Format

Send to

Choose Destination
ACS Chem Biol. 2017 Sep 15;12(9):2379-2387. doi: 10.1021/acschembio.7b00470. Epub 2017 Aug 21.

Baeyer-Villiger Monooxygenase FMO5 as Entry Point in Drug Metabolism.

Author information

1
Austrian Centre of Industrial Biotechnology, c/o Department of Chemistry, University of Graz , Heinrichstrasse 28, 8010 Graz, Austria.
2
Department of Biology and Biotechnology, University of Pavia , via Ferrata 9, 27100 Pavia, Italy.
3
Molecular Enzymology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen , Nijenborgh 4, 9747 AG, Groningen, Netherlands.
4
Department of Chemistry, University of Graz , Heinrichstrasse 28, 8010 Graz, Austria.

Abstract

Flavin-containing monooxygenases (FMOs) are emerging as effective players in oxidative drug metabolism. Until recently, the functions of the five human FMO isoforms were mostly linked to their capability of oxygenating molecules containing soft N- and S-nucleophiles. However, the human FMO isoform 5 was recently shown to feature an atypical activity as Baeyer-Villiger monooxygenase. With the aim of evaluating such an alternative entry point in the metabolism of active pharmaceutical ingredients, we selected and tested drug molecules bearing a carbonyl group on an aliphatic chain. Nabumetone and pentoxifylline, two widely used pharmaceuticals, were thereby demonstrated to be efficiently oxidized in vitro by FMO5 to the corresponding acetate esters with high selectivity. The proposed pathways explain the formation of a predominant plasma metabolite of pentoxifylline as well as the crucial transformation of the pro-drug nabumetone into the pharmacologically active compound. Using the recombinant enzyme, the ester derivatives of both drugs were obtained in milligram amounts, purified, and fully characterized. This protocol can potentially be extended to other FMO5 candidate substrates as it represents an effective and robust bench-ready platform applicable to API screening and metabolite synthesis.

PMID:
28783300
DOI:
10.1021/acschembio.7b00470
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center