Enzymatic basis of "hybridity" in thiomarinol biosynthesis

Angewandte Chemie
Zachary D DunnBo Li

Abstract

Thiomarinol is a naturally occurring double-headed antibiotic that is highly potent against methicillin-resistant Staphylococcus aureus. Its structure comprises two antimicrobial subcomponents, pseudomonic acid analogue and holothin, linked by an amide bond. TmlU was thought to be the sole enzyme responsible for this amide-bond formation. In contrast to this idea, we show that TmlU acts as a CoA ligase that activates pseudomonic acid as a thioester that is processed by the acetyltransferase HolE to catalyze the amidation. TmlU prefers complex acyl acids as substrates, whereas HolE is relatively promiscuous, accepting a range of acyl-CoA and amine substrates. Our results provide detailed biochemical information on thiomarinol biosynthesis, and evolutionary insight regarding how the pseudomonic acid and holothin pathways converge to generate this potent hybrid antibiotic. This work also demonstrates the potential of TmlU/HolE enzymes as engineering tools to generate new "hybrid" molecules.

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Citations

Mar 29, 2016·Biochemical and Biophysical Research Communications·Ying ZhaiJing He
Apr 21, 2017·ACS Chemical Biology·Sheng WuGong-Li Tang
May 23, 2017·Natural Product Reports·P Klahn, M Brönstrup
Dec 23, 2015·Natural Product Reports·Eric J N Helfrich, Jörn Piel
Oct 16, 2019·Chembiochem : a European Journal of Chemical Biology·Katherine J PicottAvena C Ross
Feb 18, 2017·Proceedings of the National Academy of Sciences of the United States of America·Andrew N ChanBo Li
Nov 21, 2020·Organic & Biomolecular Chemistry·Jamshid Amiri MoghaddamChristine Beemelmanns
Jul 10, 2019·Journal of Molecular Biology·Timothy A Wencewicz
Aug 4, 2021·Journal of the American Chemical Society·Rachel A JohnsonBo Li
Dec 14, 2018·Chemical Research in Toxicology·Andrew N ChanBo Li

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