Amino acid residues responsible for the recognition of dichloroacetate by pyruvate dehydrogenase kinase 2 |
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Authors: | Klyuyeva Alla Tuganova Alina Popov Kirill M |
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Affiliation: | Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, KAUL 440A, Birmingham, AL 35294, USA. |
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Abstract: | Dichloroacetate (DCA) is a promising anticancer and antidiabetic compound targeting the mitochondrial pyruvate dehydrogenase kinase (PDHK). This study was undertaken in order to map the DCA-binding site of PDHK2. Here, we present evidence that R114, S83, I157 and, to some extent, H115 are essential for DCA binding. We also show that Y80 and D117 are required for the communication between the DCA-binding site and active site of PDHK2. These observations provide important insights into the mechanism of DCA action that may be useful for the design of new, more potent therapeutic compounds. |
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Keywords: | PDC, pyruvate dehydrogenase complex PDHK, pyruvate dehydrogenase kinase PDHK1, PDHK2, PDHK3, and PDHK4, isozymes 1, 2, 3, and 4 of pyruvate dehydrogenase kinase E1, pyruvate dehydrogenase component of PDC E2, dihydrolipoyl acetyltransferase component of PDC E3, dihydrolipoamide dehydrogenase component of PDC DCA, dichloroacetate |
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