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Expanding the diversity of plant monoterpenoid indole alkaloids employing human cytochrome P450 3A4.

Sheludko, Yuriy and Volk, Jascha and Brandt, Wolfgang and Warzecha, Heribert (2020):
Expanding the diversity of plant monoterpenoid indole alkaloids employing human cytochrome P450 3A4.
In: Chembiochem : a European journal of chemical biology, ISSN 1439-7633,
DOI: 10.1002/cbic.202000020,
[Article]

Abstract

Human drug-metabolizing cytochrome P450 monooxygenases (CYPs) feature enormous substrate promiscuity, making them promising tools for the expansion of natural product diversity. Here, we utilized CYP3A4 for the targeted diversification of a plant biosynthetic route leading to monoterpenoid indole alkaloids. In-silico, in vitro and in planta studies proved that CYP3A4 was able to convert the indole alkaloid vinorine into vomilenine, the former being one of the central intermediates in the ajmaline pathway in the medicinal plant Rauvolfia serpentina (L.) Benth. ex Kurz. However, to a much larger extent, the investigated conversion yielded vinorine (19 R , 20 R) -epoxide, a new metabolite containing an epoxide functional group that is rare for indole alkaloids. The described work represents a successful example of combinatorial biosynthesis towards an increase in biodiversity of natural metabolites. Besides, characterisation of the products of in vitro and in planta transformation of potential pharmaceuticals with human CYPs might be indicative of the way of their conversion in the human organism.

Item Type: Article
Erschienen: 2020
Creators: Sheludko, Yuriy and Volk, Jascha and Brandt, Wolfgang and Warzecha, Heribert
Title: Expanding the diversity of plant monoterpenoid indole alkaloids employing human cytochrome P450 3A4.
Language: English
Abstract:

Human drug-metabolizing cytochrome P450 monooxygenases (CYPs) feature enormous substrate promiscuity, making them promising tools for the expansion of natural product diversity. Here, we utilized CYP3A4 for the targeted diversification of a plant biosynthetic route leading to monoterpenoid indole alkaloids. In-silico, in vitro and in planta studies proved that CYP3A4 was able to convert the indole alkaloid vinorine into vomilenine, the former being one of the central intermediates in the ajmaline pathway in the medicinal plant Rauvolfia serpentina (L.) Benth. ex Kurz. However, to a much larger extent, the investigated conversion yielded vinorine (19 R , 20 R) -epoxide, a new metabolite containing an epoxide functional group that is rare for indole alkaloids. The described work represents a successful example of combinatorial biosynthesis towards an increase in biodiversity of natural metabolites. Besides, characterisation of the products of in vitro and in planta transformation of potential pharmaceuticals with human CYPs might be indicative of the way of their conversion in the human organism.

Journal or Publication Title: Chembiochem : a European journal of chemical biology
Divisions: 10 Department of Biology
10 Department of Biology > Plant Biotechnology and Metabolic Engineering
Date Deposited: 25 Mar 2020 07:53
DOI: 10.1002/cbic.202000020
Identification Number: pmid:32181956
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