Graduate School of Pharmaceutical Sciences , The University of Tokyo , Bunkyo-ku, Tokyo 113-0033 , Japan.
Collaborative Research Institute for Innovative Microbiology , The University of Tokyo , Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657 , Japan.
Org Lett. 2019 Apr 5;21(7):2330-2334. doi: 10.1021/acs.orglett.9b00616. Epub 2019 Mar 22.
Ascochlorin is a medicinally important fungal meroterpenoid. Its biosynthetic pathway in Fusarium sp. was identified, and the stereoselective epoxidation of the farnesyl group by the multidomain, soluble P450 monooxygenase AscE and the subsequent formation of the unique timethylcyclohexanone ring by the membrane-bound cyclase AscF were investigated. Precursor-directed biosynthesis generated novel bromo-substituted derivatives, which exhibited potent cytotoxic activities. This study paves the way for the future metabolic engineering of medicinally important meroterpenoids for drug discovery.
曲酸是一种具有重要药用价值的真菌混合萜类化合物。本文鉴定了其在镰刀菌中的生物合成途径，通过多结构域可溶性 P450 单加氧酶 AscE 对法呢基基团的立体选择性环氧化，以及膜结合环化酶 AscF 随后形成独特的三甲基环己酮环，对其进行了研究。前体定向生物合成生成了新型的溴取代衍生物，表现出很强的细胞毒性活性。本研究为未来用于药物发现的重要药用混合萜类化合物的代谢工程铺平了道路。
