Search

Efficient synthetic techniques for the diversification of natural products are incremental for drug discovery processes of the pharmaceutical industry because these complex bioactive compounds often require an adjustment of properties. Human liver P450 3A4, key player of the body's detoxification system and decisive factor of a drug's metabolic fate, is renowned for its broad substrate scope including many natural products. In this study, we investigated the synthetic potential of human P450 3A4 for the diversification of natural product classes and isolated the produced metabolites of six selected natural products at a preparative 100‐mg scale. Aided by efficient expression levels in P. pastoris, this whole‐cell biocatalyst was found to be highly effective at the intended job allowing the identification of a total of 31 authentic human metabolites, many of them for the first time. By revealing an unprecedented degree of diversification, this study extends the synthetic repertoire for efficient enzymatic natural product modification in a one‐step fashion and adds a completely new view to an old enzyme traditionally used for inhibition and toxicology studies. [ABSTRACT FROM AUTHOR]

Keywords: biocatalysis; cytochrome P450 enzymes; drug discovery; natural product diversification; P450 3A4 EN biocatalysis cytochrome P450 enzymes drug discovery natural product diversification P450 3A4 1 1 1 01/18/22 20220110 NES 220110 B The Cover Feature b shows cytochrome P450 3A4 revealing its magic ability to diversify natural products such as nootkatone to many functionalised metabolites in one step, as illustrated by a grey butterfly transforming into coloured butterflies. Biocatalysis, cytochrome P450 enzymes, drug discovery, natural product diversification, P450 3A4 Cover Feature: Natural Product Diversification by One-Step Biocatalysis using Human P450 3A4 (ChemCatChem 1/2022). [Extracted from the article]