Information on EC 1.14.13.30 - leukotriene-B4 20-monooxygenase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.14.13.30
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RECOMMENDED NAME
GeneOntology No.
leukotriene-B4 20-monooxygenase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate + NADPH + H+ + O2 = (6Z,8E,10E,14Z)-(5S,12R)-5,12,20-trihydroxyicosa-6,8,10,14-tetraenoate + NADP+ + H2O
show the reaction diagram
a heme-thiolate protein P450; not identical with EC 1.14.13.34
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
omega-oxidation
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redox reaction
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reduction
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
alpha-tocopherol degradation
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Arachidonic acid metabolism
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Metabolic pathways
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SYSTEMATIC NAME
IUBMB Comments
(6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate,NADPH:oxygen oxidoreductase (20-hydroxylating)
A heme-thiolate protein (P-450). Not identical with EC 1.14.13.34, leukotriene-E4 20-monooxygenase.
CAS REGISTRY NUMBER
COMMENTARY hide
90119-11-2
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
CD-1 strain
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
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CYP4F catalyzes the omega-hydroxylation of the side chain of tocopherols and tocotrienols, the first step in their catabolism to polar metabolites excreted in urine. CYP4F2 is the only enzyme currently shown to metabolize vitamin E in humans
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate + NADPH + O2
(6Z,8E,10E,14Z)-(5S,12R)-5,12,20-trihydroxyicosa-6,8,10,14-tetraenoate + NADP+ + H2O
show the reaction diagram
(E,Z,Z,Z)-8-hydroxy-5,9,11,14-eicosatetraenoic acid + NADPH + O2
?
show the reaction diagram
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CYP4F2
-
-
?
(Z12(13))-epoxyoctadec-(Z9)-enoic acid + NADPH + O2
?
show the reaction diagram
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-
-
-
?
(Z12(13))-epoxyoctadec-Z9-enoic acid + NADPH + O2
?
show the reaction diagram
-
-
-
-
?
(Z9(10))-epoxyoctadec-(Z12)-enoic acid + NADPH + O2
?
show the reaction diagram
-
-
-
-
?
(Z9(10))-epoxyoctadec-Z12-enoic acid + NADPH + O2
?
show the reaction diagram
-
-
-
-
?
(Z9(10))-epoxyoctadecanoic acid + NADPH + O2
?
show the reaction diagram
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omega-hydroxylation activity and weak (omega-1)-hydroxylation activity
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?
12-hydroxy-5,8,10,14-eicosatetraenoic acid + NADPH + O2
?
show the reaction diagram
12-hydroxyeicosatetraenoic acid + NADPH + H+ + O2
?
show the reaction diagram
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CYP4F3A
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-
?
12-hydroxystearate + NADPH + O2
?
show the reaction diagram
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-
-
-
?
20-hydroxy-leukotriene B4 + NADPH + O2
?
show the reaction diagram
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CYP4F3
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-
?
20-hydroxy-leukotriene B4 + NADPH + O2
? + NADP+ + H2O
show the reaction diagram
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-
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?
5-deoxy-leukotriene B4 + NADPH + O2
5-deoxy-20-hydroxy-leukotriene B4
show the reaction diagram
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-
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?
5-epi-leukotriene B4 + NADPH + O2
5-epi-20-hydroxy-leukotriene B4
show the reaction diagram
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-
-
-
?
5-hydroxy-6,8,11,14-eicosatetraenoic acid + NADPH + O2
?
show the reaction diagram
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CYP4F3
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?
6-trans-12-epi-leukotriene B4 + NADPH + O2
6-trans-12-epi-20-hydroxy-leukotriene B4
show the reaction diagram
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?
6-trans-leukotriene B4 + NADPH + H+ + O2
?
show the reaction diagram
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CYP4F3A
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?
6-trans-leukotriene B4 + NADPH + O2
?
show the reaction diagram
6-trans-leukotriene B4 + NADPH + O2
? + NADP+ + H2O
show the reaction diagram
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-
-
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?
9,11-diazo-15-deoxy-prostaglandin H2 + NADPH + O2
?
show the reaction diagram
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CYP4F8
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-
?
9,11-epoxymethano-prostaglandin H2 + NADPH + O2
?
show the reaction diagram
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CYP4F8
-
-
?
alpha-tocopherol + NADPH + H+ + O2
alpha-13'-hydroxy-tocopherol + NADP+ + H2O
show the reaction diagram
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-
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?
alpha-tocotrienol + NADPH + H+ + O2
?
show the reaction diagram
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?
arachidonate + NADPH + O2
20-hydroxy-5,8,11,14-eicosatetraenoic acid + NADP+ + H2O
show the reaction diagram
arachidonic acid + NADPH + H+ + O2
?
show the reaction diagram
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?
arachidonic acid + NADPH + O2
18(R)-hydroxyarachidonate + NADP+ + H2O
show the reaction diagram
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?
delta-tocopherol + NADPH + H+ + O2
delta-13'-hydroxy-tocopherol + NADP+ + H2O
show the reaction diagram
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?
delta-tocotrienol + NADPH + H+ + O2
?
show the reaction diagram
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?
gamma-tocopherol + NADPH + H+ + O2
gamma-13'-hydroxy-tocopherol + NADP+ + H2O
show the reaction diagram
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?
gamma-tocotrienol + NADPH + H+ + O2
?
show the reaction diagram
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?
leukotriene B4 + NADPH + H+ + O2
(6Z,8E,10E,14Z)-(5S,12R)-5,12,20-trihydroxyicosa-6,8,10,14-tetraenoate + NADP+ + H2O
show the reaction diagram
leukotriene B4 + NADPH + O2
20-hydroxy-leukotriene B4 + NADP+ + H2O
show the reaction diagram
leukotriene B4 + NADPH + O2
?
show the reaction diagram
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induction of in all-trans-retinoic acid-treated HL60 cells
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?
lipoxin A4 + NADPH + H+ + O2
?
show the reaction diagram
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CYP4F3A
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?
lipoxin A4 + NADPH + O2
?
show the reaction diagram
lipoxin B4 + NADPH + O2
?
show the reaction diagram
prostaglandin A1 + NADPH + O2
20-hydroxy-prostaglandin A1 + NADP+ + H2O
show the reaction diagram
prostaglandin H1 + NADPH + O2
19-hydroxy-prostaglandin H1 + NADP+ + H2O
show the reaction diagram
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CYP4F8
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?
prostaglandin H2 + NADPH + O2
19-hydroxy-prostaglandin H2 + NADP+ + H2O
show the reaction diagram
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CYP4F8
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?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate + NADPH + O2
(6Z,8E,10E,14Z)-(5S,12R)-5,12,20-trihydroxyicosa-6,8,10,14-tetraenoate + NADP+ + H2O
show the reaction diagram
arachidonate + NADPH + O2
20-hydroxy-5,8,11,14-eicosatetraenoic acid + NADP+ + H2O
show the reaction diagram
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the enzyme is the principal arachidonate omega-hydroxylase in liver, CYP4F2
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?
leukotriene B4 + NADPH + H+ + O2
(6Z,8E,10E,14Z)-(5S,12R)-5,12,20-trihydroxyicosa-6,8,10,14-tetraenoate + NADP+ + H2O
show the reaction diagram
leukotriene B4 + NADPH + O2
20-hydroxy-leukotriene B4 + NADP+ + H2O
show the reaction diagram
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the enzyme plays a critical role in regulating the biological effect of leukotriene B4, CYP4F3
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?
leukotriene B4 + NADPH + O2
?
show the reaction diagram
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induction of in all-trans-retinoic acid-treated HL60 cells
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?
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P450
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NADPH
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Fe2+
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a cytochrome P450 enzyme
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
17-octadecynoic acid
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5-aminosalicylic acid
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50% inhibition at 0.05 mM
Acetylenic fatty acids
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suicidal inactivation
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all-trans-retinoic acid
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after 6 days of retinoid exposure, cutaneous transcripts arising from Cyp4f13, 4f14, and 4f37 are down-regulated. No changes in transcript abundance for the Cyp4f16, 4f17, and 4f18 genes
alpha-naphthoflavone
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ferricytochrome c
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leukotriene B4
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substrate prostaglandin A1
leukotriene B5
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Metyrapone
prostaglandin A1
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additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
all-trans retinoic acid
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significantly induces expression of CYP4F3A at both mRNA and protein levels in cultured HL-60 cells
all-trans-retinoic acid
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after 6 days of retinoid exposure, cutaneous transcripts arising from Cyp4f39 are up-regulated. No changes in transcript abundance for the Cyp4f16, 4f17, and 4f18 genes
Benzene
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induces CYP4F3 in human blood cells both in vivo and in vitro
lipopolysaccharide
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upregulates expression and activity of LTB4OH in ex-smokers in a dose-dependent manner, but not in smokers. In vitro smoke exposure of ex-smokers' bronchoalveolar lavage cells abrogates the lipopolysaccharide-induced up-regulation of LTB4OH mRNA expression, thus tobacco smoke alters bronchoalveolar lavage cell LTB4OH mRNA expression in response to lipopolysaccharide exposure
Phenol
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significantly induces expression of CYP4F3A at both mRNA and protein levels in cultured and differentiated HL-60 cells, in the proerythroid cell line K-562, and ex vivo in human neutrophils
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0142 - 0.0752
12-hydroxy-5,8,10,14-eicosatetraenoic acid
0.0409 - 0.0423
12-hydroxystearate
0.0065
20-hydroxy-leukotriene B4
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0.0056
5-Deoxy-leukotriene B4
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0.0066
5-epi-Leukotriene B4
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0.0038
6-trans-12-epi-Leukotriene B4
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0.0556 - 0.0961
6-trans-leukotriene B4
0.00022 - 0.868
leukotriene B4
0.0582 - 0.254
lipoxin A4
0.0179
lipoxin B4
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0.0008 - 0.001
NADPH
0.04
prostaglandin A1
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0.0618 - 0.135
Z12(13)-epoxyoctadec-Z9-enoic acid
0.0466 - 0.1631
Z9(10)-epoxyoctadec-Z12-enoic acid
0.0063 - 0.0357
Z9(10)-epoxyoctadecanoic acid
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.043
leukotriene B4
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substrate prostaglandin A1
0.001
leukotriene B5
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0.038
prostaglandin A1
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.154
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microsomal preparation
30
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recombinant protein, expressed in yeast
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5 - 8
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.8 - 9.5
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pH 6.8: about 50% of activity maximum, pH 9.5: about 70% of activity maximum
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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ex-smokers express significantly higher LTB4OH mRNA levels than smokers
Manually annotated by BRENDA team
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bone marrow-derived, in vitro differentiation
Manually annotated by BRENDA team
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CYP4F11
Manually annotated by BRENDA team
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constitutively expressed in hepatoma cell line Hep-G2
Manually annotated by BRENDA team
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CYP4F3B is the predominant CYP4F isoform
Manually annotated by BRENDA team
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exhibits greater leukotriene B4 hydroxylase activities than fresh skin tissues of either species
Manually annotated by BRENDA team
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CYP4F3 is specifically expressed in. CYP4F3 is restricted to myeloid cells
Manually annotated by BRENDA team
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mRNA for CYP4F8 detected
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
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not cytosol
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Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
55000
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recombinant CYP4F3, expressed in yeast, SDS-PAGE
56300
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recombinant CYP4F2, expressed in yeast, SDS-PAGE
59800
CYP4F14, predicted from gene sequence
61000
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recombinant isoforms CYP4F3A and CYP4F3B expressed in COS-7 cells, western blot analysis
additional information
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the isolated cDNA encodes a protein of 520 amino acids with 59805 Da, CYP4F3
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 53000, recombinant wild-type an dmutant enzymes, SDS-PAGE
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50
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completely inactivated after 1 h
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70C, 20% glycerol,1 mM dithithreitol, 3 days and 10 days, 50% resp. 100%
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-70C, 50% losss of activity after 3 days
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-70C, no loss of activity with highly purified preparations even after 4 years
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-70C, rapid loss of activity
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-70C, stable for 4 years
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
CYP4F3
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recombinant enzyme
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recombinant enzyme from insect Sf9 suspension cultures, to near homogeneity, native enzyme partially from liver and kidney by microsome preparation
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recombinant protein CYP4F2, expressed in yeast
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recombinant protein CYP4F3, expressed in yeast
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
chromosomal localization 19p; CYP4F3 gene contains 14 exons and 13 introns; expression in transfected COS-7 cells; tissue-specific expression is regulated by alternative promoter usage and mutually exclusive exon splicing, exon 3 and 4; two isoforms of CYP4F3, CYP4F3A expressed in neutrophils and CYP4F3B expressed in fetal and adult liver
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CYP4F14, expression in yeast cells
CYP4F2
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CYP4F2; expression in yeast cells
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expression in Escherichia coli
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expression in Spodoptera frugiperda Sf9 cells using the baculovirus infection system
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expression in yeast cells
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expression in yeast; expression in yeast cells, CYP4F3
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expression of wild-type and CYP4F2 mutant enzymes in Spodoptera frugiperda SF9 insect cell microsomes via the baculovrius transfection system
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gene Cyp4f18, expression analysis of CYP4F18 in different cell types, recombinant expression of the enzyme in Spodoptera frugiperda Sf9 cell microsomes via baculovirus transfection system
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wild-type and mutant DNA and amino acid sequence determinations, functional nonsynonymous polymorphisms, overview, expression of wild-type and mutant genes in Spodoptera frugiperda Sf9 cells using the baculovirus transfection method
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
after 6 days of retinoid exposure, cutaneous transcripts arising from Cyp4f13, 4f14, and 4f37 are down-regulated
after 6 days of retinoid exposure, cutaneous transcripts arising from Cyp4f39 are up-regulated
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
W12G/V433M
the functional polymorphism in human Cyp4F2 decreases 20-hydroxyeicosatetraenoic acid production, but does not influence the omega-hydroxylation of leukotriene B4, screening and genotyping of African and European Americans, overview
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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induction of CYP4F3 may play a role in the development of benzene hematotoxicity and serve as a biomarker of benzene exposure