ChemCatChem (1/2022) Cover Feature: Natural Product Diversification by One-Step Biocatalysis using Human P450 3A4


In this study, the synthetic potential of human cytochrome P450 3A4 as a Pichia pastoris-based whole-cell biocatalyst for the diversification of natural products was successfully explored.

In this article, N.D. Fessner et al. investigated the potential of human P450 CYP3A4 for diversification of several compounds belonging to a variety of different natural product classes such as terpenes, alkaloids, stilbenoids, steroids and flavonoids. The human P450 CYP3A4 is expressed in the human liver and plays a decisive role in the body’s detoxification system. It’s responsible for the detoxification of up to 50% of all FDA approved drugs. Efficient expression of this highly promiscuous enzyme in the yeast Komagataella phaffi (Pichia pastoris), produced an efficient whole-cell biocatalyst. 31 different authentic human metabolites were identified, many of them for the first time, and 6 were produced at 100 mg scale. This unprecedented degree of diversification extends the repertoire of efficient enzymatic natural product modification adding a new dimension to an enzyme that has previously been used primarily for inhibition and toxicology studies.

This work has received funding from European Union’s Horizon 2020 research and innovation programme, OXYtrain MSCA-ITN, under grant agreement No 722390. This article was supported by TU Graz Open Access Publishing Fund.

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Fessner, N.D., Grimm, C., Srdič, M., Kroutil, W., Schwaneberg, U., and Glieder, A. (2021), Natural Product Diversification by One-Step Biocatalysis using Human P450 3A4. ChemCatChem, Published manuscript.

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