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Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling
Fatty acids are essential to most organisms and are made endogenously by the fatty acid synthase (FAS). FAS is an attractive target for antibiotics and many inhibitors are in clinical development. However, some gram-negative bacteria harbor an enzyme known as the acyl-acyl carrier protein synthetase...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575536/ https://www.ncbi.nlm.nih.gov/pubmed/33082446 http://dx.doi.org/10.1038/s41598-020-74731-4 |
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author | Currie, Madeline F. Persaud, Dylan M. Rana, Niralee K. Platt, Amanda J. Beld, Joris Jaremko, Kara L. |
author_facet | Currie, Madeline F. Persaud, Dylan M. Rana, Niralee K. Platt, Amanda J. Beld, Joris Jaremko, Kara L. |
author_sort | Currie, Madeline F. |
collection | PubMed |
description | Fatty acids are essential to most organisms and are made endogenously by the fatty acid synthase (FAS). FAS is an attractive target for antibiotics and many inhibitors are in clinical development. However, some gram-negative bacteria harbor an enzyme known as the acyl-acyl carrier protein synthetase (AasS), which allows them to scavenge fatty acids from the environment and shuttle them into FAS and ultimately lipids. The ability of AasS to recycle fatty acids may help pathogenic gram-negative bacteria circumvent FAS inhibition. We therefore set out to design and synthesize an inhibitor of AasS and test its effectiveness on an AasS enzyme from Vibrio harveyi, the most well studied AasS to date, and from Vibrio cholerae, a pathogenic model. The inhibitor C10-AMS [5′-O-(N-decanylsulfamoyl)adenosine], which mimics the tightly bound acyl-AMP reaction intermediate, was able to effectively inhibit AasS catalytic activity in vitro. Additionally, C10-AMS stopped the ability of Vibrio cholerae to recycle fatty acids from media and survive when its endogenous FAS was inhibited with cerulenin. C10-AMS can be used to study fatty acid recycling in other bacteria as more AasS enzymes continue to be annotated and provides a platform for potential antibiotic development. |
format | Online Article Text |
id | pubmed-7575536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75755362020-10-21 Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling Currie, Madeline F. Persaud, Dylan M. Rana, Niralee K. Platt, Amanda J. Beld, Joris Jaremko, Kara L. Sci Rep Article Fatty acids are essential to most organisms and are made endogenously by the fatty acid synthase (FAS). FAS is an attractive target for antibiotics and many inhibitors are in clinical development. However, some gram-negative bacteria harbor an enzyme known as the acyl-acyl carrier protein synthetase (AasS), which allows them to scavenge fatty acids from the environment and shuttle them into FAS and ultimately lipids. The ability of AasS to recycle fatty acids may help pathogenic gram-negative bacteria circumvent FAS inhibition. We therefore set out to design and synthesize an inhibitor of AasS and test its effectiveness on an AasS enzyme from Vibrio harveyi, the most well studied AasS to date, and from Vibrio cholerae, a pathogenic model. The inhibitor C10-AMS [5′-O-(N-decanylsulfamoyl)adenosine], which mimics the tightly bound acyl-AMP reaction intermediate, was able to effectively inhibit AasS catalytic activity in vitro. Additionally, C10-AMS stopped the ability of Vibrio cholerae to recycle fatty acids from media and survive when its endogenous FAS was inhibited with cerulenin. C10-AMS can be used to study fatty acid recycling in other bacteria as more AasS enzymes continue to be annotated and provides a platform for potential antibiotic development. Nature Publishing Group UK 2020-10-20 /pmc/articles/PMC7575536/ /pubmed/33082446 http://dx.doi.org/10.1038/s41598-020-74731-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Currie, Madeline F. Persaud, Dylan M. Rana, Niralee K. Platt, Amanda J. Beld, Joris Jaremko, Kara L. Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling |
title | Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling |
title_full | Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling |
title_fullStr | Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling |
title_full_unstemmed | Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling |
title_short | Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling |
title_sort | synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575536/ https://www.ncbi.nlm.nih.gov/pubmed/33082446 http://dx.doi.org/10.1038/s41598-020-74731-4 |
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