Ellagic Acid and Its Metabolites as Potent and SelectiveAllosteric Inhibitors of Liver Pyruvate Kinase

Abstract: Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fattyliver 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 fourdifferent isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present innumerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolicanalogues of EA were synthesized and tested to identify the chemical features responsible forthe desired activity. Molecular modelling studies suggested that this inhibition is related to thestabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald thedevelopment of new therapeutics for NAFLD.