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Issue 36, 2019
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Molecular basis of methylation and chain-length programming in a fungal iterative highly reducing polyketide synthase

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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.

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

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Article information


Submitted
27 Jun 2019
Accepted
28 Jul 2019
First published
30 Jul 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 8478-8489
Article type
Edge Article

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

X. Yang, S. Friedrich, S. Yin, O. Piech, K. Williams, T. J. Simpson and R. J. Cox, Chem. Sci., 2019, 10, 8478
DOI: 10.1039/C9SC03173A

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