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Information on EC 1.14.13.39 - nitric-oxide synthase (NADPH)
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EC Tree
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).
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Word Map
- 1.14.13.39
- artery
- necrosis
- lipopolysaccharide
-
l-name
- lps
- cardiovascular
- tnf
- cox-2
- cyclooxygenase-2
- nitrite
- hypertension
- vessel
- cardiac
-
lps-induced
- aortic
- cerebral
-
vasodilation
- nerve
- prostaglandin
- coronary
- ischemia
- pulmonary
- tnf-alpha
- cgmp
- myocardial
- wistar
-
endothelium-dependent
- ng-nitro-l-arginine
- factor-alpha
- acetylcholine
- peroxynitrite
-
contractile
- nf-kappab
- ifn-gamma
-
reperfusion
-
neuroprotective
- il-1beta
- interferon-gamma
- nitroprusside
-
lps-stimulated
-
nitrotyrosine
- microglia
-
guanylate
-
hemodynamic
-
lipopolysaccharide-induced
-
vasoconstriction
-
vasorelaxation
- endothelin-1
-
erectile
-
guanylyl
- pharmacology
- medicine
The enzyme appears in viruses and cellular organisms
Reaction Schemes
2
+
3
+
3
+
4
=
2
+
2
+
3
+
4
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, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
bacterial nitric oxide synthase
bacterial nitric-oxide synthase
bNOS
bsNOS
cb-NOS
e-NOS
EC-NOS
endothelial nitric oxide synthase
endothelial nitric-oxide synthase
endothelial NOS
eNOS
i-NOS
inducible nitric oxide synthase
inducible nitric-oxide synthase
inducible NO synthase
inducible NOS
iNOS
mtNOS
n-NOS
neuronal nitric oxide synthase
neuronal nitric-oxide synthase
neuronal NO synthase
neuronal NOS
nitric oxide synthase
nitric-oxide synthase
nNOS
nNOSalpha
NO synthase
NO-synthase
NOS
NOS1
NOS2
NOS3
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2 Nomega-hydroxy-L-arginine + NADPH + H+ + 2 O2 = 2 L-citrulline + 2 nitric oxide + NADP+ + 2 H2O
(1b)
-
-
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
possible mechanism
-
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
cytochrome P-450 enzyme
-
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
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
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
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
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
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
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
reaction and kinetic mechanism
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
reaction and kinetic mechanism
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
analysis of catalytic site by Fourier transform infrared spectroscopy, extent of modulation of vibrational modes upon photolysis of CO compound
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
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
overall reaction
-
-
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
-
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
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
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
reaction mechanism, NO release and transport, overview, NO formation through sequential electron transfer and the oxidation of L-arginine, in the catalytic process, FMN, FAD, and tetrahydrobiopterin are required as coenzymes, and the presence of Ca2+/calmodulin can aid the electron transfer, isozymes NOS1 and NOS3 perform a similar reaction mechanism
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
reaction mechanism, the reaction of the enzyme with oxygen is fast and takes place within several steps, separated by ephemeral intermediates, two short-lived oxy-compounds OxyI and OxyII
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
reaction mechanism, the reaction of the enzyme with oxygen is fast and takes place within several steps, separated by ephemeral intermediates, two short-lived oxy-compounds OxyI and OxyII
-
2 L-arginine + 3 NADPH + 3 H+ + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
the key structural features that are involved in the substrate and active site interaction are highly conserved, e.g. residues Pro214, Glu235, Trp234, Tyr237, Asn246, and Gln129, substrate binding structure and mechanism, overview
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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PATHWAY SOURCE
PATHWAYS
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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).
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CAS REGISTRY NUMBER
COMMENTARY
125978-95-2
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
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 + ?
-
-
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 + ?
-
-
ir
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
-
-
?
2-hydroxy-1-(4-hydroxyphenyl)guanidine + NADPH + O2
? + NO + NADP+
-
-
?
ferricytochrome c + NADPH + O2
ferrocytochrome c + NO + NADP+
-
-
-
?
N-hydroxy-L-arginine + H2O2 + tetrahydrobiopterin
? + NADP+
-
-
-
?
Ngamma-hydroxy-L-arginine + H2O2
citrulline + Ndelta-cyanoornithine + NO2- + NO3-
-
tetrahydrobiopterin-free
NO2-/NO3- as aerobic decomposition products from NO-
?
Nomega-hydroxy-L-arginine + 2',3'-dialdehyde-NADPH + H+ + O2
2 L-citrulline + nitric oxide + 2',3'-dialdehyde-NADP+ + H2O
-
-
-
r
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
L-citrulline + NADP+ + NO + H2O
-
second half reaction
-
?
peroxynitrite + 4-hydroxyphenylacetic acid + NADPH + H+
4-hydroxyl-3-nitro-phenylacetic acid + NADP+ + H2O
-
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
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
-
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
endothelial nitric oxide synthase (eNOS) is responsible for maintaining systemic blood pressure, vascular remodeling and angiogenesis
-
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
-
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
the enzyme plays an important role in host defense system by catalyzing the production of nitric oxide
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
the enzyme forms a five-coordinate, high-spin complex with L-arginine and analogues, e.g. N-hydroxy-L-arginine
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
the product is a guanylyl-cyclase-relaxing factor, that is identical with nitric oxide or a NO-releasing compound
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
a cytokine-inducible, calcium independent and a constitutive, calcium dependent form
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
probably via Nomega-hydroxy-L-arginine
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
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
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
capacity to synthesize NO only through dimerization and binding of heme and tetrahydrobiopterin
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
dimeric structure is required for enzyme activity
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
dimeric structure is required for enzyme activity
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
tetrahydrobiopterin is absolutely required for partial reaction 1
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
specific for NADPH, 5-electron oxidation of L-arginine
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
acts as signal molecule for neurotransmission, vasorelaxation, and cytotoxity
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
enzyme of mammalian immune, cardiovascular and neural systems, synthesizing the free radical nitric oxide or a NO-releasing product
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
soluble cytochrome P-450 enzyme in eukaryotes
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
the product is a guanylyl-cyclase-relaxing factor, that is identical with nitric oxide or a NO-releasing compound
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
the product is a guanylyl-cyclase-relaxing factor, that is identical with nitric oxide or a NO-releasing compound
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
probably via Nomega-hydroxy-L-arginine
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
guanidino-nitrogen of L-arginine is oxidized to form NO and citrulline
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
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
-
ir
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
specific for NADPH, 5-electron oxidation of L-arginine
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
acts as signal molecule for neurotransmission, vasorelaxation, and cytotoxity
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
soluble cytochrome P-450 enzyme in eukaryotes
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
mitochondrial nitric oxide production is involved in modulation of several organelle functions, such as transmembrane potential and matrix pH, inhibition of respiration by competitive inhibition with oxygen in cytochrome c oxidase, inhibition of ATP synthesis, permeability transition pore (PTP) opening, apoptosis and cell death, overview
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
the product is a guanylyl-cyclase-relaxing factor, that is identical with nitric oxide or a NO-releasing compound
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
the product is a guanylyl-cyclase-relaxing factor, that is identical with nitric oxide or a NO-releasing compound
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
?
2,6-dichlorophenolindophenol + NADPH + O2
? + NO + NADP+
-
best substrate, about 10-fold increase in activity in presence of calmodulin
-
?
L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
-
-
?
L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
nitric-oxide synthase (NOS) is required in mammals to generate nitric-oxide for regulating blood pressure, synaptic response, and immune defense
-
?
L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
synthesis of the signaling molecule nitric oxide
-
?
L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
proposed conformational model for nitric oxide synthesis by the enzyme. Nitric oxide synthesis involves two distinct changes in the holoenzyme complex: 1. an extended-to-closed conformational equilibrium that brings the reductase domains together in a cross-monomer arrangement, and 2. release and rotation of the FMN domain triggered by CaM binding that positions the FMN cofactor for electron transfer across to the adjacent oxygenase domain in the closed state
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
overall reaction
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
overall reaction, the interactions between heme-bound NO and the substrates are finely tuned by the geometry of the Fe-ligand structure, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
overall reaction, two-step oxidation of L-arginine using an O2-dependent mechanism, detailed overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
NO is an important signalling molecule, released by numerous cells, that acts in many tissues to regulate a diverse range of physiological and biological processes, including neurotransmission, immune defence and the regulation of apoptosis. NO plays a major role in the killing of intracellular pathogens as part of the innate immune response
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
the electron transfer between cofactors FMN and FAD is reversible
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
overall reaction, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
regulatory mechanism, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
conserved residue Arg1329 of nNOS enables bound NADPH to stabilize the FMN-shielded conformation, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
NO from acetylsalicylic acid-activated enzyme is involved in thrombolysis, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
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
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
substrate and product binding analysis
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
complete reaction, during Arg hydroxylation, H4B acts as a one-electron donor and is then presumed to redox cycle, i.e. be reduced back to H4B, within NOS before further catalysis can proceed. Calmodulin-dependent reduction of a tetrahydrobiopterin radical, mechanism involving the NOS flavoprotein domain, reaction scheme, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
complete reaction, oxygen stoichiometry, effects of substrate/cofactor binding on the endothelial NOS isoform, eNOS, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
conversion of L-arginine to citrulline and nitric oxide takes place in two steps with N(G)-hydroxy-L-arginine as an intermediate product
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
overall reaction, the interactions between heme-bound NO and the substrates are finely tuned by the geometry of the Fe-ligand structure, overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
overall reaction, two-step oxidation of L-arginine using an O2-dependent mechanism, detailed overview
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
Nomega-hydroxy-L-arginine + NADP+ + H2O
-
first half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
L-arginine + NADPH + H+ + O2
Nomega-hydroxy-L-arginine + NADP+ + H2O
-
first half reaction via intermediate Nomega-hydroxy-L-arginine with consecutive appearance of heme-dioxy, ferric heme-NO, and ferric heme species, overview
-
?
L-arginine + NADPH + H+ + O2
Nomega-hydroxy-L-arginine + NADP+ + H2O
-
first half reaction
-
ir
L-arginine + NADPH + H+ + O2
Nomega-hydroxy-L-arginine + NADP+ + H2O
-
first half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
L-arginine + NADPH + H+ + O2
Nomega-hydroxy-L-arginine + NADP+ + H2O
first half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
L-arginine + NADPH + H+ + O2
Nomega-hydroxy-L-arginine + NADP+ + H2O
-
first half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
L-arginine + NADPH + O2 + tetrahydrobiopterin
citrulline + NO + NADP+ + ?
-
-
-
?
L-arginine + NADPH + O2 + tetrahydrobiopterin
citrulline + NO + NADP+ + ?
-
-
?
L-arginine + NADPH + O2 + tetrahydrobiopterin
citrulline + NO + NADP+ + ?
-
-
-
?
L-arginine + NADPH + O2 + tetrahydrobiopterin
citrulline + NO + NADP+ + ?
-
-
-
?
L-homoarginine + NADPH + O2
?
-
constitutive endothelial membrane-bound and inducible soluble macrophage enzyme
-
?
L-homoarginine + NADPH + O2
?
-
constitutive endothelial membrane-bound and inducible soluble macrophage enzyme
-
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
best substrate
-
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
best substrate
-
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
substrate is intermediate between reaction 1 and 2 to form citrulline and NO from L-arginine
-
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
reaction is possible without tetrahydrobiopterin, can also use H2O2 instead of NADPH and O2
-
?
Ngamma-hydroxy-L-arginine + NADPH + O2
citrulline + NADP+ + NO
-
substrate is intermediate between reaction 1 and 2 to form citrulline and NO from L-arginine
-
ir
nitroblue tetrazolium + 2 NADPH
nitroblue tetrazolium formazan + 2 NADP+
-
NADPH-diaphorase reaction
-
?
nitroblue tetrazolium + 2 NADPH
nitroblue tetrazolium formazan + 2 NADP+
-
NADPH-diaphorase reaction
-
?
nitroblue tetrazolium + 2 NADPH
nitroblue tetrazolium formazan + 2 NADP+
-
-
-
?
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
second half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
second half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
second half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
second half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
second half reaction via intermediate Nomega-hydroxy-L-arginine
-
?
Nomega-hydroxy-L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
second half reaction via intermediate Nomega-hydroxy-L-arginine, FeII and FeII-NO complexes bind Nomega-hydroxy-L-arginine, overview
-
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
-
-
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
-
-
-
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
-
-
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
-
wild-type and mutants
-
?
oxidized cytochrome c + NADPH + O2
reduced cytochrome c + NADP+ + H2O
-
reaction is enhanced by addition of calmodulin at 0.0002 mM
-
?
additional information
?
-
-
the enzyme is involved in a multi-turnover process that results in NO as a product, NO is important in various pathological and physiological processes, NO produced by Bacillus anthracis may also have a pivotal pathophysiological role in anthrax infection
-
?
additional information
?
-
-
the bacterial enzyme, bNOS, lacks an essential reductase domain, that supplies electrons during NO biosynthesis, and is thus limited with respect to a pool of available redox partners, but does produce NO in living cells and accomplish this task by hijacking available cellular redox partners that are not normally committed to NO production, bacterial reductase also supports NO synthesis by the oxygenase domain of mammalian NOS expressed in Escherichia coli, overview
-
?
additional information
?
-
-
the bacterial enzyme, bNOS, lacks an essential reductase domain, that supplies electrons during NO biosynthesis, and is thus limited with respect to a pool of available redox partners, but does produce NO in living cells and accomplish this task by hijacking available cellular redox partners that are not normally committed to NO production, bacterial reductase also supports NO synthesis by the oxygenase domain of mammalian NOS expressed in Escherichia coli, overview
-
?
additional information
?
-
-
mechanisms of oxygen activation by NOSs, overview
-
?
additional information
?
-
-
the bacterial NOS enzymes have no attached flavoprotein domain to reduce their heme and so must rely on unknown bacterial proteins for electrons
-
?
additional information
?
-
-
enzyme shows also superoxide formation activity, uneffected by L-arginine, inhibited by tetrahydrobiopterin and diphenyleneiodonium
-
?
additional information
?
-
-
enzyme shows also superoxide formation activity
-
?
additional information
?
-
-
endothelial NOS has a 6fold lower NO synthesis activity and 6-16fold lower cytochrome c reductase activity than neuronal NOS due to a significantly different electron transfer capacities, substrate specificity and mechanism, oveview
-
?
additional information
?
-
-
postsynaptic density 95 proteins mediate the complex formation of neuronal nitric oxide synthase and N-methyl-D-aspartate receptors
-
?
additional information
?
-
-
dNOS participates in essential developmental and behavioral aspects of the fruit fly
-
?
additional information
?
-
-
Drosophila dNOS is a more efficient and active NO synthase than the mammalian NOS enzymes, which may allow it to function more broadly in cell signaling and immune functions in the fruit fly
-
?
additional information
?
-
-
a oxygenase domain of dNOS complex with ferrous heme-NO is relatively unreactive toward O2
-
?
additional information
?
-
-
crude, boiled or ethanolic and dried extracts of Ganoderma applanatum show antioxidant activity, inhibition of lipid peroxidation, and potent hydroxylradical scavenging activity, overview
-
?
additional information
?
-
-
enzyme can also Ca2+/calmodulin-dependently produce superoxide in absence of tetrahydropterin and in depletion of L-arginine, which is inhibited by tetrahydropterin, cyanide and imidazole
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
?
additional information
?
-
-
neuronal NO synthase may be involved in the pathogenesis of acute lung injury after smoke inhalation injury followed by bacterial instillation in the airway
-
?
additional information
?
-
-
Pseudomonas aeruginosa stimulates expression of inducible nitric oxide synthase by A-549 cells. NO may be the mediator of epithelial damage caused by Pseudomonas aeruginosa
-
?
additional information
?
-
calmodulin-controlled isoforms are signal generators, overview
-
?
additional information
?
-
-
cell-specific gene regulation mechanism of the endothelial isozyme in the vascular endothelium involving endothelial-specific promoter, binding sites for AP-1, high affinity Sp1-binding sites and GATA promoter sites, and several, e.g. octameric, transcriptional regulators, epigenetic regulatory mechanisms in vascular endothelial cell-specific gene expression, genetic, endothelial-specific regulation model, overview
-
?
additional information
?
-
-
genetic regulation, mechanism, eNOS expression is controlled by both histone acetylation and lysine 4 methylation of histone H3 at eNOS proximal promoter regions, overview
-
?
additional information
?
-
both oxyFMN and oxygenase domain activity are measured by following H2O2-supported oxidation of Nomega-hydroxy-L-Arg, L-NOHA, overview
-
?
additional information
?
-
-
the enzyme interacts with Vac14, the activator of the PtdIns(3)P 5-kinase PIKfyve, the beta-finger independent interaction is based on an internal motif, sequence -G-D-H-L-D-, for PDZ recognition, PDZ domains are protein interaction modules found in single or multiple copies in a variety of proteins involved in multiprotein signaling complexes, interaction study with wild-type and mutant Vac14 proteins, binding is not abolished by deletion of the last five amino acids, but is abolished with deletions of the last 53 or last 10 residues of Vac14, overview
-
?
additional information
?
-
-
NOS has also nitrite reductase activity, the release of free nitric oxide from anoxic nitrite solutions at 0.015 mM is specific to the eNOS isoform and does not occur with the nNOS or iNOS isoforms
-
?
additional information
?
-
NOS has also nitrite reductase activity, the release of free nitric oxide from anoxic nitrite solutions at 0.015 mM is specific to the eNOS isoform and does not occur with the nNOS or iNOS isoforms
-
?
additional information
?
-
NOS has also nitrite reductase activity, the release of free nitric oxide from anoxic nitrite solutions at 0.015 mM is specific to the eNOS isoform and does not occur with the nNOS or iNOS isoforms
-
?
additional information
?
-
-
the enzyme might be involved in the infectivity and/or escaping mechanism of the parasite
-
?
additional information
?
-
-
Ngamma-hydroxylation is the first step of the reaction, Ngamma-hydroxy-L-arginine being an intermediate in the L-arginine to NO pathway
-
?
additional information
?
-
-
dimeric enzyme and subunits are equivalent in catalyzing electron transfer from NADPH to cytochrome c, dichlorophenolindiphenol, and ferricyanide
-
?
additional information
?
-
-
calmodulin-controlled isoforms are signal generators, overview
-
?
additional information
?
-
-
both oxyFMN and oxygenase domain activity are measured by following H2O2-supported oxidation of Nomega-hydroxy-L-Arg, L-NOHA, overview
-
?
additional information
?
-
-
inducible nitric-oxide synthase-derived NO contributes to the pathophysiology of intestinal inflammation in the colon
-
?
additional information
?
-
-
iNOS modulates endothelin-1-dependent release of prostacyclin and inhibition of platelet aggregation ex vivo in the mouse, overview
-
?
additional information
?
-
-
nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development
-
?
additional information
?
-
-
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
-
?
additional information
?
-
-
interaction between peroxynitrite and the oxygenase domain of inducible NOS
-
?
additional information
?
-
eNOS is an important negative regulator of AMP-activated protein kinase phosphorylation and intracellular H2O2 generation in endothelial cells
-
?
additional information
?
-
-
the enzyme exhibits NADPH-diaphorase activity, uncoupled from nitric oxide synthase activity
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
?
additional information
?
-
calmodulin-controlled isoforms are signal generators, overview
-
?
additional information
?
-
-
caveolin-1 is a prominent NOS-interacting protein in rat polymorphonuclear neutrophils
-
?
additional information
?
-
NO is implicated in the pathogenesis of liver cirrhosis, overview
-
?
additional information
?
-
both oxyFMN and oxygenase domain activity are measured by following H2O2-supported oxidation of Nomega-hydroxy-L-Arg, L-NOHA, overview
-
?
additional information
?
-
-
eNOS uncoupling is known to be controlled by substrate/cofactor availability, and the uncoupled reactions play important roles under various physiological/pathological conditions, such as atherosclerosis and septic shock
-
?
additional information
?
-
-
increased iNOS expression due to ethanol intake is responsible for gender differences in the vascular effects elicited by chronic ethanol consumption, while ovarian hormones do not play a role, overview
-
?
additional information
?
-
-
three unique structural elements are involved in the catalytic suppression of NOS: an autoinhibitory element in the FMN binding module, a CD2A loop in the connecting subdomain, and a C-terminal extension or tail, the C-terminal tail of nNOS is a regulatory element that suppresses nNOS activities in the absence of bound calmodulin, it may help stabilize the FMN-shielded conformation by holding the FMN module up against the FNR module as required for inter-flavin electron transfer, mechanism, overview
-
?
additional information
?
-
nitric-oxide synthases are catalytically self-sufficient flavo-heme enzymes that generate NO from L-arginine and display an utilization of their tetrahydrobiopterin cofactor, overview
-
?
additional information
?
-
-
the reduced recombinant trunaction mutant nNOSr performs autooxidation in presence of NADPH, interactions, overview
-
?
additional information
?
-
-
the enzyme exhibits NADPH-diaphorase activity, uncoupled from nitric oxide synthase activity
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
?
additional information
?
-
-
mechanisms of oxygen activation by NOSs, overview
-
?
additional information
?
-
-
the reductase domain has a broad substrate specificity, catalyzes a moderate Ca2+/calmodulin independent hydroxylation when the enzyme is reconstituted with purified P-450
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
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
endothelial nitric oxide synthase (eNOS) is responsible for maintaining systemic blood pressure, vascular remodeling and angiogenesis
-
-
?
2 L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
the enzyme plays an important role in host defense system by catalyzing the production of nitric oxide
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
a cytokine-inducible, calcium independent and a constitutive, calcium dependent form
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
acts as signal molecule for neurotransmission, vasorelaxation, and cytotoxity
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
enzyme of mammalian immune, cardiovascular and neural systems, synthesizing the free radical nitric oxide or a NO-releasing product
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
soluble cytochrome P-450 enzyme in eukaryotes
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
acts as signal molecule for neurotransmission, vasorelaxation, and cytotoxity
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
soluble cytochrome P-450 enzyme in eukaryotes
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
mitochondrial nitric oxide production is involved in modulation of several organelle functions, such as transmembrane potential and matrix pH, inhibition of respiration by competitive inhibition with oxygen in cytochrome c oxidase, inhibition of ATP synthesis, permeability transition pore (PTP) opening, apoptosis and cell death, overview
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
-
-
-
?
2 L-arginine + 3 NADPH + 4 O2 + 3 H+
2 L-citrulline + 2 NO + 3 NADP+ + 4 H2O
-
physiological functions and pathophysiology of the isoforms
-
-
?
L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
nitric-oxide synthase (NOS) is required in mammals to generate nitric-oxide for regulating blood pressure, synaptic response, and immune defense
-
-
?
L-arginine + 3 NADPH + 3 H+ + 4 O2
2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
synthesis of the signaling molecule nitric oxide
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
NO is an important signalling molecule, released by numerous cells, that acts in many tissues to regulate a diverse range of physiological and biological processes, including neurotransmission, immune defence and the regulation of apoptosis. NO plays a major role in the killing of intracellular pathogens as part of the innate immune response
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
overall reaction, overview
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
regulatory mechanism, overview
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
NO from acetylsalicylic acid-activated enzyme is involved in thrombolysis, overview
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
-
?
L-arginine + NADPH + H+ + O2
citrulline + nitric oxide + NADP+ + H2O
-
-
-
-
?
additional information
?
-
-
the enzyme is involved in a multi-turnover process that results in NO as a product, NO is important in various pathological and physiological processes, NO produced by Bacillus anthracis may also have a pivotal pathophysiological role in anthrax infection
-
-
?
additional information
?
-
-
the bacterial enzyme, bNOS, lacks an essential reductase domain, that supplies electrons during NO biosynthesis, and is thus limited with respect to a pool of available redox partners, but does produce NO in living cells and accomplish this task by hijacking available cellular redox partners that are not normally committed to NO production, bacterial reductase also supports NO synthesis by the oxygenase domain of mammalian NOS expressed in Escherichia coli, overview
-
-
?
additional information
?
-
-
the bacterial enzyme, bNOS, lacks an essential reductase domain, that supplies electrons during NO biosynthesis, and is thus limited with respect to a pool of available redox partners, but does produce NO in living cells and accomplish this task by hijacking available cellular redox partners that are not normally committed to NO production, bacterial reductase also supports NO synthesis by the oxygenase domain of mammalian NOS expressed in Escherichia coli, overview
-
-
?
additional information
?
-
-
enzyme shows also superoxide formation activity
-
-
?
additional information
?
-
-
postsynaptic density 95 proteins mediate the complex formation of neuronal nitric oxide synthase and N-methyl-D-aspartate receptors
-
-
?
additional information
?
-
-
dNOS participates in essential developmental and behavioral aspects of the fruit fly
-
-
?
additional information
?
-
-
Drosophila dNOS is a more efficient and active NO synthase than the mammalian NOS enzymes, which may allow it to function more broadly in cell signaling and immune functions in the fruit fly
-
-
?
additional information
?
-
-
crude, boiled or ethanolic and dried extracts of Ganoderma applanatum show antioxidant activity, inhibition of lipid peroxidation, and potent hydroxylradical scavenging activity, overview
-
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
-
?
additional information
?
-
-
neuronal NO synthase may be involved in the pathogenesis of acute lung injury after smoke inhalation injury followed by bacterial instillation in the airway
-
-
?
additional information
?
-
-
Pseudomonas aeruginosa stimulates expression of inducible nitric oxide synthase by A-549 cells. NO may be the mediator of epithelial damage caused by Pseudomonas aeruginosa
-
-
?
additional information
?
-
calmodulin-controlled isoforms are signal generators, overview
-
-
?
additional information
?
-
-
cell-specific gene regulation mechanism of the endothelial isozyme in the vascular endothelium involving endothelial-specific promoter, binding sites for AP-1, high affinity Sp1-binding sites and GATA promoter sites, and several, e.g. octameric, transcriptional regulators, epigenetic regulatory mechanisms in vascular endothelial cell-specific gene expression, genetic, endothelial-specific regulation model, overview
-
-
?
additional information
?
-
-
genetic regulation, mechanism, eNOS expression is controlled by both histone acetylation and lysine 4 methylation of histone H3 at eNOS proximal promoter regions, overview
-
-
?
additional information
?
-
-
the enzyme might be involved in the infectivity and/or escaping mechanism of the parasite
-
-
?
additional information
?
-
-
calmodulin-controlled isoforms are signal generators, overview
-
-
?
additional information
?
-
-
inducible nitric-oxide synthase-derived NO contributes to the pathophysiology of intestinal inflammation in the colon
-
-
?
additional information
?
-
-
iNOS modulates endothelin-1-dependent release of prostacyclin and inhibition of platelet aggregation ex vivo in the mouse, overview
-
-
?
additional information
?
-
-
nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development
-
-
?
additional information
?
-
-
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
-
-
?
additional information
?
-
eNOS is an important negative regulator of AMP-activated protein kinase phosphorylation and intracellular H2O2 generation in endothelial cells
-
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
-
?
additional information
?
-
calmodulin-controlled isoforms are signal generators, overview
-
-
?
additional information
?
-
-
caveolin-1 is a prominent NOS-interacting protein in rat polymorphonuclear neutrophils
-
-
?
additional information
?
-
NO is implicated in the pathogenesis of liver cirrhosis, overview
-
-
?
additional information
?
-
-
eNOS uncoupling is known to be controlled by substrate/cofactor availability, and the uncoupled reactions play important roles under various physiological/pathological conditions, such as atherosclerosis and septic shock
-
-
?
additional information
?
-
-
increased iNOS expression due to ethanol intake is responsible for gender differences in the vascular effects elicited by chronic ethanol consumption, while ovarian hormones do not play a role, overview
-
-
?
additional information
?
-
-
three unique structural elements are involved in the catalytic suppression of NOS: an autoinhibitory element in the FMN binding module, a CD2A loop in the connecting subdomain, and a C-terminal extension or tail, the C-terminal tail of nNOS is a regulatory element that suppresses nNOS activities in the absence of bound calmodulin, it may help stabilize the FMN-shielded conformation by holding the FMN module up against the FNR module as required for inter-flavin electron transfer, mechanism, overview
-
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
-
?
additional information
?
-
-
NO represents the endogenous activator of soluble guanylyl cyclase
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2',3'-dialdehyde analogue of NADPH
-
activation, can substitute for NADPH at low concentrations, inhibitory at concentrations of 40times the apparent Km-value or after prolonged incubation
flavodoxin
-
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
-
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
-
absolute requirement, recombinant from Pichia pastoris
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
5,6,7,8-tetrahydro-L-biopterin
-
i.e. (6R)-2-amino-4-hydroxy-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydropteridine, 6R-isomer, requirement, biopteroflavoprotein, 1 mol tetrahydrobiopterin per mol enzyme dimer
Calmodulin
-
the enzyme bears a Ca2+/calmodulin dependent FAD and FMN containing reductase domain which transfers electrons from NADPH to a variety of acceptors
Calmodulin
-
activation, potent stimulator of purified, not crude, enzyme preparation
Calmodulin
-
Ca2+/calmodulin is required for superoxide formation in absence of tetrahydropterin
Calmodulin
-
no stimulation with exogenous calmodulin, inducible isoform from liver
Calmodulin
-
15fold stimulation of cytochrome c reduction of wild-type and mutants C415A and C415H
Calmodulin
-
NADPH-diaphorase activity of the enzyme is Ca2+/calmodulin independent
Calmodulin
-
enzyme-bound, the binding sequence links the two enzyme domains
Calmodulin
in the absence of calmodulin, the wild type enzyme activity is less than 15% of the maximum calmodulin-dependent values
Calmodulin
maximum calmodulin-dependent activity is measured at 1.5 mM CaCl2, phosphorylation within an autoinhibitory domain in endothelial nitric oxide synthase reduces the Ca2+ concentrations required for calmodulin to bind and activate the enzyme
FAD
-
the enzyme bears Ca2+/calmodulin dependent FAD and FMN containing reductase domain which transfers electrons from NADPH to a variety of acceptors
FAD
-
electron flow within the neuronal nitric oxide synthase reductase domain includes hydride transfer from NADPH to FAD followed by two one-electron transfer reactions from FAD to FMN. Binding of the second NADPH is necessary to drive the full reduction of FMN and charge transfer and the subsequent interflavin electron transfer have distinct spectral features that can be monitored separately with stopped flow spectroscopy. Interflavin electron transfer reported at 600 nm is not limiting in nitric oxide synthase catalysis
FAD
during catalysis, NADPH-derived electrons are transfered into FAD and then distributed into the FMN domain for further transfer to internal or external heme groups. Conformational freedom of the FMN domain is essential for the electron transfer
FAD
in the neuronal enzyme, protein domain dynamics and calmodulin binding are implicated in regulating electron flow from NADPH, through the FAD and FMN cofactors, to the heme oxygenase domain, the site of NO generation
FMN
-
the enzyme bears Ca2+/calmodulin dependent FAD and FMN containing reductase domain which transfers electrons from NADPH to a variety of acceptors
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
FMN
FMN/heme electron transfer, FMN is capable of serving as a one electron heme reductant
FMN
FMN/heme electron transfer, FMN is capable of serving as a one electron heme reductant
FMN
-
an inverse correlation exists between FMN shielding and the cytochrome c reductase activity
FMN
-
regulation of the FMN module conformational equilibrium, overview
FMN
-
determination of FMN-heme intraprotein electron transfer kinetics in full length and oxygenase/FMN construct of human inducible nitric oxide synthase. The rate constant increases considerably with temperature. The FMN domain in the holoenzyme needs to sample more conformations before the intraprotein electron transfer takes place, and the FMN domain in the oxyFMN construct is better poised for efficient intraprotein electron transfer
FMN
during catalysis, NADPH-derived electrons are transfer into FAD and then distributed into the FMN domain for further transfer to internal or external heme groups. Conformational freedom of the FMN domain is essential for the electron transfer
FMN
in the neuronal enzyme, protein domain dynamics and calmodulin binding are implicated in regulating electron flow from NADPH, through the FAD and FMN cofactors, to the heme oxygenase domain, the site of NO generation
FMN
proposed conformational model for nitric oxide synthesis by the enzyme. Nitric oxide synthesis involves two distinct changes in the holoenzyme complex: 1. an extended-to-closed conformational equilibrium that brings the reductase domains together in a cross-monomer arrangement, and 2. release and rotation of the FMN domain triggered by CaM binding that positions the FMN cofactor for electron transfer across to the adjacent oxygenase domain in the closed state
heme
-
an inverse correlation exists between FMN shielding and the cytochrome c reductase activity
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
NADPH
-
-
440192, 440193, 440195, 440198, 440200, 440201, 440206, 440209, 440217, 440221, 440222, 440225, 440234, 440236, 440238, 440239, 672016, 673662, 674558, 684317, 686293, 687548, 687727, 688600, 696643
NADPH
-
-
NADPH
-
-
440190, 440191, 440192, 440198, 440203, 440208, 440213, 440220, 440228, 440230, 440236, 658119, 659257, 659330, 671278, 671728, 672363, 672524, 675257, 686293, 687615, 699997
NADPH
-
requirement, specific for, NADPH-diaphorase activity requires higher NADPH concentrations than nitric oxide formation
NADPH
-
binding structure of NADP(H) to wild-type and truncation mutant enzyme lacking parts of the C-terminus, overview
NADPH
-
electron flow within the neuronal nitric oxide synthase reductase domain includes hydride transfer from NADPH to FAD followed by two one-electron transfer reactions from FAD to FMN. Binding of the second NADPH is necessary to drive the full reduction of FMN and charge transfer and the subsequent interflavin electron transfer have distinct spectral features that can be monitored separately with stopped flow spectroscopy. Interflavin electron transfer reported at 600 nm is not limiting in nitric oxide synthase catalysis
NADPH
in the neuronal enzyme, protein domain dynamics and calmodulin binding are implicated in regulating electron flow from NADPH, through the FAD and FMN cofactors, to the heme oxygenase domain, the site of NO generation. Binding of NADPH and calmodulin influence interdomain distance relationships as well as reaction chemistry
tetrahydrobiopterin
-
oxidation product of BH4 is a protonated BH3 radical, key role of BH4 in protonation of Fe(II)-O2-, overview
tetrahydrobiopterin
-
oxidation product of BH4 is a protonated BH3 radical, key role of BH4 in protonation of Fe(II)-O2-, overview
tetrahydrobiopterin
-
the cofactor tetrahydrobiopterin binds along the side of the heme
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Ca2+/calmodulin
Fe2+
Iron
Ca2+
-
constitutive endothelial and inducible membrane bound macrophage enzyme are strictly Ca2+-dependent
Ca2+
required for calmodulin to bind and activate the enzyme, maximum calmodulin-dependent activity is measured at 1.5 mM CaCl2
Ca2+
-
Ca2+/calmodulin is required for citrulline/NO formation and for superoxide formation in absence of tetrahydropterin
Ca2+
the raise of intracellular calcium levels increases nNOS dephosphorylation and enzymatic activity
Ca2+
-
constitutive endothelial and inducible membrane bound macrophage enzyme are strictly Ca2+-dependent
Ca2+
-
stimulation of mtNOS can be achieved by elevating mitochondrial Ca2+ (0.01-0.1 mM)
Ca2+
-
the enzyme bears Ca2+/calmodulin dependent cytochrome P-450 reductase activity which catalyzes cytochrome c reduction
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
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
Ca2+/calmodulin
calmodulin activates electron transfer from NADPH through three reductase domains to the oxygenase domain, controls constitutive isoforms through regulation of electron transfer between NADPH and heme
Fe2+
-
a heme enzyme, spectral comparison of the FeIII-NO and FeII-NO complexes of the bacterial NOSs, FeIII-NO complexes lack change in Fe-N-O frequencies upon (6R) 5,6,7,8-tetrahydro-L-biopterin binding to bacterial NOSs, overview. In the FeIII-NO complexes, both L-arginine and NOHA induced the Fe-N-O bending mode at nearly the same frequency as a result of a steric interaction between the substrates and the heme-bound NO, while in FeII-NO complexes the the Fe-N-O bending mode is no observed
Fe2+
-
in the heme cofactor, substrate-ligand interaction in the Fe2+-O2 complex, overview
Fe2+
-
a heme enzyme, spectral comparison of the FeIII-NO and FeII-NO complexes of the bacterial NOSs, FeIII-NO complexes lack change in Fe-N-O frequencies upon (6R) 5,6,7,8-tetrahydro-L-biopterin binding to bacterial NOSs, overview. In the FeIII-NO complexes, both L-arginine and NOHA induced the Fe-N-O bending mode at nearly the same frequency as a result of a steric interaction between the substrates and the heme-bound NO, while in FeII-NO complexes the the Fe-N-O bending mode is no observed
Iron
-
as heme iron in protoporphyrin IX /heme, heme–substrate interactions and heme-transitions, overview
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
Iron
low-spin heme iron, L-arginine aud tetrahydrobiopterin bind and stabilize heme iron in five-coordinate high-spin state
Iron
-
2 mol iron-protoporphyrin IX per mol enzyme dimer, the heme-iron is ferric, EPR-and light absorbance spectroscopy
Iron
-
low-spin heme iron, L-arginine and tetrahydrobiopterin bind and stabilize heme iron in five-coordinate high-spin state
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-phenylimidazole
-
reversible inhibition of endothelial enzyme, competitive versus L-arginine and tetrahydrobiopterin, no inhibition of cytochrome c reduction
2',3'-dialdehyde of NADPH
-
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
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
-
4-(3-amino-propoxy)-6-chloro-1H-quinolin-2-one trifluoroacetic acid salt
IC50: 410 nM, pharmacokinetic profile
5,6,7,8-tetrahydrobiopterin
-
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-([[(3R,5S)-5-[[(6-amino-4-methylpyridin-2-yl)methoxy]methyl]pyrrolidin-3-yl]oxy]methyl)-4-methylpyridin-2-amine
exhibits antimicrobial properties
-
6-n-propyl-2-thyouracil
0.1 mg 6-n-propyl-2-thyouracil decreases nNOS activity to 45% compared to control
6-[[(2S,3S)-2-amino-3-[(6-amino-4-methylpyridin-2-yl)methoxy]butoxy]methyl]-4-methylpyridin-2-amine
exhibits antimicrobial properties
-
agmatine
-
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
carbon monoxide
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
Di-2-thienyliodonium
-
competitive, irreversible, complete, time and temperature dependent inhibition
Gly-methyl-L-arginine
-
inhibition of the isozymes in absence or presence of L-arginine
Iodoniumdiphenyl
-
competitive, irreversible, complete, time and temperature dependent inhibition
L-Asn-methyl-L-arginine
-
inhibition of the isozymes in absence or presence of L-arginine
L-N-methylarginine
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-omega-monomethyl L-arginine
potent competitive eNOS inhibitor, complete inhibition at 10 mM
N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide
-
calmodulin antagonist above 0.01 mM; i.e. W-7
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
N1-[cis-4'-[(6''-amino-4''-methylpyridin-2''-yl)methyl]pyrrolidin-3'-yl]-N2-(4'-chlorobenzyl)ethane-1,2-diamine
-
N1-[cis-4'-[(6''-aminopyridin-2''-yl)methyl]pyrrolidin-3'-yl]ethane-1,2-diamine
-
N1-[trans-4'-[(6''-amino-4''-methylpyridin-2''-yl)methyl]pyrrolidin-3'-yl]-N2-(3'-chlorobenzyl)ethane-1,2-diamine
-
Ngamma-hydroxy-Ngamma-methyl-L-arginine
-
preincubation at 37°C leads to irreversible inactivation, substrates protect
NXN-188
-
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
-
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
-
4-(3-amino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
IC50: 0.0119 mM
4-(3-amino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
-
IC50: 0.0091 mM
4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
-
IC50: 0.004 mM
4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
IC50: 0.01 mM
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: 90 nM, pharmacokinetic profile
6-chloro-4-(3-aminopropoxy)-1-benzopyran-2-one trifluoroacetic acid salt
IC50: 60 nM, pharmacokinetic profile
6-chloro-4-(3-aminopropoxy)-1-benzopyran-2-one trifluoroacetic acid salt
-
IC50: 0.00056 mM, pharmacokinetic profile
6-chloro-4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
-
IC50: 0.0041 mM
6-chloro-4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
IC50: 0.0012 mM
6-chloro-4-(3-dimethylamino-propoxy)-1-benzopyran-2-one hydrochloric acid salt
-
IC50: 0.008 mM
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt
-
IC50: 0.00011mM
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt
IC50: 0.00025mM
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt
-
IC50: 0.00053mM
7-nitroindazole
-
reversible inhibition of endothelial enzyme, competitive versus tetrahydrobiopterin, no inhibition of cytochrome c reduction
7-nitroindazole
-
inhibits the neuronal NOS in vivo and reduces L-DOPA-induced dyskinesias in a rat model of parkinsonism. The rats show a lack of tolerance for the anti-dyskinetic effects
Ca2+
-
preincubation at 37°C leads to time-dependent inhibition of the enzyme