Enzymatic macrolactonization in the presence of DNA leading to triostin A analogs

Chemistry & Biology
Kento KoketsuHideaki Oikawa

Abstract

Excised thioesterase domains are versatile catalysts for macrocyclization. However, thioesterase-catalyzed cyclization is often precluded due to the occurrence of hydrolysis and product inhibition. To circumvent these obstacles, we devised an unprecedented strategy: coincubation with DNA to capture the cyclic products possessing DNA-binding properties. In experiments involving echinomycin thioesterase-catalyzed macrolactonization leading to the cyclic triostin A analog TANDEM, we found that the addition of DNA drastically improved the yield of TANDEM (19% --> 67%), with a complete reversal of the cyclization:hydrolysis ratio (1:2 --> 18:1). Furthermore, the applicability of this protocol was demonstrated for a variety of substrates. The results described herein provide insight into the mechanism of echinomycin thioesterase-catalyzed conversions and also pave the way for chemoenzymatic synthesis of the quinoxaline antibiotics and their analogs.

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Citations

May 14, 2014·Marine Drugs·Javier FernándezFelipe Lombó
Jul 17, 2013·Current Opinion in Chemical Biology·Michio SatoKenji Watanabe
Oct 22, 2016·Cell Chemical Biology·Jakob Franke, Christian Hertweck
Jan 19, 2016·Organic & Biomolecular Chemistry·Kozo HattoriHideko Nagasawa
Jun 26, 2010·Biopolymers·Olga E ZolovaSylvie Garneau-Tsodikova
Feb 2, 2016·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Hiroki Oguri
Jul 10, 2009·Chembiochem : a European Journal of Chemical Biology·Kenji WatanabeHideaki Oikawa
Feb 3, 2016·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Hiroki Oguri
Mar 23, 2017·Angewandte Chemie·Roderich D Süssmuth, Andi Mainz
Aug 17, 2018·Journal of the American Chemical Society·Ryo TanifujiHiroki Oguri
Jan 24, 2018·The Journal of Organic Chemistry·Dhanaraju MandalapuQi Zhang

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