The reaction catalyzed by mitochondrial pyruvate dehydrogenase complex (PDC) links glycolysis and Citric Acid Cycle. However, physiological significance of this reaction goes beyond its role in energy production because it also serves as a source of carbon for biosynthesis of sterols and fatty acid and provides the general means to control the tissue levels of pyruvate. Consequently, this reaction plays an important role in general metabolism, in adaptation to starvation and hypoxia, in diabetes, ischemia, and cancer. Mammalian PDC is regulated through the reversible phosphorylation (inactivation)/dephosphorylation (re-activation) cycle catalyzed by multiple isozymes of pyruvate dehydrogenase kinase (PDHK1, PDHK2, PDHK3, and PDHK4) and pyruvate dehydrogenase phosphatase (PDP1 and PDP2). The reversible phosphorylation accounts for the short- and long-term regulation of PDC. Within the past decade, significant progress has been made in structural and biochemical characterization of PDHK and PDP isozymes. On the other hand, their roles in regulation of PDC in starvation, diabetes, or cancer remain poorly understood. It is generally believed that, at least in starvation and diabetes, the long-term regulation of PDC largely reflects the induction of isozyme PDHK4. However, the lack of a clear phenotype in PDHK4-/- mouse model strongly suggests the existence of alternative mechanism(s). Our preliminary data indicate that PDHK2 might be crucial for regulation of PDC in starvation, while PDHK3 might contribute to the Warburg effect in cancer cells. In this application, we propose to explore these hypotheses using PDHK2-/-, PDHK3-/-, and PDHK4-/- knockout mouse models. This will be achieved through the following Specific Aims: 1) to identify the molecular basis of stable changes in the specific activity of PDHK2;2) to elucidate the role of PDHK2 in adaptation to starvation;and 3) to establish the physiological role of PDHK3 in regulation of PDC. Accomplishment of these objectives will shed new light on the role of pyruvate dehydrogenase reaction in general carbohydrate and lipid metabolism, in adaptation to starvation, and in cancer. In the long run, it may lead to the development of highly specific drugs that will alleviate complications associated with diabetes, ischemia, and cancer.

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The long-term regulation of PDHK activity is central to adaptation to food deprivation, hypoxia, high-fat diet, etc. However, when similar mechanisms are activated in diabetes, ischemia, or cancer, the outcomes are detrimental. Thus, uncovering the molecular mechanisms responsible for the regulation of PDHK is crucial for the development of new therapeuticals.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Gerratana, Barbara
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University of Alabama Birmingham
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Klyuyeva, Alla; Tuganova, Alina; Popov, Kirill M (2008) Allosteric coupling in pyruvate dehydrogenase kinase 2. Biochemistry 47:8358-66
Tuganova, Alina; Klyuyeva, Alla; Popov, Kirill M (2007) Recognition of the inner lipoyl-bearing domain of dihydrolipoyl transacetylase and of the blood glucose-lowering compound AZD7545 by pyruvate dehydrogenase kinase 2. Biochemistry 46:8592-602
Klyuyeva, Alla; Tuganova, Alina; Popov, Kirill M (2007) Amino acid residues responsible for the recognition of dichloroacetate by pyruvate dehydrogenase kinase 2. FEBS Lett 581:2988-92
Tuganova, Alina; Popov, Kirill M (2005) Role of protein-protein interactions in the regulation of pyruvate dehydrogenase kinase activity. Biochem J 387:147-53
Klyuyeva, Alla; Tuganova, Alina; Popov, Kirill M (2005) The carboxy-terminal tail of pyruvate dehydrogenase kinase 2 is required for the kinase activity. Biochemistry 44:13573-82
Karpova, Tatiana; Danchuk, Svitlana; Huang, Boli et al. (2004) Probing a putative active site of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 (PDP1c) by site-directed mutagenesis. Biochim Biophys Acta 1700:43-51
Burelle, Yan; Wambolt, Richard B; Grist, Mark et al. (2004) Regular exercise is associated with a protective metabolic phenotype in the rat heart. Am J Physiol Heart Circ Physiol 287:H1055-63
Karpova, Tatiana; Danchuk, Svitlana; Kolobova, Elena et al. (2003) Characterization of the isozymes of pyruvate dehydrogenase phosphatase: implications for the regulation of pyruvate dehydrogenase activity. Biochim Biophys Acta 1652:126-35
Boulatnikov, Igor; Popov, Kirill M (2003) Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase. Biochim Biophys Acta 1645:183-92
Tuganova, Alina; Boulatnikov, Igor; Popov, Kirill M (2002) Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex. Biochem J 366:129-36

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