Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty
Department of Biochemistry
School
of Medicine & Biomedical Sciences
Faculty
MULCHAND S. PATEL, Ph.D.
SUNY Distinguished Professor
UB Distinguished Professor
Associate Dean for Biomedical Research and Education
Structure of human E3 (partial) with the E3-binding domain of its binding protein (BP). Residues of human BP are shown in dashed circles.
One goal of our research is to investigate the structure-function relationships, gene defects and gene targeting of the mammalian pyruvate dehydrogenase complex (PDC). We investigate the active site of the pyruvate dehydrogenase (E1) component and the interaction between dihydrolipoamide dehydrogenase (E3) and its binding protein of the complex to delineate the structure-function relationship and catalytic mechanism. Recombinant human mutant E1 proteins generated by site-directed mutagenesis are investigated for altered kinetics and structural characteristics. We have identified several specific mutations in this complex, and have delineated the molecular basis for impairment in PDC function based on the crystal structure of the E1 component. Based on the 3-D structure of human PDH, our current aims are to investigate the formation of intermediates in the catalysis of human PDH, to investigate the active site communication in human PDH, and to determine the loci of interactions between human E3 and its binding protein. We have developed a knock-out mouse model for PDC deficiency. Our current investigations are aimed to understand the importance of glucose metabolism (as the source of energy) for fetal development, as well as the role of PDC in glucose-stimulated insulin secretion by pancreatic beta cells.
Obesity has become an epidemic in this country. Obesity predisposes to the development of type 2 diabetes, hypertension and cardiovascular diseases. Our goal is to investigate diet-induced metabolic programming during early life. The influence of altered nutrition during the suckling period on the development of hyperinsulinemia and obesity later in adult life is being investigated using artificially-reared rats. We investigate the effects that altered nutrition during the immediate postnatal life has on adult-onset obesity. via malprogramming of hypothalamus and pancreatic beta cells. We also investigate the effects of maternal insulin resistance/obesity on malprogramming of the hypothalamic neurons and pancreatic beta cells in the fetus predisposing them to the development of obesity in adulthood. Current research focuses on the role of the hypothalamic signaling pathways especially in the development of melanocortin system in the maintenance of imbalances in energy homoeostasis in rats with diet-induced obesity and also in the progeny. Studies are also underway to investigate the effects of nutritional and pharmacological interventions on reversal of abnormalities in the hypothalamic neurons.
Selected Recent Publications
Mitrani, P., Srinivasan, M., Dodds, C. and Patel, M. S. Role of the autonomic nervous system in the development of hyperinsulinemia by high-carbohydrate formula feeding to neonatal rats. Amer. J. Physiol. Endocrinal. Metab 292 (2007) 1069-1078.Mitrani, P., Srinivasan, M., Dodds, C. and Patel, M. S. Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model. Amer. J. Physiol. Endocrinal. Metab. 292 (2007) 1364-1377.
Seifert, F., Ciszak, E., Korotchkina, L. G., Golbik, R., Spinka, M., Dominiak, P., Sidhu, S., Brauer, J., Patel, M. S., and Tittmann, K. (2007) Phosphorylation of serine 264 impedes active site accessibility in the E1 component of the human pyruvate dehydrogenase multienzyme complex, Biochemistry, 46, 6277-6287.Nemeria, N., Korotchkina, L., McLeish, M. J., Kenyon, G. L., Patel, M. S., Jordan, F. (2007) Elucidation of the chemistry of enzyme-bound thiamin diphosphate prior to substrate binding: defining internal equilibria among tautomeric and ionization states, Biochemistry, 46, 10739-10744.
Pliss, L., Mazurchuk, R., Spernyak, J. A., Patel, M. S. Brain MR imaging and proton Masspectroscopy in female mice with pyruvate dehydrogenase compelx deficiency. Nerochem. Res. 32, 645-654 (2007).
Korotchkina, L.G., and Patel, M.S. Binding of pyruvate dehydrogenase to the core of the human pyruvate dehydrogenase complex. FEBS Lett. 582 (2008) 468-472.
Srinivasan, M. and Patel, M.S. Metabolic programming in the immediate postnatal period. Trends Endrocrinal. Metabol. 19 (2008) 146-152.
Srinivasan, M., Mitrani, P., Sadhanandan, G., Dodds, C., Shbeir-ElDika, S., Thamotharan, S., Ghanim, H., Dandona, P., Devasker, S. U. and Patel, M. S. A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity. J. Endocrinol. 197 (2008) 565-574.
Sidhu, S. Gangasani, A., Korotchkina, L. G., Suzuki, G., Fallavollita, J. A., Canty, J. M., Jr. and Patel, M. S. Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male rats. Amer. J. Physiol. Heart Circ. Physiol. 295 (2008) H946-H952.
Srinivasan, M.,Catherine Dodds, C., Husam Ghanim, H.,Tao Gao, T., Ross, P. J., Richard W Browne, R. W., Dandona, P. and Patel, M. S. Maternal obesity and fetal programming: effects of a high carbohydrate nutritional modification in the immediate postnatal life of female rats. Amer. J. Physiol. Endocrinol. Metab. 295 (2008) E895-E903.
Patel, M.S., Srinivasan, M. and Laychock, S. G. Metabolic programming: Role of nutrition inimmediate postnatal life. J. Inherit. Metab. Dis.32 (2008) 218-228.
Gupta, A., Srinivasan M., Thamadilok, S. and Patel, M. S. Hypothalamic alterations in fetuses of high fat-fed obese female rats. J. Endocrinol. 200 (2008) 293-300.
Patel, M. S. and Packer, L. (Editors), Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects, CRC Press, Taylor and Francis Group, 2008, pg. 1-532.
Patel, M.S., Korotchkina, L.G. and Sidhu,S. Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex. J. Mol. Catalysis B; Enzymatic (2009) in press.
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