ArticleInternational journal of molecular sciences2013
Effect of human flavin-containing monooxygenase 3 polymorphism on the metabolism of aurora kinase inhibitors.
Article in International journal of molecular sciences, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 30 citations in OpenAlex.
- Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions.Archives of toxicology · 2022Review
- Flavin-Containing Monooxygenase 3 (FMO3) Is Critical for Dioxin-Induced Reorganization of the Gut Microbiome and Host Insulin Sensitivity.Metabolites · 2022Article
- Article
- Association of FMO3 rs1736557 polymorphism with clopidogrel response in Chinese patients with coronary artery disease.European journal of clinical pharmacology · 2021Article
- Production of drug metabolites by human FMO3 in Escherichia coli.Microbial cell factories · 2020Article
- Redox Signaling by Reactive Electrophiles and Oxidants.Chemical reviews · 2018Review
- Inactivation mechanism of N61S mutant of human FMO3 towards trimethylamine.Scientific reports · 2017Article
- Article
- Escherichia coli Overexpressing a Baeyer-Villiger Monooxygenase from Acinetobacter radioresistens Becomes Resistant to Imipenem.Antimicrobial agents and chemotherapy · 2016Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aurora kinases were recently identified as a potential target in anticancer therapy and, amongst their available inhibitors, Tozasertib (VX-680) and Danusertib (PHA-739358) have been indicated as possible substrates of human flavin-containing monooxygenase 3 (hFMO3). Here we report the in vitro rate of oxidation of these drugs by wild-type hFMO3 and its polymorphic variant V257M. The conversion of Tozasertib and Danusertib to their corresponding metabolites, identified by LC-MS, by the purified wild-type and V257M hFMO3 show significant differences. In the case of Tozasertib, the V257M variant shows a catalytic efficiency, expressed as k(cat)/K(m), similar to the wild-type: 0.39 ± 0.06 min-1µM-1 for V257M compared to 0.33 ± 0.04 min-1µM-1 for the wild type. On the other hand, in the case of Danusertib, V257M shows a 3.4× decrease in catalytic efficiency with k(cat)/K(m) values of 0.05 ± 0.01 min-1µM-1 for V257M and 0.17 ± 0.03 min-1µM-1 for the wild type. These data reveal how a simple V257M substitution ascribed to a single nucleotide polymorphism affects the N-oxidation of relevant anticancer drugs, with important outcome in their therapeutic effects. These findings demonstrate that codon 257 is important for activity of the hFMO3 gene and the codon change V to M has an effect on the catalytic efficiency of this enzyme.
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Registered trials
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