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Information on EC 1.14.13.39 - nitric-oxide synthase (NADPH) and Organism(s) Homo sapiens and UniProt Accession P35228

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IUBMB Comments
The enzyme consists of linked oxygenase and reductase domains. The eukaryotic enzyme binds FAD, FMN, heme (iron protoporphyrin IX) and tetrahydrobiopterin, and its two domains are linked via a regulatory calmodulin-binding domain. Upon calcium-induced calmodulin binding, the reductase and oxygenase domains form a complex, allowing electrons to flow from NADPH via FAD and FMN to the active center. The reductase domain of the enzyme from the bacterium Sorangium cellulosum utilizes a [2Fe-2S] cluster to transfer the electrons from NADPH to the active center. cf. EC 1.14.14.47, nitric-oxide synthase (flavodoxin).
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Homo sapiens
UNIPROT: P35228
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The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
hide(Overall reactions are displayed. Show all >>)
Synonyms
nos, inducible nitric oxide synthase, endothelial nitric oxide synthase, inducible no synthase, neuronal nitric oxide synthase, inducible nos, endothelial no synthase, endothelial nos, neuronal nos, no-synthase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
cb-NOS
247
isoform I, constitutive, from brain
cytokine inducible NOS
247
-
e-NOS
247
endothelial isoform III
EC-NOS
247
isoform III, in endothelial cells
endothelial nitric oxide synthase
endothelial nitric-oxide synthase
247
-
endothelial NO synthase
247
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endothelial NOS
endothelium-derived relaxation factor-forming enzyme
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-
-
0
endothelium-derived relaxing factor synthase
-
-
-
0
i-NOS
247
isoform II, inducible
inducible nitric oxide synthase
inducible NO synthase
287630
-
inducible NOS
247
isoform
mitochondrial NO synthase
247
-
mtNOS
247
-
n-NOS
247
isoform I, neuronal enzyme
NADPH-diaphorase
-
-
-
0
neuronal nitric oxide synthase
neuronal NO synthase
neuronal NOS
nitric oxide synthase
nitric oxide synthetase
-
-
-
0
NO synthase
-
-
-
0
NO synthase type I
287635
nNOS
NO synthase type II
287630
iNOS
NO synthase type III
287631
eNOS
NO-synthase
247
-
NOS-2
287630
-
NOS1
247
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NOS2
287630
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synthetase, nitric oxide
-
-
-
0
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
redox reaction
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-
-
0
oxidation
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-
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0
reduction
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-
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0
SYSTEMATIC NAME
IUBMB Comments
L-arginine,NADPH:oxygen oxidoreductase (nitric-oxide-forming)
The enzyme consists of linked oxygenase and reductase domains. The eukaryotic enzyme binds FAD, FMN, heme (iron protoporphyrin IX) and tetrahydrobiopterin, and its two domains are linked via a regulatory calmodulin-binding domain. Upon calcium-induced calmodulin binding, the reductase and oxygenase domains form a complex, allowing electrons to flow from NADPH via FAD and FMN to the active center. The reductase domain of the enzyme from the bacterium Sorangium cellulosum utilizes a [2Fe-2S] cluster to transfer the electrons from NADPH to the active center. cf. EC 1.14.14.47, nitric-oxide synthase (flavodoxin).
CAS REGISTRY NUMBER
COMMENTARY hide
125978-95-2
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
1,4-bis-[[2-(dimethylamino-N-oxide)ethyl]amino]-5,8-dihydroxyanthracene-9,10-dione + NADPH
1-[[2-(dimethylamino-N-oxide)ethyl]amino]-4-[[2-(dimethylamino)ethyl]amino]-5,8-dihydroxyanthracene-9,10-dione + ?
show the reaction diagram
-
-
-
ir
1-[[2-(dimethylamino-N-oxide)ethyl]amino]-4-[[2-(dimethylamino)ethyl]amino]-5,8-dihydroxyanthracene-9,10-dione + NADPH
1,4-bis[[2-(dimethylamino)ethyl]amino]-5,8-dihydroxyanthracene-9,10-dione + ?
show the reaction diagram
-
-
-
ir
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
show the reaction diagram
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
show the reaction diagram
adriamycin + NADPH + O2
? + NO + NADP+
show the reaction diagram
-
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
show the reaction diagram
L-arginine + NADPH + H+ + O2
Nomega-hydroxy-L-arginine + NADP+ + H2O
show the reaction diagram
-
first half reaction
-
-
ir
menadione + NADPH + O2
? + NO + NADP+
show the reaction diagram
-
-
-
-
?
mitomycin c + NADPH + O2
? + NO + NADP+
show the reaction diagram
-
-
-
-
?
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
L-citrulline + NADP+ + NO + H2O
show the reaction diagram
-
second half reaction
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-
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
show the reaction diagram
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-
-
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
show the reaction diagram
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
show the reaction diagram
-
NO from acetylsalicylic acid-activated enzyme is involved in thrombolysis, overview
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-
?
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADPH
(6R)-5,6,7,8-tetrahydro-L-biopterin
-
5,6,7,8-tetrahydro-L-biopterin
Calmodulin
NADPH
tetrahydrobiopterin
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+/calmodulin
Fe2+
-
-
O2
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oxygen tension influences the activity
Zinc
-
0.43 mol per mol of subunit
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(4S)-N-(4-amino-5-[aminoethyl]aminopentyl)-N''-nitroguanidine
-
3-bromo-7-nitroindazole
nNOS-specific inhibitor, complete inhibition at 0.01 mM
3-[cis-4'-[(6''-aminopyridin-2''-yl)methyl]pyrrolidin-3'-ylamino]propan-1-ol
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4-(3-amino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
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IC50: 0.0076 mM
4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
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IC50: 0.004 mM
4-(3-dimethylamino-propoxy)-1H-quinolin-2-one
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IC50: 0.0026 mM
6-chloro-4-(3-aminopropoxy)-1-benzopyran-2-one trifluoroacetic acid salt
-
IC50: 90 nM, pharmacokinetic profile
6-chloro-4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
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IC50: 0.0041 mM
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt
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IC50: 0.00011mM
7-nitroindazole
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agmatine
AR-R17477
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Calmidazolium
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cyanide
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heme-blocker inhibits superoxide formation after pretreatment of the enzyme
H2O2
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alters heme group, decrease in activity
imidazole
-
heme-blocker inhibits superoxide formation after pretreatment of the enzyme
inhibitor NS1
-
is a new prototype of a reversible inhibitor of constitutive NOS targeting their reductase domain. NS1 is designed by molecular modelling, by replacing the imbedded NADP cofactor in neuronal NOS reductase domain. NS1 shares with NADPH the nucleotide moiety that allows proper targeting to the NADPH site. NS1 competes with NADPH binding
L-N-methylarginine
NOS inhibitor, complete inhibition at 0.5 mM
L-Nomega-nitroarginine-(4R)-amino-L-proline amide
-
L-Nomega-nitroarginine-2,4-L-diaminobutyramide
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L-omega-monomethyl L-arginine
potent competitive eNOS inhibitor, complete inhibition at 10 mM
N(G),N(G)-dimethyl-L-arginine
-
asymmetric dimethyl arginine
N-nitro-L-arginine methyl ester
-
competitive NOS inhibitor
N1-[cis-4'-[(6''-amino-4''-methylpyridin-2''-yl)methyl]pyrrolidin-3'-yl]-N2-(4'-chlorobenzyl)ethane-1,2-diamine
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N1-[cis-4'-[(6''-aminopyridin-2''-yl)methyl]pyrrolidin-3'-yl]ethane-1,2-diamine
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N1-[trans-4'-[(6''-amino-4''-methylpyridin-2''-yl)methyl]pyrrolidin-3'-yl]-N2-(3'-chlorobenzyl)ethane-1,2-diamine
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Ngamma-monomethyl-L-arginine
Ngamma-nitro-L-arginine
Ngamma-nitro-L-arginine methyl ester
-
only L-isomer, inhibits NO and citrulline production from L-arginine as well as superoxide formation in absence of tetrahydropterin
NXN-188
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a dual-action oral therapeutic being developed for the treatment of acute migraine. The pharmacological mechanism of action of NXN-188 involves inhibition of both the neuronal nitric oxide synthase enzyme isoform and affinity for serotonin receptors. Clinical studies and pharmacokinetics, detailed overview
thiocoumarin
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IC50: 0.018 mM
Trifluoperazine
-
inhibition in the presence of Ca2+, reversible by calmodulin
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Acetylsalicylic acid
-
maximal activation at 0.004 mM
Ca2+/calmodulin
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Calmodulin
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dithiothreitol
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tetrahydrobiopterin
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-
additional information
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