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

Umberto Maria Battisti; Chunixa Gao; Fady Akladios; Woonghee Kim; Hong Yang; Cemil Bayram; Ismail Bolat; Metin Kiliclioglu; Nursena Yuksel; Ozlem Ozdemir Tozlu; Cheng Zhang; Jihad Sebhaoui; Shazia Iqbal; Saeed Shoaie; Ahmet Hacimuftuoglu; Serkan Yildirim; Hasan Turkez; Mathias Uhlen; Jan Boren; Adil Mardinoglu; Morten Grøtli

doi:10.3390/nu15030577

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

Umberto Maria Battisti, Chunixa Gao, Fady Akladios, Woonghee Kim, Hong Yang, Cemil Bayram, Ismail Bolat, Metin Kiliclioglu, Nursena Yuksel, Ozlem Ozdemir Tozlu, Cheng Zhang, Jihad Sebhaoui, Shazia Iqbal, Saeed Shoaie, Ahmet Hacimuftuoglu, Serkan Yildirim, Hasan Turkez, Mathias Uhlen, Jan Boren, Adil MardinogluMorten Grøtli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

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.

Original language	English
Article number	577
Journal	Nutrients
Volume	15
Issue number	3
DOIs	https://doi.org/10.3390/nu15030577
Publication status	Published - Feb 2023

Keywords

ellagic acid
enzyme inhibition
liver pyruvate kinase
NAFLD
urolithins

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Battisti, U. M., Gao, C., Akladios, F., Kim, W., Yang, H., Bayram, C., Bolat, I., Kiliclioglu, M., Yuksel, N., Tozlu, O. O., Zhang, C., Sebhaoui, J., Iqbal, S., Shoaie, S., Hacimuftuoglu, A., Yildirim, S., Turkez, H., Uhlen, M., Boren, J., ... Grøtli, M. (2023). Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase. Nutrients, 15(3), Article 577. https://doi.org/10.3390/nu15030577

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title = "Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase",

abstract = "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.",

keywords = "ellagic acid, enzyme inhibition, liver pyruvate kinase, NAFLD, urolithins",

author = "Battisti, {Umberto Maria} and Chunixa Gao and Fady Akladios and Woonghee Kim and Hong Yang and Cemil Bayram and Ismail Bolat and Metin Kiliclioglu and Nursena Yuksel and Tozlu, {Ozlem Ozdemir} and Cheng Zhang and Jihad Sebhaoui and Shazia Iqbal and Saeed Shoaie and Ahmet Hacimuftuoglu and Serkan Yildirim and Hasan Turkez and Mathias Uhlen and Jan Boren and Adil Mardinoglu and Morten Gr{\o}tli",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = feb,

doi = "10.3390/nu15030577",

language = "English",

volume = "15",

journal = "Nutrients",

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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 & Grøtli, M 2023, 'Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase', Nutrients, vol. 15, no. 3, 577. https://doi.org/10.3390/nu15030577

TY - JOUR

T1 - Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase

AU - Battisti, Umberto Maria

AU - Gao, Chunixa

AU - Akladios, Fady

AU - Kim, Woonghee

AU - Yang, Hong

AU - Bayram, Cemil

AU - Bolat, Ismail

AU - Kiliclioglu, Metin

AU - Yuksel, Nursena

AU - Tozlu, Ozlem Ozdemir

AU - Zhang, Cheng

AU - Sebhaoui, Jihad

AU - Iqbal, Shazia

AU - Shoaie, Saeed

AU - Hacimuftuoglu, Ahmet

AU - Yildirim, Serkan

AU - Turkez, Hasan

AU - Uhlen, Mathias

AU - Boren, Jan

AU - Mardinoglu, Adil

AU - Grøtli, Morten

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

KW - ellagic acid

KW - enzyme inhibition

KW - liver pyruvate kinase

KW - NAFLD

KW - urolithins

UR - http://www.scopus.com/inward/record.url?scp=85147362485&partnerID=8YFLogxK

U2 - 10.3390/nu15030577

DO - 10.3390/nu15030577

M3 - Article

C2 - 36771285

AN - SCOPUS:85147362485

SN - 2072-6643

VL - 15

JO - Nutrients

JF - Nutrients

IS - 3

M1 - 577

ER -

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

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