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Gene Regulation and Genetic Defects in the Pyruvate Dehydrogenase Complex^1,2,

Mulchand S. Patel^*,,3, Sharon Naik, Isaiah D. Wexler^,, and Douglas S. Kerr^,,

^* Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214 Department of Biochemistry Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106

The mammalian pyruvate dehydrogenase complex (PDC) is subject to both short-term (product inhibition and covalent modification) and long-term (increases in total activity and protein mass) regulation mediated by dietary and hormonal treatments. Recent advances in the isolation and characterization of the complementary DNAs as well as genes encoding several components of mammalian PDC have facilitated studies concerning long-term regulation of PDC. Analyses of the promoter-regulatory regions of the two human PDC genes show characteristics of both facultative and housekeeping gene promoters, indicating complex transcriptional regulation. Deficiency of PDC activity causes a wide range of neurological disabilities. A spectrum of genetic defects in PDC components has been reported; however, the most frequent defects are associated with the pyruvate dehydrogenase component. Heterogeneity in pyruvate dehydrogenase deficiency has been shown to occur at both protein and messenger RNA levels, and several mutations in pyruvate dehydrogenase have been identified. Dietary treatments such as ketogenic diets and vitamin supplements as well as dichloroacetate treatment have been utilized to treat PDC deficiency, but their efficacy requires further evaluation.

KEY WORDS: • pyruvate dehydrogenase complex • dietary regulation • promoter analysis • genetic defects • human

¹ Presented as part of the symposium "Alpha-Keto Acid Dehydrogenase Complexes: Nutrient Control, Gene Regulation and Genetic Defects" given at the Experimental Biology '94 meeting, Anaheim, CA, on April 27, 1994. This symposium was sponsored by the American Institute of Nutrition. Guest editors for this symposium were Mulchand S. Patel, State University of New York at Buffalo, Buffalo, NY and Robert A. Harris, Indiana University School of Medicine, Indianapolis, IN.

² Supported by PHS grants DK20478 (MSP), DK42885 (MSP), MCJ-009122 (DSK) and HD00878 (IDW), and March of Dimes Birth Defects Foundation Award 5-759 (IDW).

³ To whom correspondence should be addressed: Department of Biochemistry, State University of New York at Buffalo, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214.