Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan.
J Am Chem Soc. 2021 Jan 13;143(1):132-136. doi: 10.1021/jacs.0c12352. Epub 2020 Dec 29.
We report characterization of the biosynthetic pathway of the potent immunosuppressant (-)-FR901483 () through heterologous expression and enzymatic assays. The biosynthetic logic to form the azatricyclic alkaloid is consistent with those proposed in biomimetic syntheses and involves aza-spiro annulation of dityrosyl-piperazine to form a ketoaldehyde intermediate, followed by regioselective aldol condensation, stereoselective ketoreduction, and phosphorylation. A possible target of is proposed based on the biosynthetic studies.
我们通过异源表达和酶促反应研究，对强效免疫抑制剂（-）-FR901483（）的生物合成途径进行了表征。形成氮杂三环生物碱的生物合成逻辑与仿生合成中提出的逻辑一致，涉及二酪氨酸-哌嗪的氮杂螺环化形成酮醛中间体，然后进行区域选择性羟醛缩合、立体选择性酮还原和磷酸化。根据生物合成研究，提出了一个可能的（-）-FR901483 的靶标。
