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, Leslie Gunatilaka, Yuquan Xu, Istvan Molnar

Research output: Contribution to journalArticle

1 Citation (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 (US)
Pages (from-to)4355-4364
Number of pages10
JournalJournal of the American Chemical Society
Volume141
Issue number10
DOIs
StatePublished - Mar 13 2019

Fingerprint

Regioselectivity
Methylation
Lactones
Drug Discovery
Scaffolds
Pharmacodynamics
Pharmacokinetics
Polyketides
Methyltransferases
Enzymes
Biological Products
Pharmaceutical Preparations
Biological Availability
Catalytic Domain
Biocatalysts
Biosynthesis
Substrates
Plasticity
Molecules

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds. / Wang, Xiaojing; Wang, Chen; Duan, Lixin; Zhang, Liwen; Liu, Hang; Xu, Ya Ming; Liu, Qingpei; Mao, Tonglin; Zhang, Wei; Chen, Ming; Lin, Min; Gunatilaka, Leslie; Xu, Yuquan; Molnar, Istvan.

In: Journal of the American Chemical Society, Vol. 141, No. 10, 13.03.2019, p. 4355-4364.

Research output: Contribution to journalArticle

Wang, Xiaojing ; Wang, Chen ; Duan, Lixin ; Zhang, Liwen ; Liu, Hang ; Xu, Ya Ming ; Liu, Qingpei ; Mao, Tonglin ; Zhang, Wei ; Chen, Ming ; Lin, Min ; Gunatilaka, Leslie ; Xu, Yuquan ; Molnar, Istvan. / Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 10. pp. 4355-4364.
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