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

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posted on 2019-02-15, 00:00 authored by 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, István Molnár
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.

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