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Molecular basis of methylation and chain-length programming in a fungal iterative highly reducing polyketide synthase

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)8478-8489
JournalChemical Science
Volume10
Issue number36
DOIs
DateAccepted/In press - 28 Jul 2019
DatePublished (current) - 30 Jul 2019

Abstract

Exchange of 32 different sub-fragments of the C-methyltransferase (C-MeT), pseudo-ketoreductase (ΨKR) and ketoreductase (KR) catalytic domains of the tenellin iterative Type I polyketide synthase non ribosomal peptide synthetase (PKS-NRPS) TENS by homologous fragments from the desmethylbassianin (DMBS) and militarinone (MILS) PKS-NRPS led to the creation of chimeric synthetases in which programming fidelity was altered, resulting in the production of mixtures of products with different methylation patterns and chain lengths. Swap of KR domain subfragments with the homologous fragments from the KR of the heptaketide militarinone synthetase resulted in the synthesis of penta, hexa and heptaketides. The results of these and previous experiments are rationalised by considering the existence of competition for acyl-carrier protein (ACP) bound substrates between different catalytic domains of the PKS. In particular, competition between the C-MeT and ketoreductase domains (KR) can account for methylation programming, and competition between the KR and the off-loading NRPS accounts for chain-length selectivity.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Royal Society of Chemistry at https://doi.org/10.1039/C9SC03173A . Please refer to any applicable terms of use of the publisher.

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