Biotechnology Research Center, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
National Institute of Advanced Industrial Science and Technology , 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
J Am Chem Soc. 2017 May 24;139(20):6799-6802. doi: 10.1021/jacs.7b02071. Epub 2017 May 12.
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.
曲古抑菌素 A（TSA）因能强力抑制组蛋白去乙酰化酶（HDAC）而被广泛应用于表观遗传学领域。深入的研究揭示 TSA 中的羟肟酸基团与 HDAC 的活性位点中的锌(II)离子螯合，从而实现抑制活性。在此，我们首次从链霉菌属 RM72 中鉴定出一个完整的 TSA 生物合成基因簇，并在白色链霉菌中异源生产 TSA。生化分析明确表明，前所未有的生物合成机制催化羟胺直接从非蛋白氨基酸 l-谷氨酸γ-单羟肟酸转移到曲古抑菌酸的羧酸基团上，形成 TSA 的羟肟酸部分。本研究建立了 TSA 的生物合成途径，为理解其他含羟肟酸的天然产物的生物合成铺平了道路。
