Information on EC 1.14.13.39 - nitric-oxide synthase (NADPH)

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
1.14.13.39
-
RECOMMENDED NAME
GeneOntology No.
nitric-oxide synthase (NADPH)
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2 L-arginine + 2 NADPH + 2 H+ + 2 O2 = 2 Nomega-hydroxy-L-arginine + 2 NADP+ + 2 H2O
show the reaction diagram
(1a)
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-
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2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
show the reaction diagram
2 Nomega-hydroxy-L-arginine + NADPH + H+ + 2 O2 = 2 L-citrulline + 2 nitric oxide + NADP+ + 2 H2O
show the reaction diagram
(1b)
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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-
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redox reaction
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-
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reduction
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Arginine and proline metabolism
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-
Arginine biosynthesis
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Biosynthesis of antibiotics
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Biosynthesis of secondary metabolites
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L-citrulline-nitric oxide cycle
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Metabolic pathways
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nitric oxide biosynthesis (plants)
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SYSTEMATIC NAME
IUBMB Comments
L-arginine,NADPH:oxygen oxidoreductase (nitric-oxide-forming)
Binds FAD, FMN, heme (iron protoporphyrin IX) and tetrahydrobiopterin. This eukaryotic enzyme, which is found in plants [4] and animals [1-3], consists of oxygenase and reductase domains that 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. May produce superoxide under certain conditions [3]. cf. EC 1.14.13.165, nitric-oxide synthase [NAD(P)H].
CAS REGISTRY NUMBER
COMMENTARY hide
125978-95-2
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
mongrel cat
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Manually annotated by BRENDA team
shelf fungus, collected from forest in Darjeeling, East Sikkim, India
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Manually annotated by BRENDA team
constitutive enzyme
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
Mus musculus C57BL/6
strain C57BL/6
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
hybrid tilapia, three isozymes eNOS, iNOS and nNOS
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
Rattus norvegicus Sprague-Dawley
Sprague-Dawley
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Manually annotated by BRENDA team
neuronal isoform
UniProt
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
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
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-
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-
ir
1-butyl-2-hydroxyguanidine + NADPH + O2
? + NO + NADP+
show the reaction diagram
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-
-
?
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
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
show the reaction diagram
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-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
show the reaction diagram
2,6-dichlorophenolindophenol + NADPH + O2
? + NO + NADP+
show the reaction diagram
2-hydroxy-1-(4-hydroxyphenyl)guanidine + NADPH + O2
? + NO + NADP+
show the reaction diagram
-
-
-
?
2-hydroxy-1-isopropylguanidine + NADPH + O2
? + NO + NADP+
show the reaction diagram
-
-
-
?
adriamycin + NADPH + O2
? + NO + NADP+
show the reaction diagram
-
-
-
-
?
ferricyanide + NADPH + O2
ferrocyanide + NADP+ + H2O
show the reaction diagram
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-
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?
ferricyanide + NADPH + O2
ferrocyanide + NO + NADP+
show the reaction diagram
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?
ferricytochrome c + NADPH + O2
ferrocytochrome c + NO + NADP+
show the reaction diagram
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-
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?
L-Ala-L-Arg + NADPH + O2
?
show the reaction diagram
L-Arg-L-Arg + NADPH + O2
?
show the reaction diagram
L-Arg-L-Arg-L-Arg + NADPH + O2
?
show the reaction diagram
L-Arg-L-Phe + NADPH + O2
?
show the reaction diagram
L-arginine + H2O2 + tetrahydrobiopterin
? + 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
L-arginine + NADPH + O2 + tetrahydrobiopterin
citrulline + NO + NADP+ + ?
show the reaction diagram
L-homoarginine + NADPH + O2
?
show the reaction diagram
menadione + NADPH + O2
? + NO + NADP+
show the reaction diagram
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?
mitomycin c + NADPH + O2
? + NO + NADP+
show the reaction diagram
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?
N-hydroxy-L-arginine + H2O2 + tetrahydrobiopterin
? + NADP+
show the reaction diagram
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?
N-hydroxy-L-arginine + NADPH + O2
? + NO + NADP+
show the reaction diagram
Ngamma-hydroxy-L-arginine + H2O2
citrulline + Ndelta-cyanoornithine + NO2- + NO3-
show the reaction diagram
-
tetrahydrobiopterin-free
NO2-/NO3- as aerobic decomposition products from NO-
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
show the reaction diagram
nitroblue tetrazolium + NADPH
nitroblue tetrazolium-flavazone + NADP+
show the reaction diagram
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
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
peroxynitrite + 4-hydroxyphenylacetic acid + NADPH + H+
4-hydroxyl-3-nitro-phenylacetic acid + NADP+ + H2O
show the reaction diagram
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oxidation and nitration, although H4B binding seems unable to affect iNOSoxy capacity to activate peroxynitrite decomposition, the binding of Arg and citrulline at the distal side of the heme pocket drastically reduces peroxynitrite activation
product dimers
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additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(6R)-5,6,7,8-tetrahydro-L-biopterin
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(6R)-tetrahydrobiopterin
2',3'-dialdehyde analogue of NADPH
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activation, can substitute for NADPH at low concentrations, inhibitory at concentrations of 40times the apparent Km-value or after prolonged incubation
2,6-dichlorophenolindophenol
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activation
5,6,7,8-tetrahydro-L-biopterin
Calmodulin
cytochrome c
flavodoxin
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reduced YkuN and YkuP containing FMN, YkuN is more efficient in supporting bsNOS catalysis, Km for YkuN is 0.0016 mM, for YkuP 0.022 mM, overview
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flavodoxin I
binding site sequence, overview
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heme b
NADP+
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binding mechanism
nitroblue tetrazolium
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activation
tetrahydrobiopterin
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+/calmodulin
O2
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oxygen tension influences the activity
Zinc
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0.43 mol per mol of subunit
Zn2+
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bound by Cys104, Cys109, and Cys194 of isozyme iNOS oxygenase domain
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(4S)-N-(4-amino-5-[aminoethyl]aminopentyl)-N''-nitroguanidine
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;
1,5,6,7-tetrahydro-2H-azepin-2-imines
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1-phenylimidazole
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reversible inhibition of endothelial enzyme, competitive versus L-arginine and tetrahydrobiopterin, no inhibition of cytochrome c reduction
2',3'-dialdehyde of NADPH
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at concentrations of 40times the apparent Km-value or after prolonged incubation, independent of Ca2+/calmodulin, L-arginine or tetrahydrobiopterin, NADPH prevents inhibition, the NADPH-diaphorase activity of the enzyme is less sensitive than the nitric oxide synthase activity
2-aminopyridine derivatives
highly selective inhibitors
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3,4-dihydro-1-isoquinolinamines
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3-bromo-7-nitroindazole
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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
4-(3-amino-propoxy)-6-chloro-1H-quinolin-2-one trifluoroacetic acid salt
IC50: 410 nM, pharmacokinetic profile
4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
4-(3-dimethylamino-propoxy)-1H-quinolin-2-one
5,6,7,8-tetrahydrobiopterin
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quenches the uncoupled reactions and results in much less reactive oxygen species formation, whereas the presence of redox-incompetent 7,8-dihydrobiopterin demonstrates little quenching effect
6(R,S)-methyl-5-deazatetrahydropterin
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6-chloro-4-(3-aminopropoxy)-1-benzopyran-2-one trifluoroacetic acid salt
6-chloro-4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt
6-n-propyl-2-thyouracil
0.1 mg 6-n-propyl-2-thyouracil decreases nNOS activity to 45% compared to control
7-nitroindazole
A-23187
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high levels of A-23187 inhibit nNOS activity
agmatine
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at lower concentration than the Ki value agmatine leads to time-, concentration-, NADPH- and calmodulin-dependent inhibition of the neuronal enzyme in presence of calmodulin; causes an increase in NADPH oxidase activity of the enzyme
aminoguanidine
AR-C102222
AR-C85016
AR-R17477
Calcineurin
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-
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Calmidazolium
carbon monoxide
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carbon monoxide down-regulates iNOS activity by reducing its expression level or by inhibiting its activity by converting it to an inactive P420 form, the presence of dithiothreitol, L-Arg, or H4B partially inhibits the iNOSP450 to iNOSP420 conversion, whereas the presence of both L-Arg and 5,6,7,8-tetrahydro-L-biopterin completely prevents the transition
CO/O2
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80%:20%, mixture
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cyanide
Di-2-thienyliodonium
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competitive, irreversible, complete, time and temperature dependent inhibition
dimethylarginine
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diphenylene iodonium
ethylene glycol bis(beta-amino-ethylether)-N,N,N',N'-tetraacetic acid
Gly-methyl-L-arginine
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inhibition of the isozymes in absence or presence of L-arginine
H2O2
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alters heme group, decrease in activity
imidazole
Iodoniumdiphenyl
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competitive, irreversible, complete, time and temperature dependent inhibition
L-arginine
L-arginine methyl ester
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L-Asn-methyl-L-arginine
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inhibition of the isozymes in absence or presence of L-arginine
L-canavanine
L-N-methylarginine
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NOS inhibitor, complete inhibition at 0.5 mM; NOS inhibitor, complete inhibition at 0.5 mM; NOS inhibitor, complete inhibition at 0.5 mM
L-N6-(1-iminoethyl)lysine dihydrochloride
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5 mM, 78% inhibition
L-NG-nitro-arginine-methylester
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L-Nomega-nitroarginine-(4R)-amino-L-proline amide
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;
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
L-thiocitrulline
methylisothiourea
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0.01 mM, about 80% residual activity
N(G),N(G)-dimethyl-L-arginine
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asymmetric dimethyl arginine
N(G)-nitroarginine methyl ester
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N-(4-aminobutyl)-5-chloro-2-naphthalene sulfonamide
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N-(6-Aminohexyl)-1-naphthalene sulfonamide
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N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide
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calmodulin antagonist above 0.01 mM; i.e. W-7
N-iminoethyl-L-lysine
no isozyme specificity
N-iminoethyl-L-ornithine
no isozyme specificity
N-monomethyl-L-arginine
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0.01 mM, about 55% residual activity
N-nitro-L-arginine methyl ester
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide
inhibition of dimer formation in vivo and in vitro, efficiency is dependent on enzyme source
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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
-
;
NG-methyl arginine
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specific inhibition
NG-methyl-L-arginine
no isozyme specificity
Ng-monomethy-L-arginine
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NG-Nitro-L-arginine
Ngamma,Ngamma-dimethyl-L-arginine
Ngamma-amino-L-arginine
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Ngamma-hydroxy-Ngamma-methyl-L-arginine
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preincubation at 37°C leads to irreversible inactivation, substrates protect
Ngamma-iminoethyl-L-ornithine
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competitive inhibitor
Ngamma-monomethyl-L-arginine
Ngamma-nitro-L-arginine
Ngamma-nitro-L-arginine methyl ester
nitroblue tetrazolium
NO
-
feedback inhibition
Nomega-nitro-L-arginine methyl ester
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
PIN
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human protein enzyme inhibitor, recombinantly expressed in Escherichia coli, the recombinant CREB-binding protein-bound inhibitor protein is purified by calmodulin affinity and inhibits the enzyme to a high extent at 0.001 mM
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S-ethylisothiourea
tetrahydrobiopterin
-
inhibits peroxynitrite activation
thiocoumarin
Trifluoperazine
W7 hydrochloride
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5 mM, 50% inhibition
additional information