Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design.
Journal
Chemical science
ISSN: 2041-6520
Titre abrégé: Chem Sci
Pays: England
ID NLM: 101545951
Informations de publication
Date de publication:
16 Sep 2020
16 Sep 2020
Historique:
entrez:
7
6
2021
pubmed:
8
6
2021
medline:
8
6
2021
Statut:
epublish
Résumé
Carbasugars are structural mimics of naturally occurring carbohydrates that can interact with and inhibit enzymes involved in carbohydrate processing. In particular, carbasugars have attracted attention as inhibitors of glycoside hydrolases (GHs) and as therapeutic leads in several disease areas. However, it is unclear how the carbasugars are recognized and processed by GHs. Here, we report the synthesis of three carbasugar isotopologues and provide a detailed transition state (TS) analysis for the formation of the initial GH-carbasugar covalent intermediate, as well as for hydrolysis of this intermediate, using a combination of experimentally measured kinetic isotope effects and hybrid QM/MM calculations. We find that the α-galactosidase from
Identifiants
pubmed: 34094307
doi: 10.1039/d0sc04401f
pii: d0sc04401f
pmc: PMC8162432
doi:
Types de publication
Journal Article
Langues
eng
Pagination
10488-10495Informations de copyright
This journal is © The Royal Society of Chemistry.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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