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The 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)
[Image: see text] 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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724930/ https://www.ncbi.nlm.nih.gov/pubmed/28832133 http://dx.doi.org/10.1021/acs.biochem.7b00509 |
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author | Arnott, Zoe L. P. Nozaki, Shingo Monteiro, Diana C. F. Morgan, Holly E. Pearson, Arwen R. Niki, Hironori Webb, Michael E. |
author_facet | Arnott, Zoe L. P. Nozaki, Shingo Monteiro, Diana C. F. Morgan, Holly E. Pearson, Arwen R. Niki, Hironori Webb, Michael E. |
author_sort | Arnott, Zoe L. P. |
collection | PubMed |
description | [Image: see text] 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 such a 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. |
format | Online Article Text |
id | pubmed-5724930 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-57249302017-12-12 The 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) Arnott, Zoe L. P. Nozaki, Shingo Monteiro, Diana C. F. Morgan, Holly E. Pearson, Arwen R. Niki, Hironori Webb, Michael E. Biochemistry [Image: see text] 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 such a 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. American Chemical Society 2017-08-23 2017-09-19 /pmc/articles/PMC5724930/ /pubmed/28832133 http://dx.doi.org/10.1021/acs.biochem.7b00509 Text en Copyright © 2017 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Arnott, Zoe L. P. Nozaki, Shingo Monteiro, Diana C. F. Morgan, Holly E. Pearson, Arwen R. Niki, Hironori Webb, Michael E. The 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) |
title | The 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) |
title_full | The 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) |
title_fullStr | The 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) |
title_full_unstemmed | The 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) |
title_short | The 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) |
title_sort | 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) |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724930/ https://www.ncbi.nlm.nih.gov/pubmed/28832133 http://dx.doi.org/10.1021/acs.biochem.7b00509 |
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