Stereochemical Dissection of the Strobilurin PKS Reveals the Complex Biosynthetic Logic of Iterative EZE Triene Construction
Maurice Hauser, Jing Pang, Daowan Lai, Yunlong Sun, Hao Yao, Russell J. Cox
TL;DR
This paper reveals how a single enzyme in the strobilurin PKS can change its stereoselectivity to build a complex EZE triene structure.
Contribution
The study provides the first detailed stereochemical dissection of a highly reducing iterative Type I PKS.
Findings
The strobilurin PKS uses flexible stereoselectivities to produce an EZE triene.
2R-methylation of the triketide leads to a Z-alkene via unusual stereochemical transformations.
The PKS's selectivities differ from those of cis-AT modular PKS β-processing enzymes.
Abstract
Type I Iterative polyketide synthases (PKS) use a limited set of catalytic extension and β‐processing domains to create complex polyketides. A remarkable case is that of the strobilurin PKS where a single dehydratase (DH) domain creates an EZE triene over three dehydration cycles. Here we dissect the strobilurin PKS and assay catalytic domains individually and in combination with stereo‐defined synthetic substrates in vitro, to reveal the complex and varying selectivities of methylation, ketoreduction and dehydration that lead to this remarkable result. At the diketide stage all stereoselectivities are consistent with those known for other related systems, giving an E product. But at the triketide stage, 2R‐methylation is selectively achieved, that is followed by rapid keto‐reduction to give an unusual 3‐L‐alcohol. In‐turn, this is eliminated to give the unusual Z‐alkene. These…
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Taxonomy
TopicsMicrobial Natural Products and Biosynthesis · Enzyme Structure and Function · Carbohydrate Chemistry and Synthesis