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Information on EC 1.6.2.4 - NADPH-hemoprotein reductase and Organism(s) Saccharomyces cerevisiae and UniProt Accession P16603
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1.6.2.4 NADPH-hemoprotein reductaseIUBMB Comments
A flavoprotein containing both FMN and FAD. This enzyme catalyses the transfer of electrons from NADPH, an obligatory two-electron donor, to microsomal P-450 monooxygenases (e.g. EC 1.14.14.1, unspecific monooxygenase) by stabilizing the one-electron reduced form of the flavin cofactors FAD and FMN. It also reduces cytochrome b5 and cytochrome c. The number n in the equation is 1 if the hemoprotein undergoes a 2-electron reduction, and is 2 if it undergoes a 1-electron reduction.
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Word Map
- 1.6.2.4
- monooxygenase
- heme
- quinone
- xenobiotics
- fmn
-
1.6.99.2
- flavoproteins
- dt-diaphorase
- phenobarbital
- cyp3a4
-
benzoapyrene
-
nadph:quinone
-
one-electron
-
drug-metabolizing
-
bioreductive
- 7-ethoxycoumarin
- semiquinone
- benzphetamine
-
two-electron
-
nadh-cytochrome
- aminopyrine
- cyp2c9
- 21-hydroxylase
- n-demethylase
-
o-deethylation
-
phenobarbital-induced
-
p-450-dependent
- 3-methylcholanthrene
- androstenedione
- adrenodoxin
- dicoumarol
- 7-ethoxyresorufin
- ethylmorphine
-
phenobarbital-treated
- beta-naphthoflavone
-
mixed-function
-
p-nitroanisole
-
p450-mediated
-
nitroreduction
-
p450-catalyzed
- 7,8-benzoflavone
-
omega-hydroxylation
- cyp21a2
- chlorzoxazone
-
o-dealkylation
-
virilization
- 17alpha-hydroxylase
-
6beta-hydroxylation
- biotechnology
- medicine
- bufuralol
-
2-amino-3-methylimidazo4,5-fquinoline
The taxonomic range for the selected organisms is: Saccharomyces cerevisiae
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
nadph-cytochrome p-450 reductase, cytochrome p450 reductase, p450 reductase, p-450 reductase, nadph-p450 reductase, p450 bm3, p450 oxidoreductase, nadph cytochrome p450 reductase, cytochrome p450 oxidoreductase, cypor, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
aldehyde reductase (NADPH-dependent)
-
-
-
-
CPR
cytochrome c reductase (reduced nicotinamide adenine dinucleotide phosphate, NADPH, NADPH-dependent)
-
-
-
-
dihydroxynicotinamide adenine dinucleotide phosphate-cytochrome c reductase
-
-
-
-
FAD-cytochrome c reductase
-
-
-
-
ferrihemprotein P450 reductase
-
-
-
-
NADP-cytochrome c reductase
-
-
-
-
NADP-cytochrome reductase
-
-
-
-
NADPH-cytochrome c oxidoreductase
-
-
-
-
NADPH-cytochrome c reductase
-
-
-
-
NADPH-cytochrome p-450 reductase
-
-
-
-
NADPH-cytochrome P450 (CYP) oxidoreductase
-
-
-
-
NADPH-dependent cytochrome c reductase
-
-
-
-
NADPH-ferricytochrome c oxidoreductase
-
-
-
-
P450R
-
-
-
-
reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase
-
-
-
-
reductase, cytochrome c (reduced nicotinamide adenine dinucleotide phosphate)
-
-
-
-
TPNH-cytochrome c reductase
-
-
-
-
TPNH2 cytochrome c reductase
-
-
-
-
CPR
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
NADPH:hemoprotein oxidoreductase
A flavoprotein containing both FMN and FAD. This enzyme catalyses the transfer of electrons from NADPH, an obligatory two-electron donor, to microsomal P-450 monooxygenases (e.g. EC 1.14.14.1, unspecific monooxygenase) by stabilizing the one-electron reduced form of the flavin cofactors FAD and FMN. It also reduces cytochrome b5 and cytochrome c. The number n in the equation is 1 if the hemoprotein undergoes a 2-electron reduction, and is 2 if it undergoes a 1-electron reduction.
CAS REGISTRY NUMBER
COMMENTARY
9023-03-4
-
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
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
-
-
?
2 oxidized cytochrome c + NADPH + H+
2 reduced cytochrome c + NADP+
-
-
-
?
2 ferricytochrome P450 + NADPH
2 ferrocytochrome P450 + NADP+ + H+
-
-
-
-
?
NADPH + O2
NADP+ + O2-
-
slow reaction, presence of menadione, or duroquinone, or vitamin K3 essential
superoxide anion
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
-
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: ferricyanide
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: ferricyanide
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: ferricyanide
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: menadione
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: cytochrome P450
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: cytochrome P450
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: 2,6-dichlorophenolindophenol
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: 2,6-dichlorophenolindophenol
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: 2,6-dichlorophenolindophenol
-
?
2 ferricytochrome c + NADPH
2 ferrocytochrome c + NADP+ + H+
-
additional electron acceptor: 2,6-dichlorophenolindophenol
-
?
additional information
?
-
-
microsomal electron transport system composed of cytochrome b5, cytochrome P450, NADH-cytochrome b5 reductase and NADPH-cytochrome c reductase
-
-
?
additional information
?
-
-
microsomal electron transport system composed of cytochrome b5, cytochrome P450, NADH-cytochrome b5 reductase and NADPH-cytochrome c reductase
-
-
?
additional information
?
-
-
microsomal electron transport system composed of cytochrome b5, cytochrome P450, NADH-cytochrome b5 reductase and NADPH-cytochrome c reductase
-
-
?
additional information
?
-
-
involved in the sterol biosynthesis pathways
-
-
?
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 ferricytochrome P450 + NADPH
2 ferrocytochrome P450 + NADP+ + H+
-
-
-
-
?
additional information
?
-
-
microsomal electron transport system composed of cytochrome b5, cytochrome P450, NADH-cytochrome b5 reductase and NADPH-cytochrome c reductase
-
-
?
additional information
?
-
-
microsomal electron transport system composed of cytochrome b5, cytochrome P450, NADH-cytochrome b5 reductase and NADPH-cytochrome c reductase
-
-
?
additional information
?
-
-
microsomal electron transport system composed of cytochrome b5, cytochrome P450, NADH-cytochrome b5 reductase and NADPH-cytochrome c reductase
-
-
?
additional information
?
-
-
involved in the sterol biosynthesis pathways
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FMN
second FMN binding site is detected at the interface of the connecting and FMN binding domains. The two FMN binding sites have different accessibilities to the bulk solvent and different amino acid environments, suggesting stabilization of different electronic structures of the reduced flavin. Since only one FMN cofactor is required for function, a hypothetical mechanism of electron transfer is discussed that proposes shuttling of a single FMN between these two sites coupled with the transition between two semiquinone forms, neutral and anionic
FMN
-
binding affinity for FMN is in the submicromolar range, 30times higher than that for FAD
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
HgCl2
-
incubation with NADPH provides protection against inhibition
p-chloromercuribenzoate
-
incubation with NADPH provides protection against inhibition
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
Saccharomyces cerevisiae /Homo sapiens chimeric protein
Uniprot
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
heterologously expressed native and truncated protein
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
upon cryo-reduction of oxidized yeast CPR containing an equimolar ratio of both FAD and FMN, or FAD alone, neutral semiquinones are trapped at 77 K. During annealing at the elevated temperatures, unstable short-lived neutral semiquinones relax to spectroscopically distinct air-stable neutral semiquinones. This transition is independent of pH within the 6.0-10.7 range
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
65000 - 68000
-
sedimentation equilibrium centrifugation, values depending on pH
82000 - 85000
additional information
-
a weak band at the level of the Jerusalem artichoke reductase
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
-
2 * 34300-40000, SDS-PAGE, sedimentation equilibrium centrifugation after treatment with guanidine-HCl
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of truncated yeast NADPH-cytochrome P450 reductase, which is functionally active toward its physiological substrate cytochrome P450
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
chimeric protein: yeast FMN (residues 44-211) and human connecting/FAD (residues 232-677) domain
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
FAD and NADPH: protection against thermal inactivation
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
to analyze the molecular interaction among CYP3A4, NADPH-cytochrome P450 oxidoreductase, and b5, several fused enzyme genes are constructed and expressed in Saccharomyces cerevisiae. The recombinant fused enzymes CYP3A4-truncated(t)-P450 reductase-t-b5 (3RB) and CYP3A4-t-b5-t-P450 reductase (3BR) in yeast microsomes shows a higher specific activity in 6beta-hydroxylation of testosterone than does the reconstitution premixes of CYP3A4, P450 reductase, and b5. The purified fused enzymes exhibit lower Km values and substantially increased Vmax values in 6beta-hydroxylation of testosterone and oxidation of nifedipine. The fused enzymes shows significantly higher activities in cytochrome c reduction than the reconstitution premixes. Although the affinity of 3RB toward cytochrome c is twice as high as that of 3BR, 3BR and 3RB show nearly the same affinity toward NADPH/NADH. In addition, the heme of the CYP3A4 moiety of 3RB is reduced preferentially and more rapidly than that of 3BR, whereas the heme of the b5 moiety of 3BR is selectively reduced compared with that of 3RB
-
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
native or truncated protein reconstituts ergosterol biosynthesis when added to a cell-free system, as well as reconstitution of activity with purified Saccharomyces cerevisiae CYP61, sterol 22-desaturase, Candida albicans and human CYP51
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Benveniste, I.; Lesot, A.; Hasenfratz, M.; Durst, F.
Immunochemical characterization of NADPH-cytochrome P-450 reductase from Jerusalem artichoke and other higher plants
Biochem. J.
259
847-853
1989
Saccharomyces cerevisiae, Helianthus tuberosus, Embryophyta, Locusta migratoria migratorioides, Rattus norvegicus, Sus scrofa
Kamimura, K.; Tsuchiya, E.; Miyakawa, T.; Fuki, S.; Hirata, A.
Isolation and characterization of the nuclei from Saccharomyces cerevisiae
Curr. Microbiol.
6
175-180
1981
Saccharomyces cerevisiae
-
Tryon, E.; Cress, M.C.; Hamada, M.; Kuby, S.A.
Studies on NADPH-cytochrome c reductase I: Isolation and several properties of the crystalline enzyme from ale yeast
Arch. Biochem. Biophys.
197
104-118
1979
Saccharomyces cerevisiae
Kubota, S.; Yoshida, Y.; Kumaoka, H.; Furumichi, A.
Studies on the microsomal electron-transport system of anaerobically grown yeast. V. Purification and characterization of NADPH-cytochrome c reductase
J. Biochem.
81
197-205
1977
Saccharomyces cerevisiae
Yoshida, Y.; Kumaoka, H.; Sato, R.
Studies on the microsomal electron-transport system of anaerobically grown yeast. I. Intracellular localization and characterization
J. Biochem.
75
1201-1210
1974
Saccharomyces cerevisiae
Aoyama, Y.; Yoshida, Y.; Kubota, S.; Kamaoka, H.; Furumichi, A.
NADPH-cytochrome P-450 reductase of yeast microsomes
Arch. Biochem. Biophys.
185
362-369
1978
Saccharomyces cerevisiae
Yoshida, Y.; Aoyama, Y.; Kumaoka, H.; Kubota, S.
A highly purified preparation of cytochrome P-450 from microsomes of anaerobically grown yeast
Biochem. Biophys. Res. Commun.
78
1005-1010
1977
Saccharomyces cerevisiae
Venkateswarlu, K.; Lamb, D.C.; Kelly, D.E.; Manning, N.J.; Kelly, S.L.
The N-terminal membrane domain of yeast NADPH-cytochrome P450 (CYP) oxidoreductase is not required for catalytic activity in steril biosynthesis or in reconstitution of CYP activity
J. Biol. Chem.
273
4492-4496
1998
Saccharomyces cerevisiae, Homo sapiens, Saccharomyces cerevisiae JL20
Lamb, D.C.; Kim, Y.; Yermalitskaya, L.V.; Yermalitsky, V.N.; Lepesheva, G.I.; Kelly, S.L.; Waterman, M.R.; Podust, L.M.
A second FMN binding site in yeast NADPH-cytochrome P450 reductase suggests a mechanism of electron transfer by diflavin reductases
Structure
14
51-61
2006
Saccharomyces cerevisiae (P16603)
Inui, H.; Maeda, A.; Ohkawa, H.
Molecular characterization of specifically active recombinant fused enzymes consisting of CYP3A4, NADPH-cytochrome P450 oxidoreductase, and cytochrome b5
Biochemistry
46
10213-10221
2007
Saccharomyces cerevisiae
Lah, L.; Krasevec, N.; Trontelj, P.; Komel, R.
High diversity and complex evolution of fungal cytochrome P450 reductase: cytochrome P450 systems
Fungal Genet. Biol.
45
446-458
2008
Eremothecium gossypii, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Aspergillus terreus, Botrytis cinerea, Saccharomyces cerevisiae, Candida albicans, Debaryomyces hansenii, [Candida] glabrata, Yarrowia lipolytica, Chaetomium globosum, Coccidioides immitis, Fusarium graminearum, Kluyveromyces lactis, Pyricularia grisea, Neurospora crassa, Phytophthora sojae, Rhizopus arrhizus, Sclerotinia sclerotiorum, Ustilago maydis, Parastagonospora nodorum, Phytophthora ramorum, Schizosaccharomyces pombe (P36587), Phanerodontia chrysosporium (Q9HDG2)
Aigrain, L.; Pompon, D.; Morera, S.; Truan, G.
Structure of the open conformation of a functional chimeric NADPH cytochrome P450 reductase
EMBO Rep.
10
742-747
2009
Homo sapiens, Saccharomyces cerevisiae (P16603)
Ivanov, A.S.; Gnedenko, O.V.; Molnar, A.A.; Archakov, A.I.; Podust, L.M.
FMN binding site of yeast NADPH-cytochrome P450 reductase exposed at the surface is highly specific
ACS Chem. Biol.
5
767-776
2010
Saccharomyces cerevisiae
Davydov, R.M.; Jennings, G.; Hoffman, B.M.; Podust, L.M.
Short-lived neutral FMN and FAD semiquinones are transient intermediates in cryo-reduced yeast NADPH-cytochrome P450 reductase
Arch. Biochem. Biophys.
673
108080
2019
Saccharomyces cerevisiae (P16603), Saccharomyces cerevisiae ATCC 204508 (P16603)
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