Synthetic chain terminators off-load intermediates from a type I polyketide synthase

Chembiochem : a European Journal of Chemical Biology
Manuela TosinPeter F Leadlay

Abstract

Modular biocatalysis is responsible for the generation of countless bioactive products and its mining remains a major focus for drug discovery purposes. One of the enduring hurdles is the isolation of biosynthetic intermediates in a readily-analysed form. We prepared a series of nonhydrolysable pantetheine and N-acetyl cysteamine mimics of the natural (methyl)malonyl extender units recruited for polyketide formation. Using these analogues as competitive substrates, we were able to trap and off-load diketide and triketide species directly from an in vitro reconstituted type I polyketide synthase, the 6-deoxyerythronolide B synthase 3 (DEBS3). The putative intermediates, which were extracted in organic solvent and characterised by LC-HR-ESI-MS, are the first of their kind and prove that small-molecule chain terminators can be used as convenient probes of the biosynthetic process.

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Citations

Jan 30, 2013·Journal of the American Chemical Society·Zhizeng GaoJohn C Vederas
Jul 9, 2013·The Journal of Organic Chemistry·Jianli DuanXuechuan Hong
Feb 3, 2016·Angewandte Chemie·James S ParascandoloManuela Tosin
Aug 2, 2016·Angewandte Chemie·James S ParascandoloManuela Tosin
Mar 3, 2015·Journal of the American Chemical Society·Douglas A HansenDavid H Sherman
Apr 8, 2011·Chembiochem : a European Journal of Chemical Biology·Olivia VergnolleJennifer N Andexer
Oct 26, 2011·Angewandte Chemie·Manuela TosinPeter F Leadlay
Sep 13, 2014·Angewandte Chemie·Elena RivaManuela Tosin
Oct 22, 2016·Cell Chemical Biology·Jakob Franke, Christian Hertweck
Jan 27, 2017·Chemical Communications : Chem Comm·Marie E YurkovichPeter F Leadlay
Jan 26, 2017·Chemical Communications : Chem Comm·Judith HavemannManuela Tosin
Jun 20, 2017·Chemical Communications : Chem Comm·Y T Candace HoManuela Tosin
May 16, 2019·Organic & Biomolecular Chemistry·Marius GroteFrank Schulz
Oct 17, 2019·Chemistry : a European Journal·Samantha L KilgourManuela Tosin
Mar 21, 2020·ACS Chemical Biology·Renata SigristLuciana Gonzaga de Oliveira

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