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Results for “Pyruvate Dehydrogenase Complex”

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PubMed1978

Pyruvate metabolism after in vivo exposure to oral arsenic.

This study investigated altered pyruvate metabolism after prolonged oral arsenic exposure. Male rats were given access to deionized drinking water containing 0, 40 or 85 ppm sodium arsenate (As5+) for 3 weeks. Respiration studies with mitochondria isolated from treated animals indicated decreased state 3 respiration (with ADP) and decreased respiratory control ratios (RCR) for pyruvate/malate-mediated respiration, but not for succinate-mediated respiration, as compared to control respiration values. In addition, pyruvate dehydrogenase activity was measured, in both liver and intestine, before and after Mg-activation in vitro. After 3 weeks, the effects of arsenic at the highest dose level were pronounced on the basal pyruvate dehydrogenase activity (before activation) as well as the total pyruvate dehydrogenase (after activation). The inhibition of pyruvate dehydrogenase activity both before and after Mg-activation suggests an arsenic effect on mitochondrial pyruvate metabolism which, in part, involves inhibition of pyruvate decarboxylase. Evidence is also presented which may indicate an arsenic effect on the kinase and/or phosphatase which regulate pyruvate dehydrogenase activity.

Animals↗
PubMed1982

Determination of pyruvate dehydrogenase in cultured human fibroblasts and amniotic fluid cells.

A new assay method for pyruvate dehydrogenase in platelets [1] using in situ generation of [1-14C]pyruvate from [1-14C]lactate has been further developed for the use in cultured human fibroblasts and amniotic fluid cells. A very low blank rate was found compared to the method using [1-14C]pyruvate as substrate and an activity of 20 times the blank was obtained in normal fibroblasts and amniotic fluid cells. The pyruvate dehydrogenase was linear with time and protein concentration. The activity was greatly decreased by addition of non-radioactive pyruvate to the assay mixture and by preincubation with ATP. The cofactor requirement was similar to pyruvate dehydrogenase from other sources. Normal activities in cultured human fibroblasts and amniotic fluid cells were 13.9 pkat/mg protein (n = 15) and 21.7 pkat/mg protein (n = 10), respectively. The method was found to be very reliable and makes the diagnosis of pyruvate dehydrogenase deficiency possible in easily accessible tissue such as cultured fibroblasts. Prenatal diagnosis may also be a possibility.

Adenosine Triphosphate↗
PubMed1989

Pyruvate decarboxylase is like acetolactate synthase (ILV2) and not like the pyruvate dehydrogenase E1 subunit.

Protein sequences of pyruvate decarboxylase (PDC) derived from cloned yeast (Saccharomyces cerevisiae) and bacterial (Zymomonas mobilis) genes were compared with each other and with sequence databases. Extensive sequence similarities were found between them and with two others: cytochrome-linked pyruvate oxidase from Escherichia coli and acetolactate synthase (ilvI in E. coli; ILV2 gene in S. cerevisiae). All catalyse decarboxylation of pyruvate using thiamine pyrophosphate (TPP) as cofactor. General overall similarity suggests common ancestry for these enzymes. None of the sequences was similar to the E1 component of pyruvate dehydrogenase from E. coli which also decarboxylates pyruvate with the help of TPP.

Acetolactate Synthase↗
PubMed1993

Control of muscle pyruvate oxidation during late pregnancy.

Despite significant increases in circulating concentrations of lipid fuels (triacylglycerol, non-esterified fatty acids (NEFA) and ketone bodies) in late-pregnant rats sampled in the fed (absorptive) state, cardiac and skeletal muscle active pyruvate dehydrogenase (PDHa) activities remained comparable with those observed in fed, age-matched virgin controls. Cardiac PDHa activity was suppressed in response to acute (6 h) starvation in late-pregnant (as well as virgin) rats: this inactivation was opposed by inhibition of mitochondrial long-chain FA oxidation. Starvation (6 h) also led to PDH inactivation in skeletal muscles of late-pregnant, but not virgin, rats. Starvation for 24 h led to further suppression of cardiac PDHa activity and was associated with significant increases in PDH kinase activities in both virgin and late-pregnant rats. Late pregnancy did not itself influence cardiac PDH kinase activity.

Animals↗
PubMed1984

The elucidation of the effect of ammonium chloride on pyruvate distribution and pyruvate dehydrogenase interconversion in isolated rat hepatocytes.

The distribution of pyruvate between cell compartments measured in isolated hepatocytes in the presence of lactate was in agreement with delta pH across plasma and mitochondrial membranes. In isolated liver mitochondria NH4Cl decreased the transmembrane potential (delta psi) by about 14 mV, whereas no change of delta pH was observed. In the presence of lactate or alanine NH4Cl increased the mitochondrial pyruvate concentration presumably due to the inhibition of the flux through pyruvate carboxylase. In the presence of lactate or alanine changes in the amount of the active form of pyruvate dehydrogenase (PDHa) were correlated with the mitochondrial pyruvate concentration, NH4Cl increased the amount of PDHa by lowering the mitochondrial ATP/ADP and NADH/NAD+ ratios.

Adenosine Diphosphate↗
PubMed1986

Hepatic pyruvate metabolism during liver regeneration after partial hepatectomy in the rat.

Hepatic pyruvate kinase (PK) and pyruvate dehydrogenase (PDHa) specific activities were decreased after partial hepatectomy or sham operation. The decreases were more marked and sustained after partial hepatectomy. These activity changes ensure that hepatic carbon flux after partial hepatectomy is predominantly in the direction of gluconeogenesis. The decrease in PK specific activity observed after partial hepatectomy was associated with a decreased PK activation ratio (activity measured at 0.15 mM PEP: activity measured at 5.0 mM PEP), and hepatic concentrations of PEP were increased. The low hepatic PDHa activity observed at the first day after partial hepatectomy occurred concomitantly with an increased fatty acid concentration. PDHa activity increased after inhibition of lipolysis. The results indicate that carbohydrate utilization is unimportant for hepatic energy supply during liver regeneration. There was no evidence that the control of PK or PDH in the regenerative liver after partial hepatectomy differed from that observed in the liver of the unoperated rat.

Animals↗
PubMed1984

Familial intermittent ataxia with possible X-linked recessive inheritance. Two patients with abnormal pyruvate metabolism and a response to acetazolamide.

Five males in one kindred suffered from intermittent ataxia and one female may have been more mildly affected. The pattern of inheritance strongly suggests X-linkage. Cerebral pathology in one case had some features of Leigh's disease. A defect in pyruvate metabolism was found in two cases. Acetazolamide gave a temporary clinical and biochemical improvement in two cases.

Acetazolamide↗
PubMed1982

Evaluation of sodium acetate as a source of alkali therapy in an experimental aerobic model of lactic acidosis due to decreased pyruvate oxidation.

An "in vitro" model of one type of lactic acidosis was produced in rat hemi-diaphragms with inhibitors of pyruvate oxidation. In order to obtain this inhibition in the absence of hypoxia, two actions were sought; inhibiting the mitochondrial pyruvate transporter and lowering the rate of pyruvate diffusion into these mitochondria. alpha-Cyano-3-hydroxy cinnamate (CNCM) was utilized because it is a specific inhibitor of the mitochondrial pyruvate transporter. Aminooxyacetate (AOA) was employed because it leads indirectly to inhibition of the entry of cytoplasmic reducing power into mitochondria. As a result of the addition of this latter compound, pyruvate levels fell and this should decrease the rate of pyruvate diffusion into the mitochondria. Glucose was the only substrate provided to this tissue and its entry into the cells was promoted by insulin. The oxidation of U-14C glucose to 14CO2 was significantly reduced in the presence of CNCM and AOA, presumably reflecting the inhibition of pyruvate oxidation. Under these conditions, lactate accumulated and pyruvate fell; however, there was a significant accumulation of lactate plus pyruvate during the incubation period. This "in vitro" lactic acidosis was markedly diminished when acetate was also present. These results are consistent with the hypothesis that provision of an alternate substrate to the TCA cycle for ATP synthesis could lead to a decreased rate of glycolysis and thereby to a decreased rate of lactic acid accumulation in this "in vitro" model of lactic acidosis.

Acetates↗
PubMed1984

Release of lactate by the liver in metabolic acidosis in vivo.

Chronic metabolic acidosis was induced in dogs by HCl. Pyruvate and lactate production and extractions were studied by arteriovenous sampling and electromagnetic flow probe measurements of gut and hepatic blood flows. The following results were obtained: (1) In control, overnight-fasted dogs, no net lactate or pyruvate was extracted by the liver. (2) In chronic acidosis, large amounts of lactate were produced. (3) Reduced tissue pyruvate levels and reduced activity of pyruvate dehydrogenase were found in the liver of these dogs compared with normal. These results demonstrate an unexpected effect of acidosis on hepatic lactate metabolism.

Acidosis↗
PubMed1985

Inhibition of palmitoylcarnitine oxidation by pyruvate in rat heart mitochondria.

The oxidation of 1-14C-palmitoylcarnitine by rat heart mitochondria has been measured by assessing both the disappearance of substrate and the appearance of labelled products. Pyruvate inhibited palmitoylcarnitine oxidation by about 40%. Fifty percent inhibition occurred at about 20 mumol/L pyruvate. The inhibitory effect of pyruvate required entry of pyruvate into mitochondria since it did not occur in the presence of alpha-cyano-4-hydroxycinnamic acid, an inhibitor of the mitochondrial pyruvate transporter. The inhibitory effect of pyruvate also required an active pyruvate dehydrogenase. These studies indicate a mechanism that may be important in the replacement of fatty acids by carbohydrate as fuels of respiration of the heart during the transition from the starved to the fed state.

Animals↗
PubMed1993

Mechanisms of halothane toxicity: novel insights.

Exposure of individuals to halothane causes, in 20% of patients, a mild form of hepatotoxicity. In contrast, a very small subset of individuals only develops halothane hepatitis, which is thought to have an immunological basis. Sera of halothane hepatitis patients contain antibodies directed against some discrete liver trifluoroacetyl (TFA)-protein adducts, which arise upon oxidative biotransformation of halothane and include protein disulfide isomerase, microsomal carboxylesterase, calreticulin, ERp72, GRP 78 and ERp99. No immune response occurs in the majority of human individuals, although evidence suggests that TFA-protein adducts arise in all halothane-exposed individuals. The lack of immunological responsiveness of individuals might be due to tolerance, induced by a presumed repertoire of self-peptides that molecularly mimic TFA-protein adducts. Thus, constitutively expressed proteins of 52 and 64 kDa have been identified that confer molecular mimicry of TFA-protein adducts. The 64 kDa protein corresponds to the E2 subunit of the mitochondrial pyruvate dehydrogenase complex. Lipoic acid, the prosthetic group of the E2 subunit, is involved in the molecular mimicry process. A fraction of halothane hepatitis patients exhibit irregularities in the expression levels of the 52 kDa protein and the E2 subunit protein. Molecular mimicry of TFA-protein adducts by the 52 kDa protein and the E2 subunit protein might play a role in the susceptibility of individuals to development of halothane hepatitis.

Animals↗