Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase
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 isofo...
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MDPI AG
2023-01-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/15/3/577 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Umberto Maria Battisti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T09:30:45Z |
| format | Article |
| id | doaj.art-b9652b2eaa774a50b16cafb5805aa22f |
| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-11T09:30:45Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Nutrients |
| spelling | doaj.art-b9652b2eaa774a50b16cafb5805aa22f2023-11-16T17:38:55ZengMDPI AGNutrients2072-66432023-01-0115357710.3390/nu15030577Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate KinaseUmberto Maria Battisti0Chunixa Gao1Fady Akladios2Woonghee Kim3Hong Yang4Cemil Bayram5Ismail Bolat6Metin Kiliclioglu7Nursena Yuksel8Ozlem Ozdemir Tozlu9Cheng Zhang10Jihad Sebhaoui11Shazia Iqbal12Saeed Shoaie13Ahmet Hacimuftuoglu14Serkan Yildirim15Hasan Turkez16Mathias Uhlen17Jan Boren18Adil Mardinoglu19Morten Grøtli20Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96 Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, 412 96 Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, 412 96 Gothenburg, SwedenScience for Life Laboratory, KTH–Royal Institute of Technology, 104 50 Stockholm, SwedenScience for Life Laboratory, KTH–Royal Institute of Technology, 104 50 Stockholm, SwedenDepartment of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum 25240, TurkeyDepartment of Pathology, Faculty of Veterinary, Atatürk University, Erzurum 25240, TurkeyDepartment of Pathology, Faculty of Veterinary, Atatürk University, Erzurum 25240, TurkeyDepartment of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum 25050, TurkeyDepartment of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum 25050, TurkeyScience for Life Laboratory, KTH–Royal Institute of Technology, 104 50 Stockholm, SwedenTrustlife Labs, Drug Research & Development Center, Istanbul 34774, TurkeyTrustlife Labs, Drug Research & Development Center, Istanbul 34774, TurkeyScience for Life Laboratory, KTH–Royal Institute of Technology, 104 50 Stockholm, SwedenDepartment of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum 25240, TurkeyDepartment of Pathology, Faculty of Veterinary, Atatürk University, Erzurum 25240, TurkeyDepartment of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, TurkeyScience for Life Laboratory, KTH–Royal Institute of Technology, 104 50 Stockholm, SwedenDepartment of Molecular and Clinical Medicine, University of Gothenburg, 405 30 Gothenburg, SwedenScience for Life Laboratory, KTH–Royal Institute of Technology, 104 50 Stockholm, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, 412 96 Gothenburg, SwedenLiver 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.https://www.mdpi.com/2072-6643/15/3/577NAFLDliver pyruvate kinaseellagic acidurolithinsenzyme inhibition |
| spellingShingle | 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 Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase Nutrients NAFLD liver pyruvate kinase ellagic acid urolithins enzyme inhibition |
| title | Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase |
| title_full | Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase |
| title_fullStr | Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase |
| title_full_unstemmed | Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase |
| title_short | Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase |
| title_sort | ellagic acid and its metabolites as potent and selective allosteric inhibitors of liver pyruvate kinase |
| topic | NAFLD liver pyruvate kinase ellagic acid urolithins enzyme inhibition |
| url | https://www.mdpi.com/2072-6643/15/3/577 |
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