A Six-Oxidase Cascade for Tandem C-H Bond Activation Revealed by Reconstitution of Bicyclomycin Biosynthesis
A Six-Oxidase Cascade for Tandem C-H Bond Activation Revealed by Reconstitution of Bicyclomycin Biosynthesis
复制标题
双环霉素生物合成重建揭示了串联 C-H 键激活的六氧化酶级联。
DOI：
10.1002/anie.201710529
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发表时间：
2018-01-15
影响因子：
16.6
通讯作者：
Tang, Gong-Li
中科院分区：
文献类型：
--
作者：
Meng, Song;Han, Wei;Tang, Gong-Li
作为一种商业抗生素，双环霉素（bicyclomycin，Bicyclomycin）是目前已知的唯一靶向转录终止因子rho的天然产物。它属于高度官能化的二酮哌嗪（DKP）生物碱家族，具有独特的O-桥连双环[4.2.2]哌嗪二酮环系统、C1三醇和末端外亚甲基。我们已经通过异源生物转化、体外生物化学测定和一锅酶促合成确定并表征了β-内酰胺生物合成途径。 依赖于tRNA的环二肽合酶引导亮氨酸和异亮氨酸的异二聚化以提供DKP前体;随后，六种氧化还原酶，包括五种α-酮戊二酸/Fe 2+依赖性双加氧酶和一种细胞色素P450单加氧酶，区域和立体选择性地安装四个羟基（伯、仲和两个叔）、外亚甲基部分和通过八个未活化的C-H键的官能化的中等大小的桥环。
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/Fe2+ -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.