Fazal, A, Hemsworth, GR orcid.org/0000-0002-8226-1380, Webb, ME orcid.org/0000-0003-3574-4686 et al. (1 more author) (2021) A standalone β-ketoreductase acts concomitantly with biosynthesis of the antimycin scaffold. ACS Chemical Biology, 16 (7). pp. 1152-1158. ISSN 1554-8929
Abstract
Antimycins are anticancer compounds produced by a hybrid nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS) pathway. The biosynthesis of these compounds is well characterized, with the exception of the standalone β-ketoreductase enzyme AntM that is proposed to catalyze the reduction of the C8 carbonyl of the antimycin scaffold. Inactivation of antM and structural characterization suggested that rather than functioning as a post-PKS tailoring enzyme, AntM acts upon the terminal biosynthetic intermediate while it is tethered to the PKS acyl carrier protein. Mutational analysis identified two amino acid residues (Tyr185 and Phe223) that are proposed to serve as checkpoints controlling substrate access to the AntM active site. Aromatic checkpoint residues are conserved in uncharacterized standalone β-ketoreductases, indicating that they may also act concomitantly with synthesis of the scaffold. These data provide novel mechanistic insights into the functionality of standalone β-ketoreductases and will enable their reprogramming for combinatorial biosynthesis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 American Chemical Society. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Molecular Microbiology (Leeds) |
Funding Information: | Funder Grant number BBSRC (Biotechnology & Biological Sciences Research Council) BB/N019970/1 BBSRC (Biotechnology & Biological Sciences Research Council) BB/T008075/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 May 2021 16:12 |
Last Modified: | 30 Nov 2021 09:52 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acschembio.1c00229 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:174128 |