Differential Inhibition Of PDKs By Phenylbutyrate And Identification Of Putative Binding Sites | 17124
Journal of Biotechnology & Biomaterials
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Pyruvate dehydrogenase kinase (PDK) isoforms are molecular switches that downregulate the pyruvate dehydrogensase
complex (PDC) by reversible phosphorylation in mithocondria. To date, four PDK isoforms (PDK1-4) have been identified
in humans, each of them is able to phosphorylate (and inactivate) the complex exhibiting different site specificity. The expression
of the four PDK isoforms is tissue specific in response to needs of various tissues under different metabolic conditions. Indeed,
their activity on PDC is an important switch that regulates both diabetes (PDK2/PDK4) and cancer metabolism (PDK1/
PDK3).So far, several molecules have been investigated to inhibit PDK activity but none of them fulfils the requirements for a
safe and effective drug: strength, specificity, and absence of toxic effects. The author and her team has recently discovered that
phenylbutyrate (PB) is effective in activating the PDC by direct inhibition of PDK2 and is effective at improving a rare inborn
error of metabolism due to PDC deficiency.In this it has been investigated phenylbutyrate inhibiting activity towards the
other PDK isoenzymes (PDK1, 3 and 4) using suitable functional assays. Also, by using molecular docking, we have identified
putative binding sites of PB on each PDK isoform suggesting molecular determinants of enzyme selectivity. The information
gained from these studies give important insights on the molecular determinants in PDK inhibition and allows designing
specific PDKs inhibitor. Also, because PB is already approved for human use in other diseases, the findings of this study have
the potential to be rapidly translated into clinics.
Clara Iannuzzi obtained a degree in Chemistry at University Federico II of Naples (Italy) in 2002 and a PhD in Cellular Biochemistry at SecondaUniversit? di Napoli
(Italy) in 2006. Between 2006 and 2012 she held a Career Development fellowship at MRC-National Institute for Medical Research in London (UK). At present she
is Researcher at SecondaUniversit? di Napoli and Associate Researcher at CNR- Institute of Protein Biochemistry (Naples, Italy). She has published many research
papers on peer-reviewed journals in the field of biochemistry and molecular biophysics.
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