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A Six‐Oxidase Cascade for Tandem C−H Bond Activation Revealed by Reconstitution of Bicyclomycin Biosynthesis
Author(s) -
Meng Song,
Han Wei,
Zhao Juan,
Jian XiaoHong,
Pan HaiXue,
Tang GongLi
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201710529
Subject(s) - moiety , stereochemistry , chemistry , biosynthesis , enzyme , ring (chemistry) , monooxygenase , cofactor , heterologous expression , biochemistry , natural product , cytochrome p450 , recombinant dna , gene , organic chemistry
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.