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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, İsmail BOLAT, Metin Kiliçlioğlu, Nursena Yuksel, Ozlem Ozdemir Tozlu, Cheng Zhang, Jihad Sebhaoui, Shazia Iqbal, Saeed Shoaie, Ahmet Hacımüftüoğlu, Serkan Yıldırım, Hasan Türkez, Mathias Uhlen, Jan Boren, Adil Mardinoglu, Morten Grøtli

Nutrients Cilt 15 · Sayı 3 · 01.02.2023
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Özet

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.

Anahtar kelimeler

DISEASE CONVERSION Flavonoids enzyme inhibition ELLAGIC ACID ISOENZYMES NUTRIENT NAFLD liver pyruvate kinase urolithins CK2

Atıf için künye

Battisti, U. M., Gao, C., Akladios, F., Kim, W., Yang, H., Bayram, C., BOLAT, İ., Kiliçlioğlu, M., Yuksel, N., Tozlu, O. O., Zhang, C., Sebhaoui, J., Iqbal, S., Shoaie, S., Hacımüftüoğlu, A., Yıldırım, S., Türkez, 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). https://doi.org/10.3390/nu15030577

BibTeX 
@article{battisti2023-232275,
  author = {Battisti, Umberto Maria and Gao, Chunixa and Akladios, Fady and Kim, Woonghee and Yang, Hong and Bayram, Cemil and BOLAT, İsmail and Kiliçlioğlu, Metin and Yuksel, Nursena and Tozlu, Ozlem Ozdemir and Zhang, Cheng and Sebhaoui, Jihad and Iqbal, Shazia and Shoaie, Saeed and Hacımüftüoğlu, Ahmet and Yıldırım, Serkan and Türkez, Hasan and Uhlen, Mathias and Boren, Jan and Mardinoglu, Adil and Grøtli, Morten},
  title = {Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase},
  journal = {Nutrients},
  year = {2023},
  volume = {15},
  number = {3},
  issn = {2072-6643},
  doi = {10.3390/nu15030577},
  url = {https://akademik.atauni.edu.tr/yayinlar/232275-ellagic-acid-and-its-metabolites-as-potent-and-selective-allosteric-inhibitors}
}