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Rational Reprogramming of O‑Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds
journal contribution
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 MolnárO-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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pharmacodrug discoverybiosyntheticregiomethylated benzenediol lactone polyketidessubstratedrug developmentPKBenzenediol Lactone Scaffolds Obioactive scaffoldsDiversity-oriented combinatorial biosynthesisCombinatorial Biosynthetic TailoringoptimizationOMTchemicalMethylationstructure-guided active-site cavity engineering
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