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GenoChemetic Strategy for Derivatization of the Violacein Natural Product Scaffold.


ABSTRACT: Natural products and their analogues are often challenging to synthesize due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds, which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, six halogenated analogues of violacein or deoxyviolacein were generated, demonstrating the promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via the Suzuki-Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein we demonstrate a flexible and rapid approach to access a diverse chemical space that can be applied to a wide range of natural product scaffolds.

SUBMITTER: Lai HE 

PROVIDER: S-EPMC8609527 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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GenoChemetic Strategy for Derivatization of the Violacein Natural Product Scaffold.

Lai Hung-En HE   Obled Alan M C AMC   Chee Soo Mei SM   Morgan Rhodri M RM   Lynch Rosemary R   Sharma Sunil V SV   Moore Simon J SJ   Polizzi Karen M KM   Goss Rebecca J M RJM   Freemont Paul S PS  

ACS chemical biology 20211014 11


Natural products and their analogues are often challenging to synthesize due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds, which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an <i>Escherichia coli</i> st  ...[more]

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