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Exploring Fungal Polyketide C-Methylation through Combinatorial Domain Swaps.

ABSTRACT: Polyketide C-methylation occurs during a programmed sequence of dozens of reactions carried out by multidomain polyketide synthases (PKSs). Fungal PKSs perform these reactions iteratively, where a domain may be exposed to and act upon multiple enzyme-tethered intermediates during biosynthesis. We surveyed a collection of C-methyltransferase (CMeT) domains from nonreducing fungal PKSs to gain insight into how different methylation patterns are installed. Our in vitro results show that control of methylation resides primarily with the CMeT, and CMeTs can intercept and methylate intermediates from noncognate nonreducing PKS domains. Furthermore, the methylation pattern is likely imposed by a competition between methylation or ketosynthase-catalyzed extension for each intermediate. Understanding site-specific polyketide C-methylation may facilitate targeted C-C bond formation in engineered biosynthetic pathways.

SUBMITTER: Storm PA

PROVIDER: S-EPMC6855380 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Exploring Fungal Polyketide C-Methylation through Combinatorial Domain Swaps.

Storm Philip A PA Pal Paramita P Huitt-Roehl Callie R CR Townsend Craig A CA

ACS chemical biology 20181030 11

Polyketide C-methylation occurs during a programmed sequence of dozens of reactions carried out by multidomain polyketide synthases (PKSs). Fungal PKSs perform these reactions iteratively, where a domain may be exposed to and act upon multiple enzyme-tethered intermediates during biosynthesis. We surveyed a collection of C-methyltransferase (CMeT) domains from nonreducing fungal PKSs to gain insight into how different methylation patterns are installed. Our in vitro results show that control of ...[more]

PMID: 30350943

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