Rational
Reprogramming of <i>O</i>‑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
István Molnár
10.1021/jacs.8b12967.s001
https://acs.figshare.com/articles/journal_contribution/Rational_Reprogramming_of_i_O_i_Methylation_Regioselectivity_for_Combinatorial_Biosynthetic_Tailoring_of_Benzenediol_Lactone_Scaffolds/7776380
<i>O-</i>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 <i>O-</i>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 <i>O-</i>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.
2019-02-15 00:00:00
pharmaco
drug discovery
biosynthetic
regio
methylated benzenediol lactone polyketides
substrate
drug development
PK
Benzenediol Lactone Scaffolds O
bioactive scaffolds
Diversity-oriented combinatorial biosynthesis
Combinatorial Biosynthetic Tailoring
optimization
OMT
chemical
Methylation
structure-guided active-site cavity engineering