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Publication Abstract from PubMed

Bioengineering of natural product biosynthesis is a powerful approach to expand the structural diversity of bioactive molecules. However, in polyketide biosynthesis, the modification of polyketide extender units, which form the carbon skeletons, has remained challenging. Herein, we report the rational control of polyketide extender units by the structure-based engineering of a crotonyl-CoA carboxylase/reductase (CCR), in the biosynthesis of antimycin. Site-directed mutagenesis of the CCR enzyme AntE, guided by the crystal structure solved at 1.5 A resolution, expanded its substrate scope to afford indolylmethylmalonyl-CoA by the V350G mutation. The mutant A182L selectively catalyzed carboxylation over the regular reduction. Furthermore, the combinatorial biosynthesis of heterocycle- and substituted arene-bearing antimycins was achieved by an engineered Streptomyces strain bearing AntE(V350G) . These findings deepen our understanding of the molecular mechanisms of the CCRs, which will serve as versatile biocatalysts for the manipulation of building blocks, and set the stage for the rational design of polyketide biosynthesis.

Rational Control of Polyketide Extender Units by Structure-Based Engineering of a Crotonyl-CoA Carboxylase/Reductase in Antimycin Biosynthesis.,Zhang L, Mori T, Zheng Q, Awakawa T, Yan Y, Liu W, Abe I Angew Chem Int Ed Engl. 2015 Nov 2;54(45):13462-5. doi: 10.1002/anie.201506899., Epub 2015 Sep 10. PMID:26356484^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.