Unprecedented Noncanonical Features of the Nonlinear Nonribosomal Peptide Synthetase Assembly Line for WS9326A Biosynthesis

Myoun Su Kim, Munhyung Bae, Ye Eun Jung, Jung Min Kim, Sunghoon Hwang, Myoung Chong Song, Yeon Hee Ban, Eun Seo Bae, Suckchang Hong, Sang Kook Lee, Sun Shin Cha, Dong Chan Oh, Yeo Joon Yoon

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Systematic inactivation of nonribosomal peptide synthetase (NRPS) domains and translocation of the thioesterase (TE) domain revealed several unprecedented nonlinear NRPS assembly processes during the biosynthesis of the cyclodepsipeptide WS9326A in Streptomyces sp. SNM55. First, two sets of type ΙΙ TE (TEΙΙ)-like enzymes mediate the shuttling of activated amino acids between two sets of stand-alone adenylation (A)-thiolation (T) didomain modules and an “A-less” condensation (C)-T module with distinctive specificities and flexibilities. This was confirmed by the elucidation of the affinities of the A-T didomains for the TEΙΙs and its structure. Second, the C-T didomain module operates iteratively and independently from other modules in the same protein to catalyze two chain elongation cycles. Third, this biosynthetic pathway includes the first example of module skipping, where the interpolated C and T domains are required for chain transfer.

Original languageEnglish
Pages (from-to)19766-19773
Number of pages8
JournalAngewandte Chemie - International Edition
Volume60
Issue number36
DOIs
StatePublished - 1 Sep 2021

Bibliographical note

Funding Information:
This work was supported by the Collaborative Genome Program of the Korea Institute of Marine Science and Technology Promotion (KIMST) (No. 20180430) and the project titled “Development of potential antibiotic compounds using polar organism resources (15250103, KOPRI Grant PM21030)” funded by the Ministry of Oceans and Fisheries (MOF), the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT (MSIT) (2019R1A2B5B03069338 and 2021R1A4A2001251), the Bio & Medical Technology Development Program of the NRF funded by the MSIT (2018M3A9F3079662), Republic of Korea. We thank the staff of beamlines at the Pohang Light Source (Republic of Korea) for the help with data collection.

Publisher Copyright:
© 2021 Wiley-VCH GmbH

Keywords

  • biosynthesis
  • module iteration
  • module skipping
  • nonribosomal peptide synthetase
  • shuttling thioesterase

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