A Six‐Oxidase Cascade for Tandem C−H Bond Activation Revealed by Reconstitution of Bicyclomycin Biosynthesis. (12th December 2017)

• Record Type: Journal Article
• Authors: Meng, Song; Han, Wei; Zhao, Juan; Jian, Xiao‐Hong; Pan, Hai‐Xue; Tang, Gong‐Li
• Is Part Of: Angewandte Chemie. Volume 130:Number 3(2018)
• Page Start: 727
• Page End: 731
• Publication Date: 2017-12-12
• Subjects: Bicyclomycin -- Biosynthese -- C-H-Aktivierung -- Cytochrome -- Dioxygenasen; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201710529
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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 2+ ‐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.