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.

Pyruvate dehydrogenase deficiency and epilepsy.

Abstract: The pyruvate dehydrogenase complex (PDHc) is a mitochondrial matrix multienzyme complex that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the conversion of pyruvate into acetyl-CoA. PDHc deficiency is one of the commoner metabolic disorders of lactic acidosis presenting with neurological phenotypes that vary with age and gender. In this mini-review, we postulate mechanisms of epilepsy in the setting of PDHc deficiency using two illustrative cases (one with pyruvate dehydrogenase complex E1-alpha polypeptide (PDHA1) deficiency and the second one with pyruvate dehydrogenase complex E1-beta subunit (PDHB) deficiency (a rare subtype of PDHc deficiency)) and a selected review of published case series. PDHc plays a critical role in the pathway of carbohydrate metabolism and energy production. In severe deficiency states the resulting energy deficit impacts on brain development in utero resulting in structural brain anomalies and epilepsy. Milder deficiency states present with variable manifestations that include cognitive delay, ataxia, and seizures. Epileptogenesis in PDHc deficiency is linked to energy failure, development of structural brain anomalies and abnormal neurotransmitter metabolism. The use of the ketogenic diet bypasses the metabolic block, by providing a direct source of acetyl-CoA, leading to amelioration of some symptoms. Genetic counseling is essential as PDHA1 deficiency (commonest defect) is X-linked although females can be affected due to unfavorable lyonization, while PDHB and PDH phosphatase (PDP) deficiencies (much rarer defects) are of autosomal recessive inheritance. Research is in progress for looking into animal models to better understand pathogenesis and management of this challenging disorder.

3 Pyruvate Dehydrogenase

Abstract: Publisher Summary This chapter summarizes some aspects of the structural organization of the mammalian pyruvate dehydrogenase complex and the regulation of its activity by a phosphorylation–dephosphorylation cycle. Phosphorylation and concomitant inactivation of pyruvate dehydrogenase (E1) occurs on three serine residues in the α subunit. The phosphorylation of pyruvate dehydrogenase inhibits the decarboxylation of pyruvate and may also inhibit reductive acetylation of the lipoyl moiety. Pyruvate dehydrogenase kinase appears to be specific for pyruvate dehydrogenase. Pyruvate dehydrogenase phosphatase activity is inhibited by NADH and this inhibition is reversed by nicotinamide adenine dinucleotide (NAD + ). The phosphatase is inactive toward p -nitrophenyl phosphate. The pyruvate dehydrogenase system is well designed for fine regulation of its activity. The interconversion of the active and inactive phosphorylated forms of pyruvate dehydrogenase is a dynamic process that leads rapidly to the establishment of steady states in which the fraction of phosphorylated E1 can be varied progressively over a wide range by changing the concentration or molar ratios of effectors that regulate the activities of the kinase and phosphatase. The acute regulation of pyruvate dehydrogenase in response to hormonal and other influences is mediated by two regulatory mechanisms—namely, end-product inhibition by acetyl-CoA and NADH and reversible covalent phosphorylation. The two best-studied acute effects of hormones on the activity of pyruvate dehydrogenase are those of positive inotropic agents, such as adrenaline on the enzyme in the heart and the effect of insulin on the enzyme in several tissues, but particularly in adipose tissue.

Competition for ADP between Pyruvate Kinase and Mitochondrial Oxidative Phosphorylation as a Control Mechanism in Glycolysis

Abstract: To assess a possible role of pyruvate kinase as a site for respiratory and glycolytic interaction, competition for ADP between pyruvate kinase and respiratory phosphorylation was measured in a model system consisting of rat liver mitochondria respiring in the presence of pyruvate kinase, phosphoenolpyruvate, ATP, and an ADP-regenerating system consisting of glucose and purified yeast hexokinase. This system allowed determination of total ATP production, equivalent to ADP utilization, by measuring glucose 6-phosphate formation; ADP utilization by pyruvate kinase by pyruvate formation; and respiratory ADP utilization by Pi uptake. O2 uptake was measured by means of an oxygen electrode. In the presence of a respiratory substrate such as succinate or glutamate-malate, the addition of pyruvate kinase and phosphoenolpyruvate reduced O2 uptake as well as oxidative phosphorylation about 80%. Respiration was increasingly inhibited with increasing pyruvate kinase, and this inhibition was decreased with increased hexokinase or ATP. Mitochondrial respiratory inhibition by pyruvate kinase and phosphoenolpyruvate was accompanied by an increase in the ATP/ADP ratio from 0.3 to 32. These inhibitory effects of pyruvate kinase on respiration were abolished by addition of 2,4-dinitrophenol. These results are in acccord with a role of pyruvate kinase as a determinant of glycolytic activity by competing with oxidative phosphorylation for the available ADP; and provide additional support for our previous suggestion that high glycolysis of certain tumors may be attributable to their extraordinarily high pyruvate kinase activity.