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EC Tree
IUBMB Comments The enzyme reduces riboflavin, and, less efficiently, FMN and FAD. NADH is oxidized less efficiently than NADPH.
The taxonomic range for the selected organisms is: Homo sapiens The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
flavin reductase, blvrb, nadph-dependent diaphorase, flavin oxidoreductase, biliverdin reductase b, nadph-flavin reductase, nadph:fmn oxidoreductase, flavin reductase p, nadph:flavin oxidoreductase, nfra1,
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biliverdin IXbeta reductase
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Biliverdin-IX beta-reductase
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Green heme binding protein
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NADPH-dependent diaphorase
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NADPH-flavin reductase
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reduced-riboflavin:NADP+ oxidoreductase
The enzyme reduces riboflavin, and, less efficiently, FMN and FAD. NADH is oxidized less efficiently than NADPH.
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FAD + NADPH + H+
FADH2 + NADP+
FMN + NADPH + H+
FMNH2 + NADP+
oxidized 2,6-dichlorophenolindophenol + NADPH + H+
reduced 2,6-dichlorophenolindophenol + NADP+
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-
-
-
?
oxidized methylene blue + NADPH + H+
reduced methylene blue + NADP+
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-
-
-
?
oxidized riboflavin + NADPH + H+
reduced riboflavin + NADP+
FAD + NADPH + H+
FADH2 + NADP+
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-
-
?
FAD + NADPH + H+
FADH2 + NADP+
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-
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?
FAD + NADPH + H+
FADH2 + NADP+
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specific activity for the reduction of oxidized riboflavin, FMN and FAD is similar
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-
?
FAD + NADPH + H+
FADH2 + NADP+
the enzyme (BLVRB) binds its coenzyme NADPH 500fold more tightly than its substrate FAD
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?
FMN + NADPH + H+
FMNH2 + NADP+
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?
FMN + NADPH + H+
FMNH2 + NADP+
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?
FMN + NADPH + H+
FMNH2 + NADP+
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specific activity for the reduction of oxidized riboflavin, FMN and FAD is similar
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?
oxidized riboflavin + NADPH + H+
reduced riboflavin + NADP+
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?
oxidized riboflavin + NADPH + H+
reduced riboflavin + NADP+
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specific activity for the reduction of oxidized riboflavin, FMN and FAD is similar
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?
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NADPH
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the FMN reductase activity is highly specific for NADPH, and the activity with NADH is 10% of that with NADPH
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additional information
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Fe2+, Fe3+, Mg2+, and Ca2+ do not affect the enzyme activity
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2,3-diphosphoglycerate
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Bathocuproine sulfonate
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lumichrome
competitive inhibitor against FMN and a mixed inhibitor of NADPH
mesobiliverdin XIIIa
competitive kinetics with FMN and mixed inhibition kinetics with NADPH
NADP+
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0.1 mM, about 50% inhibition at no inhibition by NAD+ at pH 7.5, 12% inhibition at pH 4.8
proflavin hemisulfate
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additional information
enzyme coexpression with gene dcs-1 is induced by heat shock
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additional information
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enzyme coexpression with gene dcs-1 is induced by heat shock
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Adenocarcinoma of Lung
Identification of Up- and Down-Regulated Proteins in Pemetrexed-Resistant Human Lung Adenocarcinoma: Flavin Reductase and Calreticulin Play Key Roles in the Development of Pemetrexed-Associated Resistance.
Amyotrophic Lateral Sclerosis
Partial loss of NADPH-diaphorase/nitric oxide synthase-complex in amyotrophic lateral sclerosis and human type-II myofiber atrophy.
Carcinoma, Hepatocellular
MicroRNA-127-5p targets the biliverdin reductase B/nuclear factor-?B pathway to suppress cell growth in hepatocellular carcinoma cells.
Carotid Artery Diseases
Novel Multiomics Profiling of Human Carotid Atherosclerotic Plaques and Plasma Reveals Biliverdin Reductase B as a Marker of Intraplaque Hemorrhage.
Leukemia
Purification of an NADPH-dependent diaphorase from membrane of DMSO-induced differentiated human promyelocytic leukemia HL-60 cells.
Liver Cirrhosis
Proteomic and transcriptomic studies of HBV-associated liver fibrosis of an AAV-HBV-infected mouse model.
Methemoglobinemia
Flavin reductase: sequence of cDNA from bovine liver and tissue distribution.
Neoplasms
Divergent erythroid megakaryocyte fates in Blvrb-deficient mice establish non-overlapping cytoprotective functions during stress hematopoiesis.
Neoplasms
Identification of specific protein markers in microdissected hepatocellular carcinoma.
Neoplasms
MicroRNA-127-5p targets the biliverdin reductase B/nuclear factor-?B pathway to suppress cell growth in hepatocellular carcinoma cells.
Prostatic Neoplasms
MALDI-MS tissue imaging identification of biliverdin reductase B overexpression in prostate cancer.
Whooping Cough
[Cloning and analysis of genes encoding 2-naphthoate monooxygenase and NADH:flavin oxidoreductase]
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0.002
NADPH
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pH and temperature not specified in the publication
0.053
oxidized riboflavin
pH 7.5, 25°C
0.05
FMN
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pH and temperature not specified in the publication
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0.3
oxidized riboflavin
pH 7.5, 25°C
additional information
additional information
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additional information
additional information
coenzyme clamps formed by arginine side chains at two co-evolving positions within the active site serve to slow coenzyme release (Positions 14 and 78). Coenzyme release is further slowed by the weaker binding substrate, resulting in relatively slow turnover numbers
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additional information
additional information
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coenzyme clamps formed by arginine side chains at two co-evolving positions within the active site serve to slow coenzyme release (Positions 14 and 78). Coenzyme release is further slowed by the weaker binding substrate, resulting in relatively slow turnover numbers
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5.6
oxidized riboflavin
pH 7.5, 25°C
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0.076
lumichrome
pH 7.5, 25°C
0.00059
mesobiliverdin XIIIa
pH 7.5, 25°C
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4.9
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citrate-phosphate buffer
5
sharp optimum, in citrate buffer
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4.5 - 8
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pH 4.5: about 85% of maximal activity, pH 8.0: about 45% of maximal activity
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gene fre-1
SwissProt
brenda
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brenda
COS cell
brenda
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brenda
the enzyme is predominant during fetal development but sometimes detectable through adulthood
brenda
CD34+ hematopoietic cell
brenda
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brenda
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brenda
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perinuclear
brenda
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metabolism
heme degradation enzyme biliverdin IXbeta reductase is required for stem cell glutamine metabolism
physiological function
the enzyme is a critical players in cellular redox regulation
evolution
a position 15 A away from the active site within human biliverdin reductase B (T164) is inherently dynamic and can be mutated to control global micro-millisecond motions and function. By comparing the inherent dynamics through nuclear magnetic resonance (NMR) relaxation approaches of evolutionarily distinct biliverdin reductase B homologues and by applying Relaxation And Single Site Multiple Mutations (RASSMM) approach that monitors both the functional and dynamic effects of multiple mutations to the single T164 site, it is discovered that the most dramatic mutagenic effects coincide with evolutionary changes and these modulate coenzyme binding
evolution
most BLVRB enzymes have an arginine at either residue 14 or residue 78 (human numbering), although a subset maintain an arginine at both sites. In primates, the two substitutions are made on the same branch separating the common ancestor of the Simiiformes (apes, new and old-world monkeys) with the common ancestor of the Haplorhini (i.e., after the split from the common ancestor with the tarsier). This suggests possible adaptive coevolution at these two sites and adjusting the location of this arginine may serve to fine-tune coenzyme binding in BLVRB enzymes
evolution
the study elucidates the role of the evolutionarily changing biliverdin reductase (BBLVRB) active site that serves to modulate coenzyme release and shows that coenzyme release is coupled to substrate turnover
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NDOR1_HUMAN
597
0
66763
Swiss-Prot
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21500
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x * 21500, SDS-PAGE
22000
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gel filtration
22000
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x * 22000, SDS-PAGE
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?
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x * 22000, SDS-PAGE
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Q14R
mutation at active site arginine residue increases coenzyme affinity
Q14R/R78G
double mutation within the enzyme exhibits a binding affinity that is close to the average between these two individual mutations
R78A
mutation leads to both an increase in active site micro-millisecond motions and an increase in the microscopic rate constants of coenzyme binding
R78R
mutation at active site arginine residue weakens affinity slightly
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100
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boiling of the enzyme leads to complete loss of the FMN reductase activity
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freezing and thawing causes no appreciable loss of the enzyme activity
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4°C, the purified enzyme is stable at
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gene fre-1, DNA and amino acid sequence determination and analysis, transcribed as a bicistronic pre-mRNA together with gene dcs-1, encoding Hint-related 7meGMP-directed hydrolase DCS-1
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Yubisui, T.; Matsuki, T.; Takeshita, M.; Yoneyama, Y.
Characterization of the purified NADPH-flavin reductase of human erythrocytes
J. Biochem.
85
719-728
1979
Homo sapiens
brenda
Kwasnicka, D.A.; Krakowiak, A.; Thacker, C.; Brenner, C.; Vincent, S.R.
Coordinate expression of NADPH-dependent flavin reductase, Fre-1, and Hint-related 7meGMP-directed hydrolase, DCS-1
J. Biol. Chem.
278
39051-39058
2003
Caenorhabditis elegans, Homo sapiens (Q9UHB4), Homo sapiens
brenda
Chikuba, K.; Yubisui, T.; Shirabe, K.; Takeshita, M.
Cloning and nucleotide sequence of a cDNA of the human erythrocyte NADPH-flavin reductase
Biochem. Biophys. Res. Commun.
198
1170-1176
1994
Homo sapiens (P30043), Homo sapiens
brenda
Yubisui, T.; Tamura, M.; Takeshita, M.
Characterization of a second form of NADPH-flavin reductase purified from human erythrocytes
Biochem. Int.
15
1-8
1987
Homo sapiens
brenda
Cunningham, O.; Gore, M.G.; Mantle, T.J.
Initial-rate kinetics of the flavin reductase reaction catalysed by human biliverdin-IXbeta reductase (BVR-B)
Biochem. J.
345
393-399
2000
Homo sapiens (P30043), Homo sapiens
brenda
Mancuso, C.
Biliverdin reductase as a target in drug research and development Facts and hypotheses
Free Radic. Biol. Med.
172
521-529
2021
Homo sapiens (P30043)
brenda
Li, Z.; Nesbitt, N.M.; Malone, L.E.; Gnatenko, D.V.; Wu, S.; Wang, D.; Zhu, W.; Girnun, G.D.; Bahou, W.F.
Heme degradation enzyme biliverdin IXbeta reductase is required for stem cell glutamine metabolism
Biochem. J.
475
1211-1223
2018
Homo sapiens (P30043)
brenda
Redzic, J.S.; Duff, M.R.; Blue, A.; Pitts, T.M.; Agarwal, P.; Eisenmesser, E.Z.
Modulating enzyme function via dynamic allostery within biliverdin reductase B
Front. Mol. Biosci.
8
691208
2021
Homo sapiens (P30043), Homo sapiens
brenda
Duff, M.R.; Redzic, J.S.; Ryan, L.P.; Paukovich, N.; Zhao, R.; Nix, J.C.; Pitts, T.M.; Agarwal, P.; Eisenmesser, E.Z.
Structure, dynamics and function of the evolutionarily changing biliverdin reductase B family
J. Biochem.
168
191-202
2020
Homo sapiens (P30043), Homo sapiens, Microcebus murinus (XP_020138941.1)
brenda
Paukovich, N.; Xue, M.; Elder, J.R.; Redzic, J.S.; Blue, A.; Pike, H.; Miller, B.G.; Pitts, T.M.; Pollock, D.D.; Hansen, K.; DAlessandro, A.; Eisenmesser, E.Z.
Biliverdin reductase B dynamics are coupled to coenzyme binding
J. Mol. Biol.
430
3234-3250
2018
Homo sapiens (P30043)
brenda