Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds

Xiaojing Wang, Chen Wang, Lixin Duan, Liwen Zhang, Hang Liu, Ya Ming Xu, Qingpei Liu, Tonglin Mao, Wei Zhang, Ming Chen, Min Lin, A. A.Leslie Gunatilaka, Yuquan Xu (Corresponding Author), István Molnár (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

12 Citations (Scopus)

Abstract

O-Methylation modulates the pharmacokinetic and pharmacodynamic (PK/PD) properties of small-molecule natural products, affecting their bioavailability, stability, and binding to targets. Diversity-oriented combinatorial biosynthesis of new chemical entities for drug discovery and optimization of known bioactive scaffolds during drug development both demand efficient O-methyltransferase (OMT) biocatalysts with considerable substrate promiscuity and tunable regioselectivity that can be deployed in a scalable and sustainable manner. Here we demonstrate efficient total biosynthetic and biocatalytic platforms that use a pair of fungal OMTs with orthogonal regiospecificity to produce unnatural O-methylated benzenediol lactone polyketides. We show that rational, structure-guided active-site cavity engineering can reprogram the regioselectivity of these enzymes. We also characterize the interplay of engineered regioselectivity with substrate plasticity. These findings will guide combinatorial biosynthetic tailoring of unnatural products toward the generation of diverse chemical matter for drug discovery and the PK/PD optimization of bioactive scaffolds for drug development.

Original languageEnglish
Pages (from-to)4355-4364
Number of pages10
JournalJournal of the American Chemical Society
Volume141
Issue number10
DOIs
Publication statusPublished - 13 Mar 2019
MoE publication typeA1 Journal article-refereed

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