Skyrud, W, Liu, J, Thankachan, D et al. (3 more authors) (2018) Biosynthesis of the 15-membered ring depsipeptide neoantimycin. ACS Chemical Biology, 13 (5). pp. 1398-1406. ISSN 1554-8929
Abstract
Antimycins are a family of natural products possessing outstanding biological activities and unique structures, which have intrigued chemists for over a half century. Of particular interest are the ring-expanded antimycins that show promising anti-cancer potential and whose biosynthesis remains uncharacterized. Specifically, neoantimycin and its analogs have been shown to be effective regulators of the oncogenic proteins GRP78/BiP and K-Ras. The neoantimycin structural skeleton is built on a 15-membered tetralactone ring containing one methyl, one hydroxy, one benzyl and three alkylmoieties, as well as an amide linkage to a conserved 3-formamidosalicylic acid moiety. Although the biosynthetic gene cluster for neoantimycins was recently identified, the enzymatic logic that governs the synthesis of neoantimycins has not yet been revealed. In this work, the neoantimycin gene cluster is identified and an updated sequence and annotation is provided delineating a non-ribosomal peptide synthetase/polyketide synthase (NRPS/PKS) hybrid scaffold. Using cosmid expression and CRISPR/Cas-based genome editing, several heterologous expression strains for neoantimycin production are constructed in two separate Streptomyces species. A combination of in vivo and in vitro analysis is further used to completely characterize the biosynthesis of neoantimycins including the megasynthases and trans-acting domains. This work establishes a set of highly tractable hosts for producing and engineering neoantimycins and their C11 oxidized analogs, paving the way for neoantimycin-based drug discovery and development.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 American Chemical Society. ACS AuthorChoice - This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. (https://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Funding Information: | Funder Grant number BBSRC BB/N007980/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Apr 2018 13:18 |
Last Modified: | 25 Apr 2019 00:39 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acschembio.8b00298 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:130177 |