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PubMed1992

Mitochondrial factors involved in Parkinson's disease by MPTP toxicity in Macaca fascicularis and drug effect.

The maximal rates (Vmax) of some mitochondrial enzyme activities related to energy transduction (citrate synthase, succinate dehydrogenase, malate dehydrogenase, NADH-cytochrome c reductase, cytochrome oxidase) and amino acid metabolism (glutamate dehydrogenase, glutamate-pyruvate- and glutamate-oxaloacetate- transaminases) were evaluated in non-synaptic ("free") and intrasynaptic "light" and "heavy" mitochondria from hippocampus of Macaca fascicularis (Cynomolgus monkey). The different mitochondrial populations were isolated from the hippocampus of monkeys treated p.o. with dihydroergocryptine at a dose of 12 mg/kg/day before and during the induction of a Parkinson's-like syndrome by MPTP administration (i.v., 0.3 mg/kg/day for 5 days). The MPTP administration modified the activity of some enzymes related to the metabolism of glutamate and the activity of succinate dehydrogenase on selected types of mitochondria. Pharmacological treatment by dihydroergocryptine promoted return to the steady-state levels of most enzymes, demonstrating a protective effect on these biochemical parameters.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Investigation of enzyme defects in children with lactic acidosis.

Screening for enzyme deficiencies was carried out in cultured skin fibroblasts and leukocytes of 19 patients with lactic acidosis and neurological problems. Pyruvate carboxylase deficiency was demonstrated in three cases. Reduced pyruvate oxidation was found in seven cultures; six showed no significant stimulation of the oxidation rate by methylene blue and in three a decreased pyruvate dehydrogenase complex activity was confirmed. Methylene blue restored a near normal oxidation rate in the seventh culture which had decreased cytochrome c oxidase activity.

Acidosis, Lactic↗
PubMed1989

Affinity labeling of chicken liver fatty acid synthase with chloroacetyl-CoA and bromopyruvate.

Fatty acid synthase of chicken liver is inactivated rapidly and irreversibly by incubation with chloroacetyl-CoA or with bromopyruvate. Inactivation by both reagents follows saturation kinetics, indicating the formation of an E ... I complex (dissociation constants of 0.36 microM for chloroacetyl-CoA and 31 microM for bromopyruvate) prior to alkylation. The limiting rate constants are 0.15 s-1 for bromopyruvate and 0.041 s-1 for chloroacetyl-CoA. Inactivation by both reagents is protected by NADPH and 200 mM KCl, and by saturating amounts of thioester substrates which reduced the limiting rate constants 6.5-30-fold. Active-site-directed reaction of chloroacetyl-CoA is supported by the ability of this compound to form a kinetically viable complex with the enzyme as competitive inhibitor of acetyl-CoA. Chloroacetyl-CoA interacts initially at the CoA binding pocket, since the nucleotide afforded competitive protection of inactivation and caused a large decrease in its affinity. Subsequently, the phosphopantetheine prosthetic group is alkylated. Evidence is presented to show that bromopyruvate competes with chloroacetyl-CoA for the same target site.

Acetyl Coenzyme A↗
PubMed1990

Insulin activates 6-phosphofructo-2-kinase and pyruvate kinase in the liver. Indirect evidence for an action via a phosphatase.

The effect of insulin on hepatic glucose production has been studied in anesthetized rats in the postabsorptive state. Insulin decreases significantly hepatic glucose production within 5-10 min. It also increases the level of fructose 2,6-bisphosphate, via an increase in the Vmax of 6-phosphofructo-2-kinase and concomitantly decreased the activity of fructose-2,6-bisphosphatase, resulting in a 5-fold increase in the ratio of kinase/phosphatase. Insulin also increased the apparent Kd of pyruvate kinase for phosphoenolpyruvate. The changes in the activity of 6-phosphofructo-2-kinase and pyruvate kinase were measured after separation from possible modulators, and suggest a decrease in their phosphorylation state which cannot be attributed to a decrease in the level of cAMP or in the activity of cAMP-dependent protein kinase since these two parameters were not modified by insulin. In addition, neither the activity of phosphorylase a nor that of glycogen synthase were modified. The data strongly suggest that the increase in the glycolytic rate plays a role in the effect of insulin on hepatic glucose production and that insulin mediates its effect on the activity of these enzymes via one or more phosphatases.

Adenosine Triphosphate↗
PubMed1990

Tissue distribution of lipogenesis in vivo in the common murre (Uria aalge) and the domestic chicken (Gallus domesticus).

1. Total body lipogenesis was similar in the murre and the chicken. 2. The liver contributes 10.4% to whole body lipogenesis in fed murres when measured in vivo using 3H2O. 3. The liver contributes 28.0% to whole body lipogenesis in the fed chicken. 4. The lower contribution of the liver in the murre may be a consequence of the high fat diet of the murre relative to the chicken.

Acetyl-CoA Carboxylase↗
PubMed2000

Reversal of hypercapnia induces KATP channel and NO-independent constriction of basilar artery in rabbits with acute metabolic alkalosis.

The mechanism of hypocapnic constriction of the cerebral vasculature under conditions of altered acid-base balance has not been investigated. As K(ATP) channels and NO have been implicated in hypocapnic constriction, this study investigated their roles in the constriction due to lowered pCO(2) in hypercapnic rabbits with acute metabolic alkalosis. Metabolic alkalosis was induced acutely following ketamine/xylazine injection. Lowering blood pCO(2) from initial baseline hypercapnic levels to near normocapnic and hypocapnic levels constricted basilar artery by 10.2+/-0.8% (4) and 16.2+/-0.6% (44), respectively (means+/-S.E., n), as determined in an in situ cranial window preparation. The constrictions were maintained for 4-5 h and return of pCO(2) to hypercapnic levels relaxed the constriction. Changing the suffusate pH to either the pH of the cerebral spinal fluid observed during initial baseline hypercapnia or following lowered pCO(2) did not alter the magnitude of constriction due to lowered pCO(2). Neither 0.3 mM N(G)-monomethyl-L-arginine monoacetate, an NO synthase inhibitor, nor 10 microM glibenclamide, a K(ATP) channel blocker, altered the magnitude of hypocapnic constriction. These results demonstrated that under conditions of acute metabolic alkalosis and accompanying compensatory hypercapnia, subsequent pCO(2) reduction induces prolonged constriction of the basilar artery that is independent of (1) cerebral spinal fluid pH over a physiologic range, and (2) NO and K(ATP) channels.

ATP-Binding Cassette Transporters↗
PubMed1997

The rabbit kidney tubule simultaneously degrades and synthesizes glutamate. A 13C NMR study.

The rabbit kidney does not readily metabolize but synthesizes glutamine at high rates by pathways that remain poorly defined. Therefore, the metabolism of variously labeled [13C]- and [14C]glutamates has been studied in isolated rabbit kidney tubules with and without acetate. CO2, glutamine, and alanine were the main carbon and nitrogenous end products of glutamate metabolism but no ammonia accumulated. Absolute fluxes through enzymes involved in glutamate metabolism, including enzymes of four different cycles operating simultaneously, were assessed by combining mainly the 13C NMR data with a new model of glutamate metabolism. In contrast to a previous conclusion of Klahr et al. (Klahr, S., Schoolwerth, A. C., and Bourgoignie, J. J. (1972) Am. J. Physiol. 222, 813-820), glutamate metabolism was found to be initiated by glutamate dehydrogenase at high rates. Glutamate dehydrogenase also operated at high rates in the reverse direction; this, together with the operation of the glutamine synthetase reaction, masked the release of ammonia. Addition of acetate stimulated the operation of the "glutamate --> alpha-ketoglutarate --> glutamate" cycle and the accumulation of glucose but reduced both the net oxidative deamination of glutamate and glutamine synthesis. Acetate considerably increased flux through alpha-ketoglutarate dehydrogenase and citrate synthase at the expense of flux through phosphoenolpyruvate carboxykinase; acetate also caused a large decrease in flux through alanine aminotransferase, pyruvate dehydrogenase, and the "substrate cycle" involving oxaloacetate, phosphoenolpyruvate, and pyruvate.

Animals↗
PubMed2006

Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats.

In the present study we investigated the effect of intrastriatal administration of 150 nmol quinolinic acid to young rats on critical enzyme activities of energy production and transfer, as well as on 14CO2 production from [1-14C]acetate at distinct periods after quinolinic acid injection. We observed that quinolinic acid injection significantly inhibited complexes II (50%), III (46%) and II-III (35%), as well as creatine kinase (27%), but not the activities of complexes I and IV and citrate synthase in striatum prepared 12 h after treatment. In contrast, no alterations of these enzyme activities were observed 3 or 6 h after quinolinic acid administration. 14CO2 production from [1-14C]acetate was also significantly inhibited (27%) by quinolinic acid in rat striatum prepared 12 h after injection. However, no alterations of these activities were observed in striatum homogenates incubated in the presence of 100 microm quinolinic acid . Pretreatment with the NMDA receptor antagonist MK-801 and with creatine totally prevented all inhibitory effects elicited by quinolinic acid administration. In addition, alpha-tocopherol plus ascorbate and the nitric oxide synthase inhibitor l-NAME completely abolished the inhibitions provoked by quinolinic acid on creatine kinase and complex III. Furthermore, pyruvate pretreatment totally blocked the inhibitory effects of quinolinic acid injection on complex II activity and partially prevented quinolinic acid-induced creatine kinase inhibition. These observations strongly indicate that oxidative phosphorylation, the citric acid cycle and cellular energy transfer are compromised by high concentrations of quinolinic acid in the striatum of young rats and that these inhibitory effects were probably mediated by NMDA stimulation.

Animals↗
PubMed2001

Lithium chloride inhibits the expression and secretion of insulin-like growth factor-binding protein-1.

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates IGF availability for glucose homeostasis. The IGFBP-1 promoter shares common regulatory response elements with phosphoenol pyruvate carboxykinase (PEPCK), the expression and activity of which is inhibited by lithium chloride, associated with an inhibition of glycogen synthase kinase (GSK)-3 activity, in the rat hepatoma cell line H4-II-E. We therefore determined the effect of lithium chloride on IGFBP-1 expression and secretion in H4-II-E cells. Lithium chloride inhibited IGFBP-1 secretion in a dose response and reversible manner by approx 80% during 5-h and 16-h incubations. An inhibitory effect on IGFBP-1 mRNA expression was observed at 2 h. The inhibitory effect of lithium and insulin were not additive when used alone, but inhibition by lithium occurred when insulin action was blocked by activating AMP-activated protein kinase with 5-aminoimidazole-4-carboxamide-riboside (AICAR). These findings suggest that GSK-3 inhibition, or another pathway activated by lithium, may be involved in a pathway controlling IGFBP-1, inhibiting synthesis when insulin activity is absent or impaired.

Animals↗
PubMed2006

Thiamin nutrition and catalysis-induced instability of thiamin diphosphate.

Thiamin (vitamin B1) is required in animal diets because it is the precursor of the enzyme cofactor, thiamin diphosphate. Unlike other B vitamins, the dietary thiamin requirement is proportional to non-fat energy intake but there is no obvious biochemical reason for this relationship. In the present communication we show for two enzymes that the cofactor undergoes a slow destruction during catalysis, which may explain the interdependence of thiamin and energy intakes.

Acetolactate Synthase↗
PubMed1978

[Regulation processes in biological systems. II. Role of compartmentation and of organized multienzyme systems].

The picture, emerging from the experimental results on the physical association of multienzyme systems, is that the true physiological significance of the aggregated state can be understood only if it is correlated to the structural and functional integration of the cellular metabolic framework as a whole. The enzyme clusters exhibit two distinct functional properties. The first is the spatial translocation of intermediate substrates, the effect of which may be viewed as metabolic "channelling" or "vectorial catalysis" if the enzyme clusters are arrayed in some manner in the cell. The second is the coordinate regulation which represents an efficient and economical mean of controlling two or more functionally related enzymes. The common element to these two properties is the spatial character, which is potentially present in the function and the regulation of the intermediary metabolism. The biological systems, and metabolism in particular, exhibit both stability and variability; the latter sometimes assumes the character of periodicity. Whether the oscillations have a definite importance at the level of the intermediary metabolism itself, may well be questioned; the oscillatory faculties may rather serve as elements to be used in more complex functions of the biological systems. A thorough understanding of the role of clustered multienzyme systems and of the oscillatory phenomena in cellular metabolism demands a clearer physicochemical picture of the dynamic state of the living cell than we have at present. For this reason some of the generalizations derived from in vitro studies of single, isolated enzyme activities are not justified.

Adenosine Triphosphate↗
PubMed2005

Receptor-type protein tyrosine phosphatase epsilon (PTPepsilonM) is a negative regulator of insulin signaling in primary hepatocytes and liver.

Impaired insulin receptor (IR) signaling leads to insulin resistance and type 2 diabetes mellitus. Several inhibitors of the IR tyrosine kinase activity have recently been described and associated with human insulin resistance. Among these negative regulators, protein tyrosine phosphatases (PTPs) are likely to play a pivotal role in IR signaling. Transgenic studies revealed that PTP1B and TCPTP are primary candidates but IR of these animals can be finally dephosphorylated, suggesting that other PTPs are also involved in the dephosphorylation of IR. In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163 were primary targets of PTP epsilonM. Wild type as well as substrate-trapping DA forms of PTPepsilonM suppressed phosphorylation of IR downstream enzymes such as Akt, extracellular regulated kinase (ERK) and glycogen synthase kinase 3 (GSK3). It was also demonstrated that PTPepsilonM suppressed insulin-induced glycogen synthesis and inhibited insulin-induced suppression of phosphoenol pyruvate carboxykinase (PEPCK) expression in primary hepatocytes. Furthermore, adenovirally introduced PTPepsilonM also exhibited inhibitory activity against suppression of PEPCK expression in mouse liver. These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.

Analysis of Variance↗
PubMedDate not supplied

Physiological differentiation of the mitochondria during Bufo bufo development.

1) The oxygen consumption increases during Bufo bufo development in accordance with the two steps which border at the "heart beat" stage. 2) Cytochrome c oxidase activity is not proportional to the oxygen consumption: it is notable and constant in the first step, and it only increases in the second. 3) In the mitochondria of preneural embryos, citrate synthase, NADP+ dependent isocitrate dehydrogenase, and succinate dehydrogenase activities are very low in respect to malate dehydrogenase and glutamate oxaloacetate transaminase activities. The Krebs cycle results lowered at the condensing reaction level with acetyl accumulation when pyruvate is available. The same behavior has been observed in the Xenopus laevis oocytes and differentiated tissues. 4) The presence of a phosphagen system which is different from creatine phosphate and arginine phosphate, supporting ATP level, has been demonstrated in B. bufo embryos. 5) Mitochondria of postneural embryos are able to accomplish a complete Krebs cycle by increasing citrate synthase, and succinate dehydrogenase activities. 6) In all B. bufo development, malate dehydrogenase and glutamate oxaloacetate transaminase constitute a multienzymatic system by which the mitochondria accomplish a decarboxylic amino acid shunt required for the transformation of deutoplasm into protoplasm. This shunt is also operative in the X. laevis oocytes. 7) Through pyruvate production, by oxidative decarboxylation of malate, the NAD(P)+ dependent malic enzyme could carry out a fundamental anaplerotic function in the mitochondria which is specialized in the production of biosynthetic blocks belonging to the embryo in which the carbohydrates metabolism rather than the glycolytic activity is designed for pentose phosphate and glycerol phosphate synthesis for protein and cytomembrane production. 8) Consistent metabolic differences have been highlighted between B. bufo embryos and X. laevis embryos.

Animals↗
PubMed2001

The iron-sulfur center of biotin synthase: site-directed mutants.

Biotin synthase contains an essential [4Fe-4S]+ cluster that is thought to provide an electron for the cleavage of S-adenosylmethionine, a cofactor required for biotin formation. The conserved cysteine residues Cys53, Cys57 and Cys60 have been proposed as ligands to the [4Fe-4S] cluster. These residues belong to a C-X3-C-X2-C motif which is also found in pyruvate formate lyase-activating enzyme, lysine 2,3-aminomutase and the anaerobic ribonucleotide reductase-activating component. To investigate the role of the cysteine residues, Cys-->Ala mutants of the eight cysteine residues of Escherichia coli biotin synthase were prepared and assayed for activity. Our results show that six cysteines are important for biotin formation. Only two mutant proteins, C276A and C288A, closely resembled the wild-type protein, indicating that the corresponding cysteines are not involved in iron chelation and biotin formation. The six other mutant proteins, C53A, C57A, C60A, C97A, C128A and C188A, were inactive but capable of assembling a [4Fe-4S] cluster, as shown by Mössbauer spectroscopy. The C53A, C57A and C60A mutant proteins are unique in that their cluster could not undergo reduction to the [4Fe-4S]+ state, as shown by EPR and Mössbauer spectroscopy. On this basis and by analogy with pyruvate formate lyase-activating enzyme and the anaerobic ribonucleotide reductase-activating component, it is suggested that the corresponding cysteines coordinate the cluster even though one cannot fully exclude the possibility that other cysteines play that role as well. Therefore it appears that for activity biotin synthase absolutely requires cysteines that are not involved in iron chelation.

Acetyltransferases↗
PubMed1983

Effects of exercise training on muscle protein catabolism in uremia.

The effects of exercise training on muscle protein catabolism in uremia were studied in female rats. Rats made uremic by 3/4 nephrectomy were compared with sham-operated control female rats under conditions of exercise training by swimming or no exercise. The release of amino acids from epitrochlearis muscle in vitro was measured. Body weight epitrochlearis muscle weight, and epitrochlearis protein content were similar among groups. Uremia increased the release of phenylalanine and tyrosine 33% and alanine 50% from muscle of sedentary rats. Citrate synthase activity and glycogen content of muscle were increased twofold by exercise in both controls and uremics. Exercise increased the release of alanine (60%), glutamine (50%), and pyruvate (30%) from muscles of control rats, but it decreased to control levels the release of phenylalanine and tyrosine in uremic rats. Alanine release remained elevated. To determine if exercise training increases in vitro muscle sensitivity to insulin, we incubated muscle with and without 0.01 U/ml of insulin. Phenylalanine and tyrosine release was reduced minimally by insulin in both sedentary uremic and control groups. Glucose uptake was enhanced by 55% in both groups. But in the exercised uremic and control groups, insulin reduced phenylalanine and tyrosine release by 50% and increased glucose uptake by 75%. These results suggest that exercise training reduces muscle protein catabolism in uremia; and this reduction is associated with enhanced muscle response to pharmacologic doses of insulin in control and uremic rats.

Amino Acids↗