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Literature summary for 1.14.13.8 extracted from

  • Bortolussi, S.; Catucci, G.; Gilardi, G.; Sadeghi, S.J.
    N- and S-oxygenation activity of truncated human flavin-containing monooxygenase 3 and its common polymorphic variants (2021), Arch. Biochem. Biophys., 697, 108663 .
    View publication on PubMed
Search for more literature for 1.14.13.8

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of His-tagged wild-type and mutant full-length and truncated enzyme variants in Escherichia coli strain JM109 Homo sapiens

Protein Variants

Protein Variants Comment Organism
E158K naturally occuring polymorphism of FMO3, the E158K variant is mostly expressed in African-American and Europeans, the mutant shows reduced activity compared to the wild-type enzyme Homo sapiens
E308G naturally occuring polymorphism of FMO3, the E308G is widely distributed in Asians and Europeans, the mutant shows reduced activity compared to the wild-type enzyme Homo sapiens
additional information generation of truncated forms of wild-type and mutant enzymes, the 17 amino acid truncation at the C-terminal of FMO3 results in a more soluble protein, the truncated enzymes are better catalysts than the full-length proteins. The truncated enzymes are not only fully active, but also have a higher vmax compared to their full-length counterparts, the latter observation might be the result of their higher solubility. The mutations have no major effect on the interaction of the FAD cofactor with the protein Homo sapiens
V257M naturally occuring polymorphism of FMO3, the V257M polymorphic variant is predominantly present in Asians, the mutant shows reduced activity compared to the wild-type enzyme Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
 additional information Michaelis-Menten kinetics, potentiometric titrations of the flavin cofactor of FMO3 and the calculated reduction potentials for full-length wild-type and polymorphic variants of FMO3 and that of the truncated form of the wild-type Homo sapiens
0.00134
-
 tamoxifen recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens
0.0016
-
 tamoxifen recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.0025
-
 tamoxifen recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.0029
-
 tamoxifen recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
0.0056
-
 tamoxifen recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0064
-
 tamoxifen recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0071
-
 tamoxifen recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
0.0081
-
 tamoxifen recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
0.0101
-
 sulindac sulfide recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.0103
-
 sulindac sulfide recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
0.0103
-
 sulindac sulfide recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
0.0127
-
 sulindac sulfide recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0143
-
 sulindac sulfide recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
0.0151
-
 sulindac sulfide recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.0156
-
 sulindac sulfide recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0163
-
 sulindac sulfide recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens
0.0345
-
 Benzydamine recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.0373
-
 Benzydamine recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
0.038
-
 Benzydamine recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
0.0397
-
 Benzydamine recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
0.052
-
 Benzydamine recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.053
-
 Benzydamine recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0593
-
 Benzydamine recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.0659
-
 Benzydamine recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
membrane FMO3 is membrane-bound Homo sapiens 16020
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
N,N-dimethylaniline + NADPH + H+ + O2 Homo sapiens
-
 N,N-dimethylaniline N-oxide + NADP+ + H2O
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens P31513
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged wild-type and mutant full-length and truncated enzyme variants from Escherichia coli strain JM109 by anion exchange and nickel affinity chromatography followed by ultrafiltration Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
benzydamine + NADPH + H+ + O2 high activity Homo sapiens benzydamine N-oxide + NADP+ + H2O
-
 ?
additional information N- and S-oxygenation activity of truncated wild-type human flavin-containing monooxygenase 3 and its common polymorphic variants, overview. The enzyme binds noncovalently one molecule of FAD and is reduced by NADPH before exerting its catalysis Homo sapiens ?
-
-
N,N-dimethylaniline + NADPH + H+ + O2
-
 Homo sapiens N,N-dimethylaniline N-oxide + NADP+ + H2O
-
 ?
sulindac sulfide + NADPH + H+ + O2
-
 Homo sapiens sulindac sulfide S-oxide + NADP+ + H2O
-
 ?
tamoxifen + NADPH + H+ + O2
-
 Homo sapiens tamoxifen N-oxide + NADP+ + H2O
-
 ?

Synonyms

Synonyms Comment Organism
flavin-containing monooxygenase 3
-
 Homo sapiens
FMO3
-
 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
0.003
-
 Benzydamine recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.0042
-
 sulindac sulfide recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.0062
-
 tamoxifen recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.0062
-
 sulindac sulfide recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.0068
-
 sulindac sulfide recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
0.0075
-
 tamoxifen recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.008
-
 Benzydamine recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
0.0093
-
 sulindac sulfide recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0098
-
 tamoxifen recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
0.01
-
 tamoxifen recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
0.0113
-
 tamoxifen recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens
0.0115
-
 sulindac sulfide recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens
0.0142
-
 tamoxifen recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
0.0148
-
 sulindac sulfide recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
0.018
-
 Benzydamine recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.0183
-
 sulindac sulfide recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
0.0188
-
 tamoxifen recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.027
-
 sulindac sulfide recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.0272
-
 tamoxifen recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.029
-
 Benzydamine recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens
0.051
-
 Benzydamine recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
0.052
-
 Benzydamine recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.058
-
 Benzydamine recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
0.075
-
 Benzydamine recombinant His-tagged truncated wild-type enzyme, 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
additional information the enzyme binds noncovalently one molecule of FAD and is reduced by NADPH before exerting its catalysis Homo sapiens
NADPH
-
 Homo sapiens

General Information

General Information Comment Organism
malfunction naturally occurring polymorphic enzyme variants demonstrate differences in rates of turnover of its substrates: xenobiotics including drugs as well as dietary compound Homo sapiens
additional information enzyme protein structure homology-modelling using the PDB ID 6SE3 structure as the template Homo sapiens
physiological function human flavin-containing monooxygenase 3 (FMO3) is a highly polymorphic membrane-bound, phase I drug metabolizing enzyme. Human FMO3 catalyzes the monooxygenation of nucleophilic heteroatom containing chemicals (drugs, pesticides, and xenobiotics) through an unusual mechanism of activation of molecular oxygen via a stable FAD intermediate in the absence of the bound substrate. This mechanism accounts for the broad substrate range as well as uncoupling of this enzyme, i.e. the wastage of electrons without oxygenation of the substrate leading to the formation of reactive oxygen species (ROS) such as the superoxide radical and hydrogen peroxide. FMO3 is the primary catalyst of benzydamine N-oxygenation with minimal contribution from cytochrome P450 enzymes and that N-oxygenation is the major pathway of benzydamine biotransformation in various species in vitro. FMO3 catalyzes the formation of tamoxifen N-oxide. Tamoxifen N-oxide represents a detoxification pathway, after the metabolic activation carried out by cytochrome P450 (tamoxifen alpha-hydroxylation) that leads to products capable of DNA adduction, with potentially significant toxicological consequences. Administered orally, sulindac is a prodrug which is reduced by the gut flora to the active sulfide form before absorption. In vivo, the sulfide form is re-oxidized to sulindac, the latter compound is relatively inactive compared to the sulfide form: this oxidation step leading from sulindac sulfide to sulindac is carried out by FMO3 Homo sapiens

kcat/KM [mM/s]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
0.044
-
 Benzydamine recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens
0.087
-
 Benzydamine recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.202
-
 Benzydamine recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
0.278
-
 sulindac sulfide recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.304
-
 Benzydamine recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
0.476
-
 sulindac sulfide recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
0.596
-
 sulindac sulfide recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
0.614
-
 sulindac sulfide recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
0.706
-
 sulindac sulfide recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens
1
-
 Benzydamine recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
1.21
-
 tamoxifen recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
1.37
-
 Benzydamine recombinant His-tagged full-length mutant V257M, pH 7.4, 37°C Homo sapiens
1.415
-
 Benzydamine recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
1.437
-
 sulindac sulfide recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
1.526
-
 Benzydamine recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
1.777
-
 sulindac sulfide recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
2
-
 tamoxifen recombinant His-tagged truncated mutant V257M, pH 7.4, 37°C Homo sapiens
2.13
-
 sulindac sulfide recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
2.48
-
 tamoxifen recombinant His-tagged full-length mutant E308G, pH 7.4, 37°C Homo sapiens
2.94
-
 tamoxifen recombinant His-tagged full-length wild-type enzyme, pH 7.4, 37°C Homo sapiens
3.45
-
 tamoxifen recombinant His-tagged truncated mutant E308G, pH 7.4, 37°C Homo sapiens
4.69
-
 tamoxifen recombinant His-tagged full-length mutant E158K, pH 7.4, 37°C Homo sapiens
4.86
-
 tamoxifen recombinant His-tagged truncated wild-type enzyme, pH 7.4, 37°C Homo sapiens
8.43
-
 tamoxifen recombinant His-tagged truncated mutant E158K, pH 7.4, 37°C Homo sapiens