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Information on EC 1.14.13.39 - nitric-oxide synthase (NADPH) and Organism(s) Mus musculus and UniProt Accession P29477
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EC Tree 1 Oxidoreductases
1.14 Acting on paired donors, with incorporation or reduction of molecular oxygen
1.14.13 With NADH or NADPH as one donor, and incorporation of one atom of oxygen into the other donor
1.14.13.39 nitric-oxide synthase (NADPH)
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).
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
- 1.14.13.39
- artery
- necrosis
- lipopolysaccharide
-
l-name
- lps
- tnf
- cardiovascular
- cox-2
- nitrite
- cyclooxygenase-2
- vessel
- hypertension
- cardiac
-
lps-induced
- dismutase
- cerebral
-
vasodilation
- nerve
- aortic
- ischemia
- pulmonary
- prostaglandin
- myocardial
- cgmp
- ng-nitro-l-arginine
- factor-alpha
- coronary
- acetylcholine
- wistar
-
endothelium-dependent
- tnf-alpha
- peroxynitrite
-
contractile
-
neuroprotective
-
lps-stimulated
-
reperfusion
- nf-kappab
-
nitrotyrosine
- microglia
- interferon-gamma
- nitroprusside
- ifn-gamma
-
vasoconstriction
-
guanylate
-
vasorelaxation
- il-1beta
-
lipopolysaccharide-induced
-
erectile
- endothelin-1
-
guanylyl
- pharmacology
- medicine
showSynonyms
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
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
endothelium-derived relaxation factor-forming enzyme
-
-
-
-
endothelium-derived relaxing factor synthase
-
-
-
-
eNOS
NADPH-diaphorase
-
-
-
-
nitric oxide synthase
nitric oxide synthetase
-
-
-
-
NO synthase
-
-
-
-
NOS
synthetase, nitric oxide
-
-
-
-
nitric oxide synthase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
analysis of transition states via stopped-flow spectroscopy
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
alignment of heme-binding domain amino acid sequences of NOS
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
dimerization is required, activation of NO-synthesis by enabling electron transfer between the reductase and the oxygenase domains, isolated monomers are inactive
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
possible mechanism
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
relation between structure, function and binding of prosthetic groups during dissociation, unfolding and renaturation
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
isoform I and II are regulated by Ca2+/calmodulin, isoform II is Ca2+-independent, but requires calmodulin, inducible by cytokines
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
cytochrome P-450 enzyme
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
structure-function study of macrophage enzyme
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
subunits align in head-to-head manner with oxygenase domains interacting to form a dimer and reductase domains existing as independent extensions
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
interaction and electrontransfer between enzyme domains and bound cofactors calmodulin, FMN, FAD, tetrahydrobiopterin, heme, and NADPH, overview
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
MetaCyc
nitric oxide biosynthesis II (mammals)
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
125978-95-2
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
Substrates: overall reaction
Products: -
Products: -
?
L-arginine + NADPH + O2 + tetrahydrobiopterin
citrulline + NO + NADP+ + ?
Substrates: -
Products: -
Products: -
?
N-hydroxy-L-arginine + NADPH + O2
? + NO + NADP+
Substrates: -
Products: -
Products: -
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
Substrates: -
Products: -
Products: -
?
L-Ala-L-Arg + NADPH + O2
?
-
Substrates: endothelial microsomes, macrophage
Products: -
Products: -
?
L-Arg-L-Arg + NADPH + O2
?
-
Substrates: endothelial, microsomes, macrophage
Products: -
Products: -
?
L-Arg-L-Arg-L-Arg + NADPH + O2
?
-
Substrates: endothelial microsomes
Products: -
Products: -
?
L-homoarginine + NADPH + O2
?
-
Substrates: constitutive endothelial membrane-bound and inducible soluble macrophage enzyme
Products: -
Products: -
?
Ngamma-hydroxy-L-arginine + H2O2
citrulline + Ndelta-cyanoornithine + NO2- + NO3-
-
Substrates: tetrahydrobiopterin-free
Products: NO2-/NO3- as aerobic decomposition products from NO-
Products: NO2-/NO3- as aerobic decomposition products from NO-
?
peroxynitrite + 4-hydroxyphenylacetic acid + NADPH + H+
4-hydroxyl-3-nitro-phenylacetic acid + NADP+ + H2O
-
Substrates: 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
Products: product dimers
Products: product dimers
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
Substrates: dimeric structure is required for enzyme activity
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
Substrates: NOS catalyzes the formation of NO via a consecutive two-step reaction. In the first step, L-arginine is converted to N-hydroxy-L-arginine, in the second step, N-hydroxy-L-arginine is further converted to citrulline and nitric oxide, two different mechanisms, overview. During catalysis, mediated by calcium/calmodulin, electrons flow from NADPH through FAD and FMN in the reductase domain of one subunit of the homodimer to the oxygenase domain of the other subunit, substrate-ligand interaction in the Fe2+-O2 complex, overview
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
Substrates: substrate and product binding analysis
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
440193, 440195, 440200, 440201, 440204, 440206, 440209, 440217, 440225, 440226, 440234, 440236, 440238, 440239
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: -
Products: probably via Nomega-hydroxy-L-arginine
Products: probably via Nomega-hydroxy-L-arginine
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: the overall reaction proceeds via 2 partial reactions: reaction 1 converts L-arginine into L-Ngamma-hydroxyarginine, reaction 2 converts L-Ngamma-hydroxyarginine into citrulline and nitric oxide
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: capacity to synthesize NO only through dimerization and binding of heme and tetrahydrobiopterin
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: dimeric structure is required for enzyme activity
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: tetrahydrobiopterin is absolutely required for partial reaction 1
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: specific for NADPH, 5-electron oxidation of L-arginine
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: physiological functions and pathophysiology of the isoforms
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: acts as signal molecule for neurotransmission, vasorelaxation, and cytotoxity
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: enzyme of mammalian immune, cardiovascular and neural systems, synthesizing the free radical nitric oxide or a NO-releasing product
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: soluble cytochrome P-450 enzyme in eukaryotes
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
Substrates: -
Products: -
Products: -
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
Substrates: substrate is intermediate between reaction 1 and 2 to form citrulline and NO from L-arginine
Products: -
Products: -
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
Substrates: reaction is possible without tetrahydrobiopterin, can also use H2O2 instead of NADPH and O2
Products: -
Products: -
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
Substrates: -
Products: -
Products: -
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
Substrates: best substrate
Products: -
Products: -
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
-
Substrates: -
Products: -
Products: -
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
-
Substrates: wild-type and mutants
Products: -
Products: -
?
additional information
?
-
-
Substrates: Ngamma-hydroxylation is the first step of the reaction, Ngamma-hydroxy-L-arginine being an intermediate in the L-arginine to NO pathway
Products: -
Products: -
?
additional information
?
-
-
Substrates: dimeric enzyme and subunits are equivalent in catalyzing electron transfer from NADPH to cytochrome c, dichlorophenolindiphenol, and ferricyanide
Products: -
Products: -
?
additional information
?
-
-
Substrates: D-arginine is no substrate
Products: -
Products: -
?
additional information
?
-
-
Substrates: calmodulin-controlled isoforms are signal generators, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: both oxyFMN and oxygenase domain activity are measured by following H2O2-supported oxidation of Nomega-hydroxy-L-Arg, L-NOHA, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: iNOS modulates endothelin-1-dependent release of prostacyclin and inhibition of platelet aggregation ex vivo in the mouse, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: inducible nitric-oxide synthase-derived NO contributes to the pathophysiology of intestinal inflammation in the colon
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme exclusively performs the nitric oxide synthesis, an essential biological mediator, and of peroxynitrite, a well known cytotoxic agent involved innumerouspathophysiological processes, NOSs have the unique ability to both produce and activate peroxynitrite, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development
Products: -
Products: -
?
additional information
?
-
-
Substrates: interaction between peroxynitrite and the oxygenase domain of inducible NOS
Products: -
Products: -
?
additional information
?
-
Substrates: eNOS is an important negative regulator of AMP-activated protein kinase phosphorylation and intracellular H2O2 generation in endothelial cells
Products: -
Products: -
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
Substrates: overall reaction
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: physiological functions and pathophysiology of the isoforms
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: acts as signal molecule for neurotransmission, vasorelaxation, and cytotoxity
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: enzyme of mammalian immune, cardiovascular and neural systems, synthesizing the free radical nitric oxide or a NO-releasing product
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: soluble cytochrome P-450 enzyme in eukaryotes
Products: -
Products: -
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: calmodulin-controlled isoforms are signal generators, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: iNOS modulates endothelin-1-dependent release of prostacyclin and inhibition of platelet aggregation ex vivo in the mouse, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: inducible nitric-oxide synthase-derived NO contributes to the pathophysiology of intestinal inflammation in the colon
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme exclusively performs the nitric oxide synthesis, an essential biological mediator, and of peroxynitrite, a well known cytotoxic agent involved innumerouspathophysiological processes, NOSs have the unique ability to both produce and activate peroxynitrite, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development
Products: -
Products: -
?
additional information
?
-
Substrates: eNOS is an important negative regulator of AMP-activated protein kinase phosphorylation and intracellular H2O2 generation in endothelial cells
Products: -
Products: -
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
heme
-
the heme is coordinated by a cysteine residue on the proximal side, and the substrates, Arg or N-hydroxy-L-arginine, bind above the heme iron atom in the distal pocket, while the cofactor, tetrahydrobiopterin, binds along the side of the heme
5,6,7,8-tetrahydro-L-biopterin
-
enzyme purified in absence of biopterin contains substoichiometric concentration, if purified in presence of biopterin it contains 1 mol biopterin per mol MW 130000 subunit
5,6,7,8-tetrahydro-L-biopterin
-
activity is correlated directly to bound biopterin concentration
5,6,7,8-tetrahydro-L-biopterin
-
required for the first partial reaction, formation of NG-hydroxy-L-arginine
Calmodulin
-
15fold stimulation of cytochrome c reduction of wild-type and mutants C415A and C415H
FMN
-
wild-type and mutant C415H contain 0.8 and 0.9 mol per mol of subunit, respectively
FMN
-
FMN/heme electron transfer, FMN is capable of serving as a one electron heme reductant
NADPH
-
-
440192, 440193, 440195, 440198, 440200, 440201, 440206, 440209, 440217, 440221, 440222, 440225, 440234, 440236, 440238, 440239
tetrahydrobiopterin
-
the cofactor tetrahydrobiopterin binds along the side of the heme
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Iron
low-spin heme iron, L-arginine aud tetrahydrobiopterin bind and stabilize heme iron in five-coordinate high-spin state
Ca2+
Ca2+/calmodulin
-
calmodulin activates electron transfer from NADPH through three reductase domains to the oxygenase domain, controls constitutive isoforms through regulation of electrontransfer between NADPH and heme
Fe2+
-
in the heme cofactor, substrate-ligand interaction in the Fe2+-O2 complex, overview
Iron
Ca2+
-
constitutive endothelial and inducible membrane bound macrophage enzyme are strictly Ca2+-dependent
Iron
-
2 mol iron-protoporphyrin IX per mol enzyme dimer, the heme-iron is ferric, EPR-and light absorbance spectroscopy
Iron
-
naturally occuring neuronal mutant with a 105-amino acid deletion in the heme-binding domain as a result of in-frame mutation by specific alternative splicing, contains heme, but shows no L-arginine and NADPH-dependent citrulline-forming activity in presence of Ca2+-promoted calmodulin, the heme coordination geometry is highly abnormal
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4-(3-amino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
IC50: 0.0119 mM
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
IC50: 0.01 mM
6-chloro-4-(3-aminopropoxy)-1-benzopyran-2-one trifluoroacetic acid salt
IC50: 60 nM, pharmacokinetic profile
6-chloro-4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
IC50: 0.0012 mM
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt
IC50: 0.00025mM
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
Di-2-thienyliodonium
-
competitive, irreversible, complete, time and temperature dependent inhibition
diphenylene iodonium
-
competitive, irreversible, complete, time and temperature dependent inhibition
ethylene glycol bis(beta-amino-ethylether)-N,N,N',N'-tetraacetic acid
-
i.e. EGTA, complete inhibition of cytosolic enzyme, partial inhibition of particulate 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
Iodoniumdiphenyl
-
competitive, irreversible, complete, time and temperature dependent inhibition
Ngamma-hydroxy-Ngamma-methyl-L-arginine
-
preincubation at 37°C leads to irreversible inactivation, substrates protect
Ngamma-monomethyl-L-arginine
-
L-arginine protects against enzyme inactivation, thus inactivation occurs at or near active site
Ngamma-monomethyl-L-arginine
-
inducible isoform: after preincubation irreversible, time- and concentration-dependent inactivation, without preincubation reversible inhibition
Ngamma-nitro-L-arginine
-
L-arginine protects against enzyme inactivation, thus inactivation occurs at or near active site
Ngamma-nitro-L-arginine
-
reversible inhibitor of inducible isoform from macrophage
additional information
inhibitory activity for coumarin derivatives, inhibitor screening, overview
-
additional information
-
inhibitory activity for coumarin derivatives, inhibitor screening, overview
-
additional information
-
the macrophage enzyme is not inhibited by calmodulin antagonists (N-4-aminobutyl-), (N-6-aminohexyl)-5-chloro-2-naphthalene sulfonamide
-
additional information
-
not inhibitory: N-nitro-L-arginine methyl ester, or specific inhibitor of inducible NOS, 1400W
-
additional information
-
inhibition of PSD-95/nNOS interaction by the nNOSalpha beta-finger antibody
-
additional information
-
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
-
additional information
there is decreased eNOS activity in tight-skin 1-mouse skin tissue
-
additional information
-
there is decreased eNOS activity in tight-skin 1-mouse skin tissue
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(6R,S)-Methyl-tetrahydropterin
-
activation in the absence of biopterin, not as effective as tetrahydrobiopterin
Ca2+/calmodulin
-
calmodulin activates electron transfer from NADPH through three reductase domains to the oxygenase domain, controls constitutive isoforms through regulation of electrontransfer between NADPH and heme
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
kinetic analysis of the interaction between peroxynitrite and the oxygenase domain of inducible NOS at three different pH values, overview
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000022
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide
-
0.0081
Ngamma-nitro-L-arginine
-
reversible inhibition of inducible macrophage isoform
0.0026
Ngamma-monomethyl-L-arginine
-
inducible isoform from macrophage after preincubation
0.0039
Ngamma-monomethyl-L-arginine
-
inducible isoform from macrophage without preincubation
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0119
4-(3-amino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
Mus musculus
IC50: 0.0119 mM
0.00041
4-(3-amino-propoxy)-6-chloro-1H-quinolin-2-one trifluoroacetic acid salt
Mus musculus
IC50: 410 nM, pharmacokinetic profile
0.01
4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
Mus musculus
IC50: 0.01 mM
0.00006
6-chloro-4-(3-aminopropoxy)-1-benzopyran-2-one trifluoroacetic acid salt
Mus musculus
IC50: 60 nM, pharmacokinetic profile
0.0012
6-chloro-4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
Mus musculus
IC50: 0.0012 mM
0.00025
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt
Mus musculus
IC50: 0.00025mM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.031
-
purified recombinant enzyme, NADPH/O2-supported reduction of Ngamma-hydroxy-L-arginine, tetrahydrobiopterin-free, 25°C
0.12
-
purified recombinant enzyme, H2O2-supported reduction of Ngamma-hydroxy-L-arginine, tetrahydrobiopterin-free, 25°C
0.17
-
purified recombinant enzyme, NADPH/O2-supported reduction of Ngamma-hydroxy-L-arginine, with tetrahydrobiopterin, 25°C
0.815
-
purified recombinant enzyme, H2O2-supported reduction of Ngamma-hydroxy-L-arginine, with tetrahydrobiopterin, 25°C
additional information
additional information
-
iNOS activities in wild-type and chimeric mice, both with induced colitis, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
n the skin, eNOS is present in the epidermal layer, hair follicles and also in the endothelial cells lining the blood vessels
additional information
-
central nervous system, natural variant with 105-amino acid deletion in the heme-binding domain
additional information
-
3 isoforms: 1. neuronal, soluble isoform I is constitutively expressed in brain and other tissues and Ca2+-regulated, 2. soluble isoform II is usually not constitutively expressed, but inducible in macrophages and other cells, 3. isoform III is membrane-bound and expressed in endothelial cells
additional information
-
3 distinct isoforms: 1. a membrane-associated, constitutive enzyme from tha vascular endothelium, 2. a soluble, constitutive enzyme from neuronal cells, 3. an endotoxin- and cytokine-inducible enzyme exemplified by that from murine macrophages
additional information
-
activity of constitutive enzymes is regulated by binding of calmodulin and Ca2+, the inducible enzyme is regulated by binding of calmodulin, not by Ca2+
additional information
-
nNOS splicing variants tissue distribution, immunohistochemic analysis, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
iNOS contains several characteristic endoplasmic reticulum (ER)-localization sequences. iNOS is likely to be glycosylated in the endoplasmic reticulum
-
constitutive endothelial enzyme: predominantly membrane-bound, inducible macrophage enzyme: equally distributed between cytosol and membrane, small constitutive membrane-bound portion in murine macrophages
additional information
additional information
N-glycosylation of proteins starts in the endoplasmic reticulum, continues in the Golgi, and ends at the plasma membrane. As mentioned above, iNOS has characteristic ER localization sequences and locates in the Golgi and cell membrane. iNOS is located both in cytoplasm and on cell membrane, it is not only a cytoplasmic protein but also a membrane protein
-
additional information
-
N-glycosylation of proteins starts in the endoplasmic reticulum, continues in the Golgi, and ends at the plasma membrane. As mentioned above, iNOS has characteristic ER localization sequences and locates in the Golgi and cell membrane. iNOS is located both in cytoplasm and on cell membrane, it is not only a cytoplasmic protein but also a membrane protein
-
additional information
-
3 distinct isoforms: 1. a membrane-associated, constitutive enzyme from the vascular endothelium, 2. a soluble, constitutive enzyme from neuronal cells, 3. an endotoxin- and cytokine-inducible enzyme exemplified by that from murine macrophages
-
additional information
-
3 isoforms: 1. neuronal, soluble isoform I is constitutively expressed in brain and other tissues and Ca2+-regulated, 2. soluble isoform II is usually not constitutively expressed, but inducible in macrophages and other cells, 3. isoform III is membrane-bound and expressed in endothelial cells
-
additional information
-
activity of constitutive enzymes is regulated by binding of calmodulin and Ca2+, the inducible enzyme is regulated by binding of calmodulin, not by Ca2+
-
Highest Expressing Human Cell Lines
Cell Line LinksGENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
attachment of N-glycan to the Asn695 residue inhibits activity by disturbing electron transfer. N-glycosylated iNOS consumes NADPH more slowly than the unliganded enzyme. Mutating Asn695 to Gln695 yields an iNOS that exhibits greater enzyme activity compared to wild-type. NO produced by N695Q iNOS-transformed HEK293 cells is 1.32fold greater than that of N-glycosylated iNOS, the increased enzyme activity of N695Q iNOS in HEK293 cells was caused by loss of N-glycan
physiological function
physiological function
si-RNA mediated knockdown of eNOS leads to a striking increase in AMP-activated protein kinase phosphorylation, homozygot eNOS knockout mice show a marked increase in AMP-activated protein kinase phosphorylation in liver and lung compared to wild type mice
additional information
physiological function
NADPH oxidases (NOX2/NOX4) and inducible nitric oxide synthase (iNOS) derived oxidative stress play a key role in psoriasis induced kidney dysfunction. NADPH oxidase (NOX2 and NOX4) isoforms, and inducible nitric oxidase synthase (iNOS) are elevated in the renal tissue under inflammatory conditions such as acute kidney injury and chronic kidney disease. These enzymes are capable of producing reactive oxygen species (ROS) in large quantities under inflammatory conditions, which may cause oxidative damage to biological macromolecules such as lipids, proteins and nucleic acids leading to malfunction of cellular structures through dysregulation of ion pumps, and enzymatic activity
physiological function
inducible nitric oxide synthase (iNOS) is a key inflammatory factor. It functions in both acute and chronic inflammation. Nitric oxide (NO) is a signaling mediator with many diverse and often contradictory biological activities. In mammals, NO is produced by a family of nitric oxide synthase (NOS). The NOS family includes neuronal nitric oxide synthase (nNOS, type I), inducible nitric oxide synthase (iNOS, type II), and endothelial nitric oxide synthase (eNOS, type III). All these three NOS isoforms catalyze a similar reaction. Consuming NADPH and O2, NOS oxidizes L-arginine into L-citrulline and releases NO. The reaction is an oxidation-reduction reaction, and electron transfer plays a vital role. Inducible nitric oxide synthase (iNOS) plays critical roles in the inflammatory response and host defense. The essence of nitric oxide synthase catalytic reaction is an electron transfer process, which involves a series of conformational changes, and the linker between the flavin mononucleotide-binding domain and the flavin adenine dinucleotide-binding domain plays vital roles in the conformational changes. Residue Asn695 is part of the linker. Enzyme iNOS is N-glycosylated at its Asn695 residue and N-glycosylation of Asn695 might suppress iNOS activity by disturbing electron transfer
additional information
residue Asn695 of the mouse iNOS locates at the hinge segment which connects the FMN-binding domain to the FAD-binding domain. The electrostatic and flexibility properties of hinge segment are critical for electron transfer from CPR to its redox partners. For mouse iNOS, N-glycosylation of Asn695 might disturb electron transfer by influencing the electrostatic and flexibility properties of the hinge segment
additional information
-
residue Asn695 of the mouse iNOS locates at the hinge segment which connects the FMN-binding domain to the FAD-binding domain. The electrostatic and flexibility properties of hinge segment are critical for electron transfer from CPR to its redox partners. For mouse iNOS, N-glycosylation of Asn695 might disturb electron transfer by influencing the electrostatic and flexibility properties of the hinge segment
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
dissociates irreversibly into subunits in the absence of L-arginine, FAD and tetrahydrobiopterin
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
all three NOS isoforms are composed of an N-terminal catalytic oxygenase module (NOSox) and a C-terminal-electron-supplying reductase module (NOSred), and NOSox and NOSred are linked by a Ca2+/calmodulin binding region. NOSox contains a heme-binding site, a tetrahydrobiopterin-binding site and an arginine-binding site. NOSred contains an flavin mononucleotide-binding site, an flavin adenine dinucleotide-binding site and an NADPH-binding site. Only dimerized NOS has catalytic activity
dimer
additional information
dimer
-
subunit disassembly and unfolding of the protein following a pH jump from 7.5 to 2.8
additional information
-
D-arginine inhibits reconstitution of dimer from subunits
additional information
-
dimer formation, each subunit consists of: 1 oxygenase domain containing heme, tetrahydrobiopterin, substrate binding site and 1 reductase domain containing FAD, FMN, calmodulin, NADPH binding site
additional information
-
dimer formation, each subunit consists of: 1 oxygenase domain containing heme, tetrahydrobiopterin, substrate binding site and 1 reductase domain containing FAD, FMN, calmodulin, NADPH binding site
additional information
-
dimer formation, each subunit consists of: 1 oxygenase domain containing heme, tetrahydrobiopterin, substrate binding site and 1 reductase domain containing FAD, FMN, calmodulin, NADPH binding site
additional information
-
dimeric structure is required for enzyme activity, interaction between subunits via oxygenase domains
additional information
-
dimeric structure is required for enzyme activity, interaction between subunits via oxygenase domains
additional information
-
significant amino acid sequence homology to NADPH-cytochrome P-450-type hemoprotein
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
iNOS is N-glycosylated in vitro and in vivo. Mass spectrometry studies identify Asn695 as an N-glycosylation site of murine iNOS, mapping of the iNOS N-glycosylation site. iNOS expressed by LPS- and IFN-gamma-stimulated Raw-264.7 cells can be recognized by concanavalin A (ConA). Glycosylation at Asn695 might suppress inducible nitric oxide synthase activity by disturbing electron transfer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
orthorhombic crystals from NOS oxygenase domain lacking the N-terminal 114 residues, preparation in presence of imidazole, structure analysis via x-ray diffraction, also with bound inhibitor N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide
x-ray crystal structure of the heme-binding domains of neuronal wild-type and mutant with deletion in the heme-binding domain
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N695Q
site-directed mutagenesis, mutating Asn695 to Gln695 yields an iNOS that exhibits greater enzyme activity compared to wild-type. NO produced by N695Q iNOS-transformed HEK293 cells is 1.32fold greater than that of N-glycosylated iNOS, the increased enzyme activity of N695Q iNOS in HEK293 cells was caused by loss of N-glycan
W457A
increase in Km-value of tetrahydrobiopterin and L-arginine, decrease in NO synthesis activity, slower building of enzyme heme-NO complex and slower reactivity of heme-dioxy intermediate
C415A
-
contains no heme, no bound tetrahydrobiopterin, unable to oxidize NADPH and to synthezise nitric oxide, unaltered ability to reduce cytochrome c
C415H
-
contains nearly no heme, no bound tetrahydrobiopterin, unable to oxidize NADPH and to synthezise nitric oxide, unaltered ability to reduce cytochrome c
additional information
additional information
monomers encoding NOS oxygenase domain lacking the N-terminal 114 residues, His-tagged, expression in Escherichia coli
additional information
-
monomers encoding NOS oxygenase domain lacking the N-terminal 114 residues, His-tagged, expression in Escherichia coli
additional information
-
construction of a heterodimer with one subunit being His-tagged
additional information
-
naturally occuring neuronal mutant with a 105-amino acid deletion in the heme-binding domain as a result of in-frame mutation by specific alternative splicing, contains heme, but shows no L-arginine and NADPH-dependent citrulline-forming activity in presence of Ca2+-promoted calmodulin
additional information
-
construction of eNOS and of iNOS knockout mice, phenotype, overview
additional information
-
generation of mice chimeric for iNOS expression, wild-type animals receive bone marrow cells from CD45.1-expressing congenic wild-type mice, resulting in three different chimeric strains, phenotype with induced colitis, overview
additional information
-
knock out mice deficient for the splice-isoform alpha of neuronal nitric oxide synthase display residual nitric oxide synthase activity and immunosignal
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
subunit disassembly and unfolding of the protein following a pH jump from 7.5 to 2.8, kinetic unfolding mechanism of the inducible enzymes' oxygenase domain, the initial step of the reaction is the disruption of the iNOSCOD dimer, to generate heme-bound monomeric species in various degrees of unfolding, which is accompanied by the loss of two tetrahydrobiopterin cofactors, subsequent heme loss generates monomeric apoproteins exhibiting various degrees of unfolding, modeling of the denaturation process, overview
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
37
-
tetrahydrobiopterin-free enzyme is not stable, therefore reaction is performed at 25°C
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
mutants less stable than wild-type, precipitation during incubation at 15°C, partial stabilization with NaCl, stabilization by purification in presence of L-arginine and tetrahydrobiopterin
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme oxygenase domain from Escherichia coli in the absence of both Arg and tetrahydrobiopterin
-
recombinant His-tagged or GST-tagged truncated nNOS, comprising residues 1-198, from Escherichia coli by nickel affinity or glutathione affinity chromatography, respectively
-
wild-type and natural mutant, recombinant from Escherichia coli and insect cells
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of His-tagged NOS oxygenase domain lacking the N-terminal 114 residues in Escherichia coli
gene nos2, recombinant expression of wild-type and mutant enzymes in HEK293 cells or Escherichia coli
expression of His-tagged and GST-tagged truncated nNOS, comprising residues 1-198, in Escherichia coli
-
expression of neuronal isoform wild type and mutants C415H, C415A in Spodoptera frugiperda cells via baculovirus infection
-
expression of the C-terminally His-tagged iNOS oxygenase domain, iNOSoxy, in Escherichia coli strain BL21
-
expression of the oxygenase domain of inducible nitric oxide synthase in Escherichia coli
-
neuronal wild-type and natural mutant, specifically expressed in the central nervous system, expression in Escherichia coli and in insect cells of Spodoptera frugiperda via baculovirus infection
-
transient expression of GFP-tagged isozyme NOS1 in COS-1 cell mitochondria, N-terminally truncated GFP-tagged isozyme NOS1 is localized in the cytosol
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
exposure of primary cortical astrocytes to a low concentration of Mn2+ (0.01 mM) potentiates expression of NOS2 mRNA and protein
investigated the effect of imiquimod (IMQ)-induced psoriatic inflammation on kidney function and inflammation in a murine model. Psoriatic inflammation in mice is associated with kidney dysfunction as reflected by increased serum creatinine and blood urea nitrogen. Kidney dysfunction is paralleled by upregulation of reactive oxygen species (ROS) generating enzymes such as NOX2, NOX4 and iNOS
mitogen-activated protein kinase phosphatase-1 may negatively regulate iNOS expression by controlling the expression of microRNA-155 and consequently the signal transducer and activator of transcription pathway via suppressor of cytokine signaling-1
expression of both the eNOS protein and gene is significantly reduced in tight-skin 1-mouse skin tissue
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
refolding after treatment/equilibration with 5 M urea in presence of L-arginine and tetrahydrobiopterin
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Stuehr, D.J.; Ikeda-Saito, M.
Spectral characterization of brain and macrophage nitric oxide synthases. Cytochrome P-450-like hemeproteins that contain a flavin semiquinone radical
J. Biol. Chem.
267
20547-20550
1992
Rattus norvegicus, Mus musculus
Pufahl, R.A.; Nanjappan, P.G.; Woodard, R.W.; Marletta, M.A.
Mechanistic probes of N-hydroxylation of L-arginine by the inducible nitric oxide synthase from murine macrophages
Biochemistry
31
6822-6828
1992
Mus musculus
Hevel, J.M.; Marletta, M.A.
Macrophage nitric oxide synthase: relationship between enzyme-bound tetrahydrobiopterin and synthase activity
Biochemistry
31
7160-7165
1992
Mus musculus
White, K.A.; Marletta, M.A.
Nitric oxide synthase is a cytochrome P-450 type hemoprotein
Biochemistry
31
6627-6631
1992
Rattus norvegicus, Mus musculus
Xie, Q.W.; Hearn, J.C.; Calaycay, J.; Mumford, R.A.; Swiderek, K.M.; Lee, T.D.; Ding, A.; Troso, T.; Nathan, C.
Cloning and characterization of inducible nitric oxide synthase from mouse macrophages
Science
256
225-228
1992
Mus musculus
Stuehr, D.J.; Cho, H.J.; Kwon, N.S.; Weise, M.F.; Nathan, C.F.
Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein
Proc. Natl. Acad. Sci. USA
88
7773-7777
1991
Mus musculus
Hecker, M.; Walsh, D.T.; Vane, J.R.
On the substrate specificity of nitric oxide synthase
FEBS Lett.
294
221-224
1991
Mus musculus, Bos taurus
Hevel, J.M.; White, K.A.; Marletta, M.A.
Purification of the inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein
J. Biol. Chem.
266
22789-22791
1991
Mus musculus
Stuehr, D.J.; Fasehun, O.A.; Kwon, N.S.; Gross, S.S.; Gonzalez, J.A.; Levi, R.; Nathan, C.F.
Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs
FASEB J.
5
98-103
1991
Mus musculus
Iwasaki, T.; Hori, H.; Hayashi, Y.; Nishino, T.; Tamura, K.; Oue, S.; Iizuka, T.; Ogura, T.; Esumi, H.
Characterization of mouse nNOS2, a natural variant of neuronal nitric-oxide synthase produced in the central nervous system by selective alternative splicing
J. Biol. Chem.
274
17559-17566
1999
Mus musculus
McMillan, K.; Adler, M.; Auld, D.S.; Baldwin, J.J.; Blasko, E.; Browne, L.J.; Chelsky, D.; Davey, D.; Dolle, R.E.; Eagen, K.A.; Erickson, S.; Feldman, R.I.; Glaser, C.B.; Mallari, C.; Morrissey, M.M.; Ohlmeyer, M.H.J.; Pan, G.; Parkinson, J.F.; Phillips, G.B.; Polokoff, M.A.; Sigal, N.H.; Vergona, R.; Whitlow, M.; Young, T.A.; Devlin, J.J
Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry
Proc. Natl. Acad. Sci. USA
97
1506-1511
2000
Mus musculus (P29477), Mus musculus, Homo sapiens
Siddhanta, U.; Wu, C.; Abu-Soud, H.M.; Zhang, J.; Ghosh, D.K.; Stuehr, D.J.
Heme iron reduction and catalysis by a nitric oxide synthase heterodimer containing one reductase and two oxygenase domains
J. Biol. Chem.
271
7309-7312
1996
Mus musculus
Rusche, K.M.; Spiering, M.M.; Marletta, M.A.
Reactions catalyzed by tetrahydrobiopterin-free nitric oxide synthase
Biochemistry
37
15503-15512
1998
Mus musculus
Baek, K.J.; Thiel, B.A.; Lucas, S.; Stuehr, D.J.
Macrophage nitric oxide synthase subunits. Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme
J. Biol. Chem.
268
21120-21129
1993
Mus musculus
Ghosh, D.K.; Stuehr, D.J.
Macrophage NO synthase: characterization of isolated oxygenase and reductase domains reveals a head-to-head subunit interaction
Biochemistry
34
801-807
1995
Mus musculus
Foerstermann, U.; Closs, E.I.; Pollock, J.S.; Nakane, M.; Schwarz, P.; Gath, I.; Kleinert, H.
Nitric oxide synthase isoenzymes. Characterization, purification, molecular cloning, and functions
Hypertension
23
1121-1131
1994
Rattus norvegicus, Mus musculus, Homo sapiens, Bos taurus, Sus scrofa
Richards, M.K.; Clague, M.J.; Marletta, M.A.
Characterization of C415 mutants of neuronal nitric oxide synthase
Biochemistry
35
7772-7780
1996
Mus musculus
Reif, D.W.; McCreedy, S.A.
N-Nitro-L-arginine and N-monomethyl-L-arginine exhibit a different pattern of inactivation toward the three nitric oxide synthases
Arch. Biochem. Biophys.
320
170-176
1995
Rattus norvegicus, Mus musculus, Homo sapiens, Rattus norvegicus Sprague-Dawley
Abu-Soud, H.M.; Loftus, M.; Stuehr, D.J.
Subunit dissociation and unfolding of macrophage NO synthase: relationship between enzyme structure, prosthetic group binding, and catalytic function
Biochemistry
34
11167-11175
1995
Mus musculus
Lacza, Z.; Puskar, M.; Figueroa, J.P.; Zhang, J.; Rajapakse, N.; Busija, D.W.
Mitochondrial nitric oxide synthase is constitutively active and is functionally upregulated in hypoxia
Free Radic. Biol. Med.
31
1609-1615
2001
Mus musculus, Mus musculus C57BL/6
Wang, Z.Q.; Wei, C.C.; Santolini, J.; Panda, K.; Wang, Q.; Stuehr, D.J.
A tryptophan that modulates tetrahydrobiopterin-dependent electron transfer in nitric oxide synthase regulates enzyme catalysis by additional mechanisms
Biochemistry
44
4676-4690
2005
Rattus norvegicus, Mus musculus (P29477), Mus musculus
Lacza, Z.; Snipes, J.A.; Zhang, J.; Horvath, E.M.; Figueroa, J.P.; Szabo, C.; Busija, D.W.
Mitochondrial nitric oxide synthase is not eNOS, nNOS or iNOS
Free Radic. Biol. Med.
35
1217-1228
2003
Mus musculus
Wang, Z.Q.; Wei, C.C.; Sharma, M.; Pant, K.; Crane, B.R.; Stuehr, D.J.
A conserved Val to Ile switch near the heme pocket of animal and bacterial nitric-oxide synthases helps determine their distinct catalytic profiles
J. Biol. Chem.
279
19018-19025
2004
Bacillus subtilis, Bacillus subtilis (O34453), Mus musculus (P29477), Mus musculus, Bacillus subtilis 168 (O34453)
Fedorov, R.; Vasan, R.; Ghosh, D.K.; Schlichting, I.
Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design
Proc. Natl. Acad. Sci. USA
101
5892-5897
2004
Homo sapiens, Rattus norvegicus (P29476), Mus musculus (P29477), Mus musculus
Wilson, D.J.; Rafferty, S.P.; Konermann, L.
Kinetic unfolding mechanism of the inducible nitric oxide synthase oxygenase domain determined by time-resolved electrospray mass spectrometry
Biochemistry
44
2276-2283
2005
Mus musculus
Jackson, S.A.; Sahni, S.; Lee, L.; Luo, Y.; Nieduzak, T.R.; Liang, G.; Chiang, Y.; Collar, N.; Fink, D.; He, W.; Laoui, A.; Merrill, J.; Boffey, R.; Crackett, P.; Rees, B.; Wong, M.; Guilloteau, J.P.; Mathieu, M.; Rebello, S.S.
Design, synthesis and characterization of a novel class of coumarin-based inhibitors of inducible nitric oxide synthase
Bioorg. Med. Chem.
13
2723-2739
2005
Mus musculus (P29477), Mus musculus, Rattus norvegicus, Homo sapiens
Zemojtel, T.; Kolanczyk, M.; Kossler, N.; Stricker, S.; Lurz, R.; Mikula, I.; Duchniewicz, M.; Schuelke, M.; Ghafourifar, P.; Martasek, P.; Vingron, M.; Mundlos, S.
Mammalian mitochondrial nitric oxide synthase: characterization of a novel candidate
FEBS Lett.
580(2)
455-462
2006
Mus musculus
Ghosh, D.K.; Holliday, M.A.; Thomas, C.; Weinberg, J.B.; Smith, S.M.; Salerno, J.C.
Nitric-oxide synthase output state. Design and properties of nitric-oxide synthase oxygenase/FMN domain constructs
J. Biol. Chem.
281
14173-14183
2006
Homo sapiens (P29474), Mus musculus, Rattus norvegicus (P29476)
Krieglstein, C.F.; Anthoni, C.; Cerwinka, W.H.; Stokes, K.Y.; Russell, J.; Grisham, M.B.; Granger, D.N.
Role of blood- and tissue-associated inducible nitric-oxide synthase in colonic inflammation
Am. J. Pathol.
170
490-496
2007
Mus musculus
Langnaese, K.; Richter, K.; Smalla, K.H.; Krauss, M.; Thomas, U.; Wolf, G.; Laube, G.
Splice-isoform specific immunolocalization of neuronal nitric oxide synthase in mouse and rat brain reveals that the PDZ-complex-building nNOSalpha beta-finger is largely exposed to antibodies
Dev. Neurobiol.
67
422-437
2007
Rattus norvegicus, Mus musculus
Li, D.; Kabir, M.; Stuehr, D.J.; Rousseau, D.L.; Yeh, S.R.
Substrate- and isoform-specific dioxygen complexes of nitric oxide synthase
J. Am. Chem. Soc.
129
6943-6951
2007
Mus musculus
Marechal, A.; Mattioli, T.A.; Stuehr, D.J.; Santolini, J.
Activation of peroxynitrite by inducible nitric-oxide synthase: a direct source of nitrative stress
J. Biol. Chem.
282
14101-14112
2007
Mus musculus
Huang, D.; Cai, D.T.; Chua, R.Y.; Kemeny, D.M.; Wong, S.H.
Nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development
J. Biol. Chem.
283
1713-1722
2008
Mus musculus
Carrier, E.; Brochu, I.; de Brum-Fernandes, A.J.; DOrleans-Juste, P.
The inducible nitric-oxide synthase modulates endothelin-1-dependent release of prostacyclin and inhibition of platelet aggregation ex vivo in the mouse
J. Pharmacol. Exp. Ther.
323
972-978
2007
Mus musculus
Moreno, J.A.; Sullivan, K.A.; Carbone, D.L.; Hanneman, W.H.; Tjalkens, R.B.
Manganese potentiates nuclear factor-kappaB-dependent expression of nitric oxide synthase 2 in astrocytes by activating soluble guanylate cyclase and extracellular responsive kinase signaling pathways
J. Neurosci. Res.
86
2028-2038
2008
Mus musculus (P29477)
Lee, Y.Z.; Yang, C.W.; Kang, I.J.; Wu, S.H.; Chao, Y.S.; Chern, J.H.; Lee, S.J.
Analogues of 2-phenyl-ethenesulfonic acid phenyl ester have dual functions of inhibiting expression of inducible nitric oxide synthase and activating peroxisome proliferator-activated receptor gamma
Bioorg. Med. Chem. Lett.
18
5676-5679
2008
Mus musculus
Wang, X.; Zhao, Q.; Matta, R.; Meng, X.; Liu, X.; Liu, C.G.; Nelin, L.D.; Liu, Y.
Inducible nitric-oxide synthase expression is regulated by mitogen-activated protein kinase phosphatase-1
J. Biol. Chem.
284
27123-27134
2009
Mus musculus (P29477)
Jin, B.Y.; Sartoretto, J.L.; Gladyshev, V.N.; Michel, T.
Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells
Proc. Natl. Acad. Sci. USA
106
17343-17348
2009
Mus musculus (P70313)
Dooley, A.; Low, S.Y.; Holmes, A.; Kidane, A.G.; Abraham, D.J.; Black, C.M.; Bruckdorfer, K.R.
Nitric oxide synthase expression and activity in the tight-skin mouse model of fibrosis
Rheumatology
47
272-280
2008
Mus musculus (P70313), Mus musculus
Al-Harbi, N.O.; Nadeem, A.; Ansari, M.A.; Al-Harbi, M.M.; Alotaibi, M.R.; AlSaad, A.M.; Ahmad, S.F.
Psoriasis-like inflammation leads to renal dysfunction via upregulation of NADPH oxidases and inducible nitric oxide synthase
Int. Immunopharmacol.
46
1-8
2017
Mus musculus (P29477), Mus musculus
Rouaud, F.; Romero-Perez, M.; Wang, H.; Lobnysheva, I.; Ramassamy, B.; Henry, E.; Tauc, P.; Giacchero, D.; Boucher, J.L.; Deprez, E.; Rocchi, S.; Slama-Schwok, A.
Regulation of NADPH-dependent nitric oxide and reactive oxygen species signalling in endothelial and melanoma cells by a photoactive NADPH analogue
Oncotarget
5
10650-10664
2014
Mus musculus (P70313), Homo sapiens
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