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Bestatin is a non-competitive inhibitor of porcine M1 family glutamyl aminopeptidase: Insights for selective inhibitor design

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Title Statement Bestatin is a non-competitive inhibitor of porcine M1 family glutamyl aminopeptidase: Insights for selective inhibitor design
 
Added Entry - Uncontrolled Name Valdés-Tresanco, Mario E.; Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba Department of Biological Sciences, University of Calgary, Calgary, Canada
Sánchez, Yarini Arrebola; Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba
Méndez, Laura Rivera; Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba
Almeida, Fabiola ; Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba
Sánchez, Belinda ; Centro de Inmunología Molecular, Habana, Cuba
Charli, Jean-Louis ; Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, México
Alonso, Isel Pascual; Faculty of Biology. University of Havana
CIM-UH project: “New inhibitors of aminopeptidases with potential applications in cancer” (2016-2020) and by Coordinación de la Investigación Científica, UNAM (8862-2019).
 
Uncontrolled Index Term chemical biology; natural products; drug design
Amastatin, Bestatin; Glutamyl aminopeptidase; Non-competitive inhibitors; Phebestin; Probestin.
 
Summary, etc. <p class="Abstract" style="text-align: justify;">Glutamyl aminopeptidase (APA) is an M1 family membrane-bound ectoenzyme that is a target for the development of antihypertensive and anticancer agents. Bestatin is a natural product described as a classical inhibitor of metallo-aminopeptidases. Although the IC<sub>50</sub> value of bestatin vs human APA has been reported, the mechanism of inhibition is unknown. In the present contribution, we demonstrated that bestatin is a non-competitive (α&gt;1) inhibitor of porcine APA (pAPA), with a K<sub>i</sub> value of 31.59 µM (α=3.7). A model of the bestatin-pAPA complex predicted that bestatin binds to pAPA similarly to porcine aminopeptidase N (pAPN). The interaction involved catalytic and chelating residues conserved in the M1 family. Additionally, a salt bridge with R877 and a hydrogen bond interaction with T346, both key residues for APA specificity for N-terminal acidic residues were identified. These residues and E213, which forms a hydrogen bond interaction with bestatin, are not conserved in human and porcine APN. The extension of the <em>in silico</em> analysis to amastatin and bestatin analogs probestin, and phebestin, which are APA inhibitors, indicated that they may interact with the same residues. The results indicate that bestatin analogues currently reported to inhibit APN are dual inhibitors of APA and APN and that some APA residues could be targeted to improve inhibitor selectivity.</p>
 
Publication, Distribution, Etc. Indian Journal of Natural Products and Resources (IJNPR) [Formerly Natural Product Radiance (NPR)]
2021-08-02 14:11:01
 
Electronic Location and Access application/pdf
http://op.niscair.res.in/index.php/IJNPR/article/view/38284
 
Data Source Entry Indian Journal of Natural Products and Resources (IJNPR) [Formerly Natural Product Radiance (NPR)]; ##issue.vol## 12, ##issue.no## 2 (2021): June 2021
 
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Nonspecific Relationship Entry http://op.niscair.res.in/index.php/IJNPR/article/download/38284/465519024
http://op.niscair.res.in/index.php/IJNPR/article/download/38284/465571983
 
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