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Literature summary for 1.14.13.8 extracted from

  • Catucci, G.; Bortolussi, S.; Rampolla, G.; Cusumano, D.; Gilardi, G.; Sadeghi, S.J.
    Flavin-containing monooxygenase 3 polymorphic variants significantly affect clearance of tamoxifen and clomiphene (2018), Basic Clin. Pharmacol. Toxicol., 123, 687-691 .
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli strain JM109 Homo sapiens

Protein Variants

Protein Variants Comment Organism
E158K naturally occuring mutation and site-directed mutagenesis, the mutant exhibits a significant increase in all the kinetic parameters measured with substrate tamoxifen with nearly two times faster clearance. The mutation has no effect on the clearance of GSK5182 Homo sapiens
E308G naturally occuring mutation and site-directed mutagenesis, the mutant exhibits a significant increase in all the kinetic parameters measured with substrate clomiphene with nearly two times faster clearance. The mutation has no effect on the clearance of GSK5182 Homo sapiens
V257M naturally occuring mutation and site-directed mutagenesis, residue V257 is not in the immediate vicinity of the active site and is part of the hFMO3 insert region in a loop that protrudes from the NADP+-binding domain across the FAD-binding domain, the mutant exhibits a significant increase in all the kinetic parameters measured with substrate clomiphene with nearly two times faster clearance, while the clearance with substrate tamoxifen is reduced. The mutation has no effect on the clearance of GSK5182 Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
additional information Michaelis-Menten steady-state kinetics Homo sapiens
0.00156
-
tamoxifen recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
0.0025
-
tamoxifen recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
0.00457
-
GSK5182 recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
0.0064
-
tamoxifen recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0081
-
tamoxifen recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
0.00982
-
GSK5182 recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0183
-
clomiphene recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0205
-
clomiphene recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
0.0285
-
GSK5182 recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
0.0332
-
clomiphene recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
0.0444
-
clomiphene recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
0.0587
-
GSK5182 recombinant mutant E308G, pH 7.4, 37°C Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
membrane
-
Homo sapiens 16020
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
clomiphene + NADPH + H+ + O2 Homo sapiens clomiphene is used in infertility medication clomiphene N-oxide + NADP+ + H2O
-
?
GSK5182 + NADPH + H+ + O2 Homo sapiens an antidiabetic lead molecule GSK5182 N-oxide + NADP+ + H2O
-
?
tamoxifen + NADPH + H+ + O2 Homo sapiens tamoxifen is used in breast cancer medication tamoxifen N-oxide + NADP+ + H2O
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens P31513
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain JM109 by negative anionic exchange chromatography (the protein is not retained by the DEAE resin at pH 7.4) and nickel affinity chromatography, followed by ultrafiltration Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
liver
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
clomiphene + NADPH + H+ + O2
-
Homo sapiens clomiphene N-oxide + NADP+ + H2O
-
?
clomiphene + NADPH + H+ + O2 clomiphene is used in infertility medication Homo sapiens clomiphene N-oxide + NADP+ + H2O
-
?
GSK5182 + NADPH + H+ + O2
-
Homo sapiens GSK5182 N-oxide + NADP+ + H2O
-
?
GSK5182 + NADPH + H+ + O2 an antidiabetic lead molecule Homo sapiens GSK5182 N-oxide + NADP+ + H2O
-
?
additional information identification of GSK5182 N-oxide products by mass spectrometry Homo sapiens ?
-
-
tamoxifen + NADPH + H+ + O2
-
Homo sapiens tamoxifen N-oxide + NADP+ + H2O
-
?
tamoxifen + NADPH + H+ + O2 tamoxifen is used in breast cancer medication Homo sapiens tamoxifen N-oxide + NADP+ + H2O
-
?

Subunits

Subunits Comment Organism
? x * 58700, SDS-PAGE Homo sapiens
More the amino acid sequence of PtFMO contains some conserved sequences of FMO: NADPH- and FAD-binding domains Homo sapiens

Synonyms

Synonyms Comment Organism
flavin-containing monooxygenase 3
-
Homo sapiens
FMO3
-
Homo sapiens
hFMO3
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Homo sapiens

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.0012
-
clomiphene recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0042
-
clomiphene recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
0.005
-
clomiphene recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
0.0063
-
tamoxifen recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
0.0075
-
tamoxifen recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
0.01
-
clomiphene recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
0.01
-
tamoxifen recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
0.0188
-
tamoxifen recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0193
-
GSK5182 recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
0.02
-
GSK5182 recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
0.037
-
GSK5182 recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.095
-
GSK5182 recombinant mutant V257M, pH 7.4, 37°C Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.4
-
assay at Homo sapiens

Cofactor

Cofactor Comment Organism Structure
FAD
-
Homo sapiens
NADPH
-
Homo sapiens

pI Value

Organism Comment pI Value Maximum pI Value
Homo sapiens isoelectric focusing
-
8.52

General Information

General Information Comment Organism
additional information enzyme hFMO3 structural modeling with NADP-binding domain and FAD-binding domain with bound cofactors, overview Homo sapiens

kcat/KM [mM/s]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
0.151
-
clomiphene recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
0.488
-
clomiphene recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
0.656
-
clomiphene recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.946
-
clomiphene recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
1.234
-
tamoxifen recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
2.52
-
tamoxifen recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
2.935
-
GSK5182 recombinant mutant E308G, pH 7.4, 37°C Homo sapiens
3.33
-
GSK5182 recombinant mutant V257M, pH 7.4, 37°C Homo sapiens
3.77
-
GSK5182 recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens
4.22
-
GSK5182 recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
4.81
-
tamoxifen recombinant mutant E158K, pH 7.4, 37°C Homo sapiens
53.19
-
tamoxifen recombinant wild-type enzyme, pH 7.4, 37°C Homo sapiens