A Six‐Oxidase Cascade for Tandem C−H Bond Activation Revealed by Reconstitution of Bicyclomycin Biosynthesis. Issue 3 (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 international edition. Volume 57:Issue 3(2018)
• Page Start: 719
• Page End: 723
• Publication Date: 2017-12-12
• Subjects: bicyclomycin -- biosynthesis -- C−H bond activation -- cytochromes -- dioxygenases; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201710529
• Languages: English
• ISSNs: 1433-7851

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. Abstract : Enzymatic characterization of the biosynthesis of the antibiotic bicyclomycin revealed a tRNA‐dependent cyclodipeptide synthase for the heterodimerization of Leu and Ile to afford the diketopiperazine precursor. Subsequently, six redox enzymes activate eight unactivated C−H bonds through regio‐ and stereoselective hydroxylation, alkenylation, heterocyclization, and desaturation/epoxidation.