State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
Angew Chem Int Ed Engl. 2018 Jan 15;57(3):719-723. doi: 10.1002/anie.201710529. Epub 2017 Dec 12.
As a commercial antibiotic, bicyclomycin (BCM) is currently the only known natural product targeting the transcription termination factor rho. It belongs to a family of highly functionalized diketopiperazine (DKP) alkaloids and bears a unique O-bridged bicyclo[4.2.2]piperazinedione ring system, a C1 triol, and terminal exo-methylene groups. We have identified and characterized the BCM biosynthetic pathway by heterologous biotransformations, in vitro biochemical assays, and one-pot enzymatic synthesis. A tRNA-dependent cyclodipeptide synthase guides the heterodimerization of leucine and isoleucine to afford the DKP precursor; subsequently, six redox enzymes, including five α-ketoglutarate/Fe -dependent dioxygenases and one cytochrome P450 monooxygenase, regio- and stereoselectively install four hydroxy groups (primary, secondary, and two tertiary), an exo-methylene moiety, and a medium-sized bridged ring through the functionalization of eight unactivated C-H bonds.
作为一种商业抗生素，双环霉素（BCM）是目前唯一已知的靶向转录终止因子 rho 的天然产物。它属于高度功能化二酮哌嗪（DKP）生物碱家族，具有独特的 O-桥联二环[4.2.2]哌嗪二酮环系统、C1 三醇和末端外亚甲基基团。我们通过异源生物转化、体外生化测定和一锅酶合成鉴定并表征了 BCM 的生物合成途径。一种依赖 tRNA 的环二肽合酶指导亮氨酸和异亮氨酸的杂二聚化，生成 DKP 前体；随后，六个氧化还原酶，包括五个 α-酮戊二酸/Fe 依赖性双加氧酶和一个细胞色素 P450 单加氧酶，通过对八个未激活的 C-H 键的功能化，区域和立体选择性地安装四个羟基（伯、仲和两个叔）、一个外亚甲基部分和一个中桥环。
