Dept. of Biochemistry & Molecular Genetics
Moscow State University
MS, Biochemistry, 1982
Institute of Organic Chemistry
Indiana University Medical Center
The major objective of our studies is to understand the molecular mechanisms governing the oxidation of carbohydrates. In order to survive, all living organisms have to burn some respiratory fuels. In humans, the major respiratory fuels are carbohydrates, lipids, and certain amino acids. On average, the modern diet provides about 45-50% of total fuel mix in the form of carbohydrates, 33- 43% as fat and 13-17% as protein. Thus, under normal circumstances, carbohydrates satisfy a considerable percent of the total demand for energy. It is generally believed that in well-oxygenated tissues the major determinant of carbohydrates oxidation is the activity of the mitochondrial pyruvate dehydrogenase complex (PDC). PDC catalyzes the irreversible decarboxylation of the pyruvic acid and, by this means, commits carbohydrates to further catabolism. It is not surprising, therefore, that this reaction is heavily regulated by a variety of nutritional and hormonal stimuli. This regulation is carried out by two dedicated enzymes – pyruvate dehydrogenase kinase (PDK) that phosphorylates and inactivates PDC and pyruvate dehydrogenase phosphatase (PDP) that reverses the action of kinase dephosphorylating and re-activating PDC. Thus, the coordinated action of PDK and PDP determines the amount of active, dephosphorylated PDC in any particular tissue. Both PDK and PDP activities are the subjects of regulation by hormones and nutrients and, therefore, adjust the phosphorylation state of PDC reflecting the stimulation the cells receive at the moment. To complicate matters even further, it appears that, in humans, there are multiple isoenzymes of PDK and PDP. As a result, almost every tissue has its own subset of isoenzymes that are somewhat different with respect to their enzymatic properties and regulation. Thus, the objectives that our laboratory is currently pursuing are: 1) to understand how both PDK and PDP function at the atomic level and how they manage to integrate a variety of metabolic stimuli; 2) to understand the molecular mechanisms responsible for regulation of kinase and phosphatase activities by hormones; and 3) to evaluate the molecular basis for abnormal regulation of PDC observed in diabetes, cancer, and ischemia.
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