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Structure–Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family
[Image: see text] The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca(2+)-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are i...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498158/ https://www.ncbi.nlm.nih.gov/pubmed/32787138 http://dx.doi.org/10.1021/acs.jmedchem.0c00522 |
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author | Zhou, Juan Mock, Elliot D. Al Ayed, Karol Di, Xinyu Kantae, Vasudev Burggraaff, Lindsey Stevens, Anna F. Martella, Andrea Mohr, Florian Jiang, Ming van der Wel, Tom Wendel, Tiemen J. Ofman, Tim P. Tran, Yvonne de Koster, Nicky van Westen, Gerard J.P. Hankemeier, Thomas van der Stelt, Mario |
author_facet | Zhou, Juan Mock, Elliot D. Al Ayed, Karol Di, Xinyu Kantae, Vasudev Burggraaff, Lindsey Stevens, Anna F. Martella, Andrea Mohr, Florian Jiang, Ming van der Wel, Tom Wendel, Tiemen J. Ofman, Tim P. Tran, Yvonne de Koster, Nicky van Westen, Gerard J.P. Hankemeier, Thomas van der Stelt, Mario |
author_sort | Zhou, Juan |
collection | PubMed |
description | [Image: see text] The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca(2+)-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs. |
format | Online Article Text |
id | pubmed-7498158 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-74981582020-09-18 Structure–Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family Zhou, Juan Mock, Elliot D. Al Ayed, Karol Di, Xinyu Kantae, Vasudev Burggraaff, Lindsey Stevens, Anna F. Martella, Andrea Mohr, Florian Jiang, Ming van der Wel, Tom Wendel, Tiemen J. Ofman, Tim P. Tran, Yvonne de Koster, Nicky van Westen, Gerard J.P. Hankemeier, Thomas van der Stelt, Mario J Med Chem [Image: see text] The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca(2+)-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs. American Chemical Society 2020-08-02 2020-09-10 /pmc/articles/PMC7498158/ /pubmed/32787138 http://dx.doi.org/10.1021/acs.jmedchem.0c00522 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. |
spellingShingle | Zhou, Juan Mock, Elliot D. Al Ayed, Karol Di, Xinyu Kantae, Vasudev Burggraaff, Lindsey Stevens, Anna F. Martella, Andrea Mohr, Florian Jiang, Ming van der Wel, Tom Wendel, Tiemen J. Ofman, Tim P. Tran, Yvonne de Koster, Nicky van Westen, Gerard J.P. Hankemeier, Thomas van der Stelt, Mario Structure–Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family |
title | Structure–Activity
Relationship Studies of
α-Ketoamides as Inhibitors of the Phospholipase A and
Acyltransferase Enzyme Family |
title_full | Structure–Activity
Relationship Studies of
α-Ketoamides as Inhibitors of the Phospholipase A and
Acyltransferase Enzyme Family |
title_fullStr | Structure–Activity
Relationship Studies of
α-Ketoamides as Inhibitors of the Phospholipase A and
Acyltransferase Enzyme Family |
title_full_unstemmed | Structure–Activity
Relationship Studies of
α-Ketoamides as Inhibitors of the Phospholipase A and
Acyltransferase Enzyme Family |
title_short | Structure–Activity
Relationship Studies of
α-Ketoamides as Inhibitors of the Phospholipase A and
Acyltransferase Enzyme Family |
title_sort | structure–activity
relationship studies of
α-ketoamides as inhibitors of the phospholipase a and
acyltransferase enzyme family |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498158/ https://www.ncbi.nlm.nih.gov/pubmed/32787138 http://dx.doi.org/10.1021/acs.jmedchem.0c00522 |
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