Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase.

Battisti UM, Gao C, Akladios F, Kim W, Yang H, Bayram C, Bolat I, Kiliclioglu M, Yuksel N, Tozlu OO, Zhang C, Sebhaoui J, Iqbal S, Shoaie S, Hacimuftuoglu A, Yildirim S, Turkez H, Uhlen M, Boren J, Mardinoglu A, Gr√łtli M

Nutrients 15 (3) - [2023-01-22; online 2023-01-22]

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.

Adil Mardinoglu

SciLifeLab Fellow

PubMed 36771285

DOI 10.3390/nu15030577

Crossref 10.3390/nu15030577

pmc: PMC9919951
pii: nu15030577

Publications 9.5.0