Biosynthetic Origin of the Hydroxamic Acid Moiety of Trichostatin A: Identification of Unprecedented Enzymatic Machinery Involved in Hydroxylamine Transfer

Journal of the American Chemical Society
Kei KudoTomohisa Kuzuyama

Abstract

Trichostatin A (TSA) is widely used in the field of epigenetics because it potently inhibits histone deacetylase (HDAC). In-depth studies have revealed that the hydroxamic acid group in TSA chelates the zinc(II) ion in the active site of HDAC to realize the inhibitory activity. Here we report the first identification of a complete TSA biosynthetic gene cluster from Streptomyces sp. RM72 and the heterologous production of TSA in Streptomyces albus. Biochemical analyses unambiguously demonstrate that unprecedented biosynthetic machinery catalyzes the direct transfer of hydroxylamine from a nonproteinogenic amino acid, l-glutamic acid γ-monohydroxamate, to the carboxylic acid group of trichostatic acid to form the hydroxamic acid moiety of TSA. The present study establishes the biosynthetic pathway of TSA, paving the way toward understanding the biosynthesis of other hydroxamic acid-containing natural products.

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Citations

Dec 8, 2017·Nature Communications·Franziska LeipoldtLeonard Kaysser
Mar 31, 2018·Chembiochem : a European Journal of Chemical Biology·Felix WolfLeonard Kaysser
Apr 2, 2020·Angewandte Chemie·Sebastian Obermaier, Michael Müller
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Jan 14, 2021·Organic & Biomolecular Chemistry·Maogang RanQiuli Yao
Dec 6, 2020·Chemistry : a European Journal·Tomoya MiuraMasahiro Murakami
Mar 31, 2021·Nature Chemistry·Hai-Yan He, Katherine S Ryan
Dec 24, 2019·Chemical Reviews·Jason B Hedges, Katherine S Ryan

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