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.

Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms.

Abstract: The mammalian pyruvate dehydrogenase complex (PDC) plays central and strategic roles in the control of the use of glucose-linked substrates as sources of oxidative energy or as precursors in the biosynthesis of fatty acids The activity of this mitochondrial complex is regulated by the continuous operation of competing pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) reactions The resulting interconversion cycle determines the fraction of active (nonphosphorylated) pyruvate dehydrogenase (E1) component Tissue-specific and metabolic state-specific control is achieved by the selective expression and distinct regulatory properties of at least four PDK isozymes and two PDP isozymes The PDK isoforms are members of a family of serine kinases that are not structurally related to cytoplasmic Ser/Thr/Tyr kinases The catalytic subunits of the PDP isoforms are Mg2+-dependent members of the phosphatase 2C family that has binuclear metal-binding sites within the active site The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex One or more of their three lipoyl domains (two in E2) selectively bind each PDK and PDP1 These adaptive interactions predominantly influence the catalytic efficiencies and effector control of these regulatory enzymes When fatty acids are the preferred source of acetyl-CoA and NADH, feedback inactivation of PDC is accomplished by the activity of certain kinase isoforms being stimulated upon preferentially binding a lipoyl domain containing a reductively acetylated lipoyl group PDC activity is increased in Ca2+-sensitive tissues by elevating PDP1 activity via the Ca2+-dependent binding of PDP1 to a lipoyl domain of E2 During starvation, the irrecoverable loss of glucose carbons is restricted by minimizing PDC activity due to high kinase activity that results from the overexpression of specific kinase isoforms Overexpression of the same PDK isoforms deleteriously hinders glucose consumption in unregulated diabetes

Regulation of mammalian pyruvate dehydrogenase.

Abstract: Dichloroacetate and other halogenated carboxylic acids can activate pyruvate dehydrogenase in rat heart and in rat heart mitochondria by effecting conversion of phosphorylated (inactive) pyruvate dehydrogenase into an active (dephosphorylated) form. These compounds are inhibitors of pig heart pyruvate dehydrogenase kinase. Pig heart pyruvate dehydrogenase phosphate phosphatase requires both Mg2+and Ca2+ for activity. Evidence is given for a dual metal requirement of the phosphatase in rat fat cell mitochondria. It is concluded that Mg2+ and Ca2+ are essential cofactors for the phosphatase but that their physiological significance as regulators remains to be established. Pig heart pyruvate dehydrogenase kinase is inhibited by high concentrations of magnesium and by low concentrations of calcium.

Purification and characterization of branched chain α-keto acid dehydrogenase complex of bovine kidney

Abstract: A branched chain α-keto acid dehydrogenase-dihydrolipoyl transacylase complex was purified to apparent homogeneity from bovine kidney mitochondria. As usually isolated, the complex (s20,w = 40 S) contained little, if any, dihydrolipoyl dehydrogenase. When saturated with the latter enzyme the complex had a specific activity of about 12 μmol of α-ketoisovalerate oxidized per min per mg of protein at 30° with NAD+ as electron acceptor. In addition to α-ketoisovalerate, the complex also oxidized α-ketoisocaproate, α-keto-β-methylvalerate, α-ketobutyrate, and pyruvate. The ratios of the specific activities were 2.0:1.5:1.0:1.0:0.4, and the apparent Km values were 40, 50, 37, 56, and 1000 μM. The complex was separated into its component enzymes. The branched chain α-keto acid dehydrogenase (6 S) consists of two different subunits with estimated molecular weights of 46,000 and 35,000. The dihydrolipoyl transacylase (20 S) contains apparently identical subunits of molecular weight about 52,000. In the electron microscope, the transacylase has the appearance of a cube, and the molecules of branched chain α-keto acid dehydrogenase appear to be distributed on the surface of the cube. In contrast to the pyruvate dehydrogenase complex of bovine kidney, the branched chain α-keto acid dehydrogenase complex apparently is not regulated by phosphorylation-dephosphorylation. Its activity, however, is subject to modulation by end-product inhibition.

Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

Abstract: The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.