Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase.
NAFLD
ellagic acid
enzyme inhibition
liver pyruvate kinase
urolithins
Journal
Nutrients
ISSN: 2072-6643
Titre abrégé: Nutrients
Pays: Switzerland
ID NLM: 101521595
Informations de publication
Date de publication:
22 Jan 2023
22 Jan 2023
Historique:
received:
14
12
2022
revised:
14
01
2023
accepted:
18
01
2023
entrez:
11
2
2023
pubmed:
12
2
2023
medline:
15
2
2023
Statut:
epublish
Résumé
Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.
Identifiants
pubmed: 36771285
pii: nu15030577
doi: 10.3390/nu15030577
pmc: PMC9919951
pii:
doi:
Substances chimiques
Pyruvate Kinase
EC 2.7.1.40
Ellagic Acid
19YRN3ZS9P
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The Knut and Alice Wallenberg Foundation
ID : proof-of-concept grant
Organisme : the Swedish Research Council
ID : 2019-01049
Organisme : Ogonoris Foundation
ID : 0063869
Organisme : the Torsten Söderberg Foundation
ID : M105/19
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