHPArrowR-HSA-1474184 (Reactome)
PTHPR-HSA-1475414 (Reactome)
PTPS hexamerR-HSA-1475422 (Reactome)
PeroxynitriteArrowR-HSA-1497878 (Reactome)
PeroxynitriteR-HSA-1497866 (Reactome)
R-HSA-1474146 (Reactome) The first and rate-limiting enzyme in tetrahydrobiopterin de novo biosynthesis is GTP cyclohydrolase I (GCH1, GTPCHI). Three different isoforms are produced but only isoform 1 is functionally active (Gütlich et al. 1994). GCH1 is functional as a homodecamer. First, a monomer of GCH1 forms a dimer. Then five dimers arrange into a ring-like structure to form the homodecamer (Nar et al. 1995).
R-HSA-1474158 (Reactome) High levels of the end product, BH4, negatively regulates GCH1. It does this via GTP cyclohydrolase 1 feedback regulatory protein (GCHFR). BH4-dependant GCHFR in the form of a homopentamer complexes with the decameric GCH1 enzyme in the ratio 2:1 to inactivate it. L-phenylalanine reverses this inhibition. These regulatory steps control the biosynthesis of BH4. (Swick & Kapatos 2006, Chavan et al. 2006, Harada et al. 1993).
R-HSA-1474184 (Reactome) 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) (Takikawa et al. 1986) catalyses the second step in BH4 biosynthesis, the dephosphorylation of DHNTP to 6-pyruvoyl-tetrahydropterin (PTHP). PTPS is believed to function as a homohexamer (Nar et al. 1994, Bürgisser et al. 1994) and has a requirement for Zn2+ (one Zn2+ ion bound per subunit) and Mg2+ ions for activity (Bürgisser et al. 1995). The phosphorylation of Ser-19 is an essential modification for enzyme activity (Scherer-Oppliger et al. 1999).
R-HSA-1475414 (Reactome) Sepiapterin reductase (SPR) (Ichinose et al. 1991) reduces DHNTP to tetrahydrobiopterin (BH4).
R-HSA-1475422 (Reactome) 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) requires phosphorylation on Ser-19 for enzyme activity (Scherer-Oppliger et al. 1999).
R-HSA-1497784 (Reactome) The cofactor tetrahydrobiopterin (BH4) ensures endothelial nitric oxide synthase (eNOS) couples electron transfer to L-arginine oxidation (Berka et al. 2004). During catalysis, electrons derived from NADPH transfer to the flavins FAD and FMN in the reductase domain of eNOS and then on to the ferric heme in the oxygenase domain of eNOS. BH4 can donate an electron to intermediates in this electron transfer and is oxidised in the process, forming the BH3 radical. This radical can be reduced back to BH4 by iron, completing the cycle and forming ferrous iron again. Heme reduction enables O2 binding and L-arginine oxidation to occur within the oxygenase domain (Stuehr et al. 2009).