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© 2020, The Author(s). Complex polyketides of bacterial origin are biosynthesised by giant assembly-line like megaenzymes of the type 1 modular polyketide synthase (PKS) class. The trans-AT family of modular PKSs, whose biosynthetic frameworks diverge significantly from those of the archetypal cis-AT type systems represent a new paradigm in natural product enzymology. One of the most distinctive enzymatic features common to trans-AT PKSs is their ability to introduce methyl groups at positions β to the thiol ester in the growing polyketide chain. This activity is achieved through the action of a five protein HCS cassette, comprising a ketosynthase, a 3-hydroxy-3-methylglutaryl-CoA synthase, a dehydratase, a decarboxylase and a dedicated acyl carrier protein. Here we report a molecular level description, achieved using a combination of X-ray crystallography, in vitro enzyme assays and site-directed mutagenesis, of the bacillaene synthase dehydratase/decarboxylase enzyme couple PksH/PksI, responsible for the final two steps in β-methyl branch installation in this trans-AT PKS. Our work provides detailed mechanistic insight into this biosynthetic peculiarity and establishes a molecular framework for HCS cassette enzyme exploitation and manipulation, which has future potential value in guiding efforts in the targeted synthesis of functionally optimised ‘non-natural’ natural products.
Author(s): Nair AV, Robson A, Ackrill TD, Till M, Byrne MJ, Back CR, Tiwari K, Davies JA, Willis CL, Race PR
Publication type: Article
Publication status: Published
Journal: Scientific Reports
Year: 2020
Volume: 10
Issue: 1
Online publication date: 18/09/2020
Acceptance date: 30/07/2020
ISSN (electronic): 2045-2322
Publisher: Nature Research
URL: https://doi.org/10.1038/s41598-020-71850-w
DOI: 10.1038/s41598-020-71850-w
PubMed id: 32948786
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