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Pyruvate dehydrogenase kinase

About: Pyruvate dehydrogenase kinase is a research topic. Over the lifetime, 4224 publications have been published within this topic receiving 161052 citations. The topic is also known as: [pyruvate dehydrogenase (lipoamide)] kinase & pyruvate dehydrogenase (lipoamide) kinase.


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Journal ArticleDOI
TL;DR: In this article, the overall activity and distribution of pyruvate carboxylase and PPI carboxykinase in rat liver was studied by applying an improved technique for the fractional extraction of hepatic enzymes.
Abstract: The overall activity and distribution of pyruvate carboxylase and of phosphoenolpyruvate carboxykinase in rat liver was studied by applying an improved technique for the fractional extraction of hepatic enzymes. In the rat the mean activity of pyruvate carboxylase amounted to 10 units/g fresh liver (1 unit = 1 μmole pyruvate carboxylated/min at 30°). In the human liver the corresponding value was about 1 unit/g fresh wt. For phosphoenolpyruvate carboxy-kinase 2.5 and 10 units/g fresh wt. were measured in rat and human liver, respectively. During fractional extraction only negligible quantities of pyruvate carboxylase appeared in the soluble cytoplasmatic fraction. It is concluded that the bulk of enzyme activity is located within the mitochondria. By digitonin treatment of isolated rat liver mitochondria pyruvate carboxylase could be localized within the matrix space. Phosphoenolpyruvate carboxykinase was found to be located mainly in the soluble cytoplasmatic fraction. Our results strongly support the view that in rat liver gluconeogenesis pyruvate has to enter the mitochondria prior to its carboxy-lation to oxaloacetate.

105 citations

Journal ArticleDOI
TL;DR: This work has evaluated how binding to the lipoyl domains of the dihydrolipoyl acetyltransferase (E2) produces the predominant changes in the rates of phosphorylation of the pyruvate dehydrogenases (E1) component by PDK2 and PDK3.

105 citations

Journal ArticleDOI
TL;DR: The effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors are described and PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.
Abstract: Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.

104 citations

Journal ArticleDOI
TL;DR: It is concluded that the N-terminal domain of PDHK has a key regulatory function and proposed that the different inhibitor classes act by discrete mechanisms.
Abstract: Pyruvate dehydrogenase kinase (PDHK) regulates the activity of the pyruvate dehydrogenase multienzyme complex. PDHK inhibition provides a route for therapeutic intervention in diabetes and cardiovascular disorders. We report crystal structures of human PDHK isozyme 2 complexed with physiological and synthetic ligands. Several of the PDHK2 structures disclosed have C-terminal cross arms that span a large trough region between the N-terminal regulatory (R) domains of the PDHK2 dimers. The structures containing bound ATP and ADP demonstrate variation in the conformation of the active site lid, residues 316−321, which enclose the nucleotide β and γ phosphates at the active site in the C-terminal catalytic domain. We have identified three novel ligand binding sites located in the R domain of PDHK2. Dichloroacetate (DCA) binds at the pyruvate binding site in the center of the R domain, which together with ADP, induces significant changes at the active site. Nov3r and AZ12 inhibitors bind at the lipoamide bindin...

104 citations

Journal ArticleDOI
01 May 2001-Glia
TL;DR: It is suggested that the conversion of alanine to releasable lactate proceeds at the expense of flux of glycolytic pyruvate through lactate dehydrogenase, which is used for ammonia fixation byAlanine synthesis in the cytosol and for mitochondrial TCA cycle activity.
Abstract: After incubation of glial cells with both 13C-labeled and unlabeled glucose and alanine, 13C isotopomer analysis indicates two cytosolic pyruvate compartments in astrocytes. One pyruvate pool is in an exchange equilibrium with exogenous alanine and preferentially synthesizes releasable lactate. The second pyruvate pool, which is of glycolytic origin, is more closely related to mitochondrial pyruvate, which is oxidized via tri carbonic acid (TCA) cycle activity. In order to provide 2-oxoglutarate as a substrate for cytosolic alanine aminotransferase, glycolytic activity is increased in the presence of exogenous alanine. Furthermore, in the presence of alanine, glutamate is accumulated in astrocytes without subsequent glutamine synthesis. We suggest that the conversion of alanine to releasable lactate proceeds at the expense of flux of glycolytic pyruvate through lactate dehydrogenase, which is used for ammonia fixation by alanine synthesis in the cytosol and for mitochondrial TCA cycle activity. In addition, an intracellular trafficking occurs between cytosol and mitochondria, by which these two cytosolic pyruvate pools are partly connected. Thus, exogenous alanine modifies astrocytic glucose metabolism for the synthesis of releasable lactate disconnected from glycolysis. The data are discussed in terms of astrocytic energy metabolism and the metabolic trafficking via a putative alanine-lactate shuttle between astrocytes and neurons. GLIA 34:200–212, 2001. © 2001 Wiley-Liss, Inc.

104 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202329
202234
202161
202063
201959
201851