Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three further patients with mutations in the codon for arginine 302 of the E1alpha subunit of the pyruvate dehydrogenase complex have been identified. Mutations in this codon have now been found in nine patients with pyruvate dehydrogenase deficiency in seven unrelated families, in sharp contrast to the great majority of other PDH E1alpha mutations which have been described in single individuals only. Because of the relatively high frequency of this mutation and because very few PDH E1alpha mutations have been demonstrated to be causative, we have established a system for analysing the consequences of defined mutations using transfection of normal and mutant PDH E1alpha cDNA into transformed human fibroblasts which have no endogenous E1alpha mRNA or protein. Using this test system, we have demonstrated that the R302C mutation results in the production of PDH E1alpha protein which is devoid of enzymic activity.
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PMID:Arginine 302 mutations in the pyruvate dehydrogenase E1alpha subunit gene: identification of further patients and in vitro demonstration of pathogenicity. 967 Dec 72

The tissue-specific expression of the mitochondrial pyruvate dehydrogenase complex (PDHc) has been studied in an animal model of obesity with hyperinsulinemia, the obese (fa/fa) Zucker rat. Liver and heart were obtained from 4 and 8 week-old obese rats and age-matched lean animals, and in each tissue the following parameters were analyzed: (1) total activity of the mitochondrial PDHc; (2) abundance of the mitochondrial PDHc subunits on Western blots; and (3) abundance of the E1alpha and E1beta subunit mRNAs on Northern blots and semi-quantitative RT-PCR. Regardless of age, obese rats showed an increase in liver total PDHc activity and a coordinate increase in liver E1alpha and E1beta PDHc subunit abundance. At 4 weeks, obese rats also showed an increase in liver PDH E1alpha mRNA level, but regardless of age E1beta mRNA level was unchanged. In contrast, neither total PDHc activity nor the concentration of its protein subunits were increased in heart of obese rats. Thus, obese Zucker rats display a liver-specific early increase in PDHc which results from a selective up-regulation of the E1alpha gene expression.
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PMID:Longitudinal study of tissue- and subunit-specific obesity-induced regulation of the pyruvate dehydrogenase complex. 986 34

Aberrations in cell Ca2+ homeostasis have been known to parallel both changes in membrane lipid composition and aging. Previous work has shown that the lowered efficiency of work performance, which occurs in isolated hearts from rats fed a diet rich in n-6 polyunsaturated fatty acids (PUFA), relative to those fed n-3 PUFA, could be raised by mitochondrial (Mito) Ca2+ transport inhibition. We tested whether, after Ca2+-dependent stress, the Ca2+-dependent activation of pyruvate dehydrogenase (PDHA/PDHTotal) and Mito Ca2+ cycling could be manipulated by varying the ratio of n-3 to n-6 PUFA in Mito membranes in young (6 mo) and aged (24 mo) isolated rat hearts treated to n-3 or n-6 PUFA-rich diet. Inotropic stimulation by 1 microM norepinephrine (NE) of 24-mo n-6 PUFA-rich hearts elevated total Mito Ca2+ content 38% more than in 6-mo hearts (P < 0. 05). However, both the NE-induced rise in Mito Ca2+ and the difference in response between 6- and 24-mo hearts were partially abolished by n-3 PUFA treatment. NE increased the fractional activation of PDH by 44% above control levels in the 6-mo group compared with 49% in the 24-mo group after n-6 PUFA diet. However, NE stimulation of PDHA was attenuated by n-3 PUFA diet, attaining values only 29 and 23% above control levels in 6- and 24-mo mitochondria, respectively (P < 0.05). Global ischemia and reperfusion (I/R) in n-6 PUFA hearts gave rise to higher levels of total Mito Ca2+ concentration (P < 0.0001) and PDHA (P < 0.0001) compared with n-3 PUFA. Ruthenium red (3.4 microM) abolished the effects of I/R in all groups. With aging, heart Mito membrane phosphatidylcholine was increased after n-6 PUFA-rich diet (by approximately 15%, P < 0.05), whereas cardiolipin and n-3 PUFA content were diminished by 31% (P < 0.05) and 73% (P < 0.05), respectively. These effects were prevented by n-3 PUFA-rich diet. The present study, by directly manipulating the cardiac Mito membrane n-3-to-n-6 PUFA ratio, shows that the activation of Ca2+-dependent PDH can be augmented when the n-3-to-n-6 PUFA ratio is low (n-6 PUFA-rich diet; 24-mo hearts) or attenuated when this ratio is relatively high (n-3 PUFA-rich diet). We propose that one of the consequences of dietary-induced manipulation of membrane phospholipids and PUFAs may be the altered flux of Ca2+ across the Mito membrane and thus altered intramitochondrial Ca2+-dependent processes.
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PMID:PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. 988 28

The effect of arsenic compounds depends on the chemical form and is specific for certain organs. The lack of specific biological indicators for the effects of each arsenic species makes it difficult to differentiate their toxicity. Five prospective biological indicators of systemic toxicity were examined at time points ranging from 15 min to 24 h using male Sprague-Dawley rats, B6C3F1 mice, Golden-Syrian hamsters, and Hartley guinea pigs, following intraperitoneal dosing with 0.1 and 1 mg/kg sodium arsenite. Rats and mice were also dosed with 1 mg/kg sodium arsenate. Total blood arsenic levels were determined in all animal species to show that exposure occurred and as an index of the severity of the change is an indicator of toxicity. Total blood arsenic levels were increased in all animal species. This increase was dose, arsenic species, and animal dependent. Renal pyruvate dehydrogenase activity was significantly decreased at early time points in mice, hamsters, and guinea pigs, and at later time points in rats dosed with arsenite. Rats and mice dosed with arsenate also exhibited PDH decrease at early time points. Blood hematocrit and glucose were increased in the rat and guinea pig, respectively, after arsenite administration. Creatinine and urea nitrogen were found to be unresponsive to arsenic in most animal species. Data suggested that the mouse and secondly the hamster appear to be the most appropriate animal models for the study of acute arsenic toxicity.
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PMID:Systemic indicators of inorganic arsenic toxicity in four animal species. 1065 39

The purpose of the study was to examine the roles of active pyruvate dehydrogenase (PDH(a)), glycogen phosphorylase (Phos), and their regulators in lactate (Lac(-)) metabolism during incremental exercise after ingestion of 0.3 g/kg of either NaHCO(3) [metabolic alkalosis (ALK)] or CaCO(3) [control (CON)]. Subjects (n = 8) were studied at rest, rest postingestion, and during constant rate cycling at three stages (15 min each): 30, 60, 75% of maximal O(2) uptake (VO(2 max)). Radial artery and femoral venous blood samples, leg blood flow, and biopsies of the vastus lateralis were obtained during each power output. ALK resulted in significantly (P < 0.05) higher intramuscular Lac(-) concentration ([Lac(-)]; ALK 72.8 vs. CON 65.2 mmol/kg dry wt), arterial whole blood [Lac(-)] (ALK 8.7 vs. CON 7.0 mmol/l), and leg Lac(-) efflux (ALK 10.0 vs. CON 4.2 mmol/min) at 75% VO(2 max). The increased intramuscular [Lac(-)] resulted from increased pyruvate production due to stimulation of glycogenolysis at the level of Phos a and phosphofructokinase due to allosteric regulation mediated by increased free ADP (ADP(f)), free AMP (AMP(f)), and free P(i) concentrations. PDH(a) increased with ALK at 60% VO(2 max) but was similar to CON at 75% VO(2 max). The increased PDH(a) may have resulted from alterations in the acetyl-CoA, ADP(f), pyruvate, NADH, and H(+) concentrations leading to a lower relative activity of PDH kinase, whereas the similar values at 75% VO(2 max) may have reflected maximal activation. The results demonstrate that imposed metabolic alkalosis in skeletal muscle results in acceleration of glycogenolysis at the level of Phos relative to maximal PDH activation, resulting in a mismatch between the rates of pyruvate production and oxidation resulting in an increase in Lac(-) production.
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PMID:Effect of induced metabolic alkalosis on human skeletal muscle metabolism during exercise. 1066 17

The cellular and molecular physiology and pathology of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are mostly studied and understood through the use of animal models. Fundamental differences between the IDDM and NIDDM animal models may help to explain the etiology behind diabetic cardiomyopathy, one of the most severe complications of IDDM. Experimental rat models of IDDM exhibit a characteristic increase in tissue levels of taurine in the heart, a change that is not seen in NIDDM rats. This article deals with the causes and possible consequences of this observation which may contribute to the development of diabetic cardiomyopathy. Modulation of pyruvate dehydrogenase (lipoamide) (PDH; EC 1.2.4.1) activity was found to be a possible mode for taurine involvement. PDH is a mitochondrial protein and is the rate-limiting step in the generation of acetyl CoA from glycolysis. In IDDM, PDH activity is decreased through a mechanism that includes the stimulation of the de novo synthesis of a kinase activator protein (KAP) which phosphorylates PDH and inactivates the enzyme. This lesion does not occur in NIDDM rat hearts. Taurine is known to inhibit the phosphorylation of PDH in vitro, and in taurine-depleted rats PDH phosphorylation is known to increase. Thus, the increased levels of taurine in the diabetic heart may be inhibiting this phosphorylation which in turn may be stimulating the synthesis of KAP through a negative feedback process. The main argument for this theory would be the lack of change in both the taurine levels and the activity of PDH in the NIDDM rat model.
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PMID:The role of taurine in the pathogenesis of the cardiomyopathy of insulin-dependent diabetes mellitus. 1091 50

During the onset of exercise in hypoxia, the increased lactate accumulation is associated with a delayed activation of pyruvate dehydrogenase (PDH; Parolin ML, Spreit LL, Hultman E, Hollidge-Horvat MG, Jones NL, and Heigenhauser GJF. Am J Physiol Endocrinol Metab 278: E522-E534, 2000). The present study investigated whether activation of PDH with dichloroacetate (DCA) before exercise would reduce lactate accumulation during exercise in acute hypoxia by increasing oxidative phosphorylation. Six subjects cycled on two occasions for 15 min at 55% of their normoxic maximal oxygen uptake after a saline (control) or DCA infusion while breathing 11% O(2). Muscle biopsies of the vastus lateralis were taken at rest and after 1 and 15 min of exercise. DCA increased PDH activity at rest and at 1 min of exercise, resulting in increased acetyl-CoA concentration and acetylcarnitine concentration at rest and at 1 min. In the first minute of exercise, there was a trend toward a lower phosphocreatine (PCr) breakdown with DCA compared with control. Glycogenolysis was lower with DCA, resulting in reduced lactate concentration ([lactate]), despite similar phosphorylase a mole fractions and posttransformational regulators. During the subsequent 14 min of exercise, PDH activity was similar, whereas PCr breakdown and muscle [lactate] were reduced with DCA. Glycogenolysis was lower with DCA, despite similar mole fractions of phosphorylase a, and was due to reduced posttransformational regulators. The results from the present study support the hypothesis that lactate production is due in part to metabolic inertia and cannot solely be explained by an oxygen limitation, even under conditions of acute hypoxia.
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PMID:Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia. 1100 55

To gain further insight into the nature and function of the domains of the human protein X (a pyruvate dehydrogenase complex component also known as the E3-binding protein), we expressed the wild-type as well as two artificially created variants, K37E and S422H, in SV40-immortalized protein X-deficient and E2-deficient human skin fibroblasts. The former mutant does not carry the lipoic acid moiety, the latter mutant was designed to investigate the possibility that protein X could exhibit an intrinsic acetyltransferase activity and use either its own catalytic center or the catalytic center of E2. Similar experiments have been performed in the past using the Saccharomyces cerevisiae expression system. However, lack of sequence similarity between the mammalian and the yeast protein X homologues suggests they are not biochemically equivalent. Mutant cells transfected with the wild-type gene for protein X produced a PDH complex that exhibited about 50% overall activity of the control cells. None of the expressed protein X variants had an effect on the specific activity of the PDH complex, suggesting that the human protein X plays a purely structural role in the functioning of the pyruvate dehydrogenase complex.
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PMID:Expression and functional characterization of human protein X variants in SV40-immortalized protein X-deficient and E2-deficient human skin fibroblasts. 1106 72

Tight glycemic control during diabetic pregnancy has been shown to significantly reduce the occurrence of congenital malformations and other effects of maternal diabetes on the offspring. However, intensive insulin therapy often causes recurring acute maternal hypoglycemia, which has been found to be harmful to the developing fetus, although the mechanisms involved are not clear. The aim of our work was to study the effect of acute insulin-induced maternal hypoglycemia on glucose metabolism in the fetal brain. To this end, near-term pregnant New Zealand rabbits were rendered hypoglycemic, and [U-(13)C]glucose was infused into maternal circulation. The metabolic fate of the (13)C-labeled glucose was then studied in fetal brain extracts by (13)C NMR isotopomer analysis, together with conventional biochemical assays of glucose and lactate levels in both plasma and brain. For comparison [U-(13)C]glucose was also administered to insulin-induced hypoglycemic young adult rabbits. Our results showed that while plasma glucose levels were significantly reduced (approximately 70%) relative to controls, no changes in cerebral glucose levels could be detected. Lactate levels were found to be significantly decreased in hypoglycemic fetal plasma and brain. No differences in lactate levels between control and hypoglycemic young rabbit plasma and brain were observed. These differences were attributed to the utilization of lactate as an energy substrate in the fetal brain, but not in the adult brain. Higher relative (13)C enrichments of most glucose metabolites, except lactate, in the hypoglycemic fetal and young rabbit brains, observed by (13)C NMR, stem from reduced endogenous plasma glucose pools, thereby diluting the labeled glucose to a lower extent. The relative glucose (or glucose-derived lactate) flux via the pyruvate carboxylase and pyruvate dehydrogenase pathways (PC/PDH ratio) was not altered under hypoglycemic conditions in the fetal brain for both glutamine and glutamate, but significantly increased in the adult brain for both glutamine and glutamate. The presented data indicate the ability of the fetal brain to maintain energy metabolism during acute hypoglycemia, via lactate utilization. The increase in the adult PC/PDH ratio was suggested by us to stem from increased PC activity, in order to replenish TCA cycle intermediates.
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PMID:Effect of acute insulin-induced hypoglycemia on fetal versus adult brain fuel utilization, assessed by (13)C MRS isotopomer analysis of [U-(13)C]glucose metabolites. 1111 Nov 61

The metabolic importance of pyruvate oxidase (PoxB), which converts pyruvate directly to acetate and CO(2), was assessed using an isogenic set of genetically engineered strains of Escherichia coli. In a strain lacking the pyruvate dehydrogenase complex (PDHC), PoxB supported acetate-independent aerobic growth when the poxB gene was expressed constitutively or from the IPTG-inducible tac promoter. Using aerobic glucose-limited chemostat cultures of PDH-null strains, it was found that steady-states could be maintained at a low dilution rate (0.05 h(-1)) when PoxB is expressed from its natural promoter, but not at higher dilution rates (up to at least 0.25 h(-1)) unless expressed constitutively or from the tac promoter. The poor complementation of PDH-deficient strains by poxB plasmids was attributed to several factors including the stationary-phase-dependent regulation of the natural poxB promoter and deleterious effects of the multicopy plasmids. As a consequence of replacing the PDH complex by PoxB, the growth rate (mu(max)), growth yield (Y(max)) and the carbon conversion efficiency (flux to biomass) were lowered by 33%, 9-25% and 29-39% (respectively), indicating that more carbon has to be oxidized to CO(2) for energy generation. Extra energy is needed to convert PoxB-derived acetate to acetyl-CoA for further metabolism and enzyme analysis indicated that acetyl-CoA synthetase is induced for this purpose. In similar experiments with a PoxB-null strain it was shown that PoxB normally makes a significant contribution to the aerobic growth efficiency of E. coli. In glucose minimal medium, the respective growth rates (mu(max)), growth yields (Y(max)) and carbon conversion efficiencies were 16%, 14% and 24% lower than the parental values, and correspondingly more carbon was fluxed to CO(2) for energy generation. It was concluded that PoxB is used preferentially at low growth rates and that E. coli benefits from being able to convert pyruvate to acetyl-CoA by a seemingly wasteful route via acetate.
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PMID:Pyruvate oxidase contributes to the aerobic growth efficiency of Escherichia coli. 1139 Jun 79


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