Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 3, Pages 719-723Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201710529
Keywords
bicyclomycin; biosynthesis; C-H bond activation; cytochromes; dioxygenases
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Funding
- National Natural Science Foundation of China [31330003, 81473124, 21621002]
- Science and Technology Commission of Shanghai Municipality [15JC1400400]
- Chinese Academy of Sciences (Youth Innovation Promotion Association) [2016235, XDB20000000]
- Chinese Academy of Sciences (K.C. Wong Education Foundation)
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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, invitro 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 alpha-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.
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