Structural Characterization and Extended Substrate Scope Analysis of Two Mg2+‐Dependent O‐Methyltransferases from Bacteria**

Author:

Sokolova Nika1ORCID,Zhang Lili2,Deravi Sadaf1,Oerlemans Rick2ORCID,Groves Matthew R.2ORCID,Haslinger Kristina1ORCID

Affiliation:

1. Department of Chemical and Pharmaceutical Biology University of Groningen Antonius Deusinglaan 1 9731AV Groningen The Netherlands

2. XB20 Department of Drug Design University of Groningen Antonius Deusinglaan 1 9731AV Groningen The Netherlands

Abstract

AbstractOxygen‐directed methylation is a ubiquitous tailoring reaction in natural product pathways catalysed by O‐methyltransferases (OMTs). Promiscuous OMT biocatalysts are thus a valuable asset in the toolkit for sustainable synthesis and optimization of known bioactive scaffolds for drug development. Here, we characterized the enzymatic properties and substrate scope of two bacterial OMTs from Desulforomonas acetoxidans and Streptomyces avermitilis and determined their crystal structures. Both OMTs methylated a wide range of catechol‐like substrates, including flavonoids, coumarins, hydroxybenzoic acids, and their respective aldehydes, an anthraquinone and an indole. One enzyme also accepted a steroid. The product range included pharmaceutically relevant compounds such as (iso)fraxidin, iso(scopoletin), chrysoeriol, alizarin 1‐methyl ether, and 2‐methoxyestradiol. Interestingly, certain non‐catechol flavonoids and hydroxybenzoic acids were also methylated. This study expands the knowledge on substrate preference and structural diversity of bacterial catechol OMTs and paves the way for their use in (combinatorial) pathway engineering.

Funder

H2020 Marie Skłodowska-Curie Actions

Publisher

Wiley

Subject

Organic Chemistry,Molecular Biology,Molecular Medicine,Biochemistry

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