Article Metrics


Online attention

GenoChemetic strategy for derivatization of the violacein natural product scaffold

DOI: 10.1021/acschembio.1c00483 DOI Help

Authors: Hung-En Lai (Imperial College London) , Alan M. C. Obled (University of St Andrews) , Soo Mei Chee (Imperial College London) , Rhodri M. Morgan (Imperial College London) , Rosemary Lynch (University of St Andrews) , Sunil V. Sharma (University of St Andrews) , Simon J. Moore (Imperial College London) , Karen M. Polizzi (Imperial College London) , Rebecca J. M. Goss (University of St Andrews) , Paul S. Freemont (Imperial College London; London Biofoundry; UK DRI Care Research and Technology Centre)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 25

State: Published (Approved)
Published: October 2021
Diamond Proposal Number(s): 12579

Open Access Open Access

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.

Journal Keywords: Peptides and proteins; Monomers; Biosynthesis; Cross coupling reaction; Pharmaceuticals

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 18/10/2021 08:32


Discipline Tags:

Organic Chemistry Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)