Arnott, ZLP, Nozaki, S, Monteiro, DCF et al. (4 more authors) (2017) Mechanism of regulation of pantothenate biosynthesis by the PanD-PanZ.AcCoA complex reveals an additional mode of action for the antimetabolite N-pentyl pantothenamide (N5-Pan). Biochemistry, 56 (37). pp. 4931-4939. ISSN 0006-2960
Abstract
The antimetabolite pentyl pantothenamide has broad spectrum antibiotic activity but exhibits enhanced activity against Escherichia coli. The PanDZ complex has been proposed to regulate the pantothenate biosynthetic pathway in E. coli by limiting the supply of β-alanine in response to coenzyme A concentration. We show that formation of this complex between activated aspartate decarboxylase (PanD) and PanZ leads to sequestration of the pyruvoyl cofactor as a ketone hydrate and demonstrate that both PanZ overexpression-linked β-alanine auxotrophy and pentyl pantothenamide toxicity are due to formation of this complex. This both demonstrates that the PanDZ complex regulates pantothenate biosynthesis in a cellular context and validates the complex as a target for antibiotic development
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that will appear in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.7b00509. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Metabolic regulation; antimetabolites; antibiotics; vitamin biosynthesis; Pyruvoyl-dependent enzymes |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 096684/Z/11/Z Wellcome Trust 094232/Z/10/Z Wellcome Trust 105615/Z/14/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Aug 2017 09:52 |
Last Modified: | 23 Aug 2018 00:38 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.biochem.7b00509 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:120576 |