GenoChemetic strategy for derivatization of the violacein natural product scaffold

Hung-En Lai, Alan M. C. Obled, Soo Mei Chee, Rhodri M. Morgan, Rosemary Lynch, Sunil V. Sharma, Simon J. Moore, Karen M. Polizzi, Rebecca J. M. Goss, Paul S. Freemont

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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.
Original languageEnglish
Number of pages8
JournalACS Chemical Biology
VolumeArticles ASAP
Early online date14 Oct 2021
Publication statusE-pub ahead of print - 14 Oct 2021


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