Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular free Zn(2+) is elevated in a variety of pathological conditions, including ischemia-reperfusion injury and Alzheimer's disease. Impairment of mitochondrial respiration is also associated with these pathological conditions. To test whether elevated Zn(2+) and impaired respiration might be linked, respiration of isolated rat liver mitochondria was measured after addition of Zn(2+). Zn(2+) inhibition (K(i)(app) = approximately 1 micrometer) was observed for respiration stimulated by alpha-ketoglutarate at concentrations well within the range of intracellular Zn(2+) reported for cultured hepatocytes. The bc(1) complex is inhibited by Zn(2+) (Link, T. A., and von Jagow, G. (1995) J. Biol. Chem. 270, 25001-25006). However, respiration stimulated by succinate (K(i)(app) = approximately 6 micrometer) was less sensitive to Zn(2+), indicating the existence of a mitochondrial target for Zn(2+) upstream from bc(1) complex. Purified pig heart alpha-ketoglutarate dehydrogenase complex was strongly inhibited by Zn(2+) (K(i)(app) = 0.37 +/- 0.05 micrometer). Glutamate dehydrogenase was more resistant (K(i)(app) = 6 micrometer), malate dehydrogenase was unaffected, and succinate dehydrogenase was stimulated by Zn(2+). Zn(2+) inhibition of alpha-ketoglutarate dehydrogenase complex required enzyme cycling and was reversed by EDTA. Reversibility was inversely related to the duration of exposure and the concentration of Zn(2+). Physiological free Zn(2+) may modulate hepatic mitochondrial respiration by reversible inhibition of the alpha-ketoglutarate dehydrogenase complex. In contrast, extreme or chronic elevation of intracellular Zn(2+) could contribute to persistent reductions in mitochondrial respiration that have been observed in Zn(2+)-rich diseased tissues.
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PMID:Zn2+ inhibits alpha-ketoglutarate-stimulated mitochondrial respiration and the isolated alpha-ketoglutarate dehydrogenase complex. 1078 56

Aluminum is a neurotoxic agent for animals and humans that has been implicated as an etiological factor in several neurodegenerative diseases and as a destabilizer of cell membranes. Due to its high reactivity, Al3+ is able to interfere with several biological functions, including enzymatic activities in key metabolic pathways. In this paper we report that, among the enzymes that constitute the Krebs cycle, only two are activated by aluminum: alpha-ketoglutarate dehydrogenase and succinate dehydrogenase. In contrast, aconitase, shows decreased activity in the presence of the metal ion. Al3+ also inhibits glutamate dehydrogenase, an allosteric enzyme that is closely linked to the Krebs cycle. A possible correlation between aluminum, the Krebs cycle and aging processes is discussed.
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PMID:Effects of aluminum on activity of krebs cycle enzymes and glutamate dehydrogenase in rat brain homogenate. 1080 5

Studies of respiration on glucose in procyclic Trypanosoma congolense in the presence of rotenone, antimycin, cyanide, salicylhydroxamic acid and malonate have indicated the presence of NADH dehydrogenase, cytochrome b-c1, cytochrome aa3, trypanosome alternate oxidase and NADH fumarate reductase/succinate dehydrogenase pathway that contributes electrons to coenzyme Q of the respiratory chain. The rotenone sensitive NADH dehydrogenase, the trypanosome alternate oxidase, and cytochrome aa3 accounted for 24.5 +/- 6.5, 36.2 +/- 4.2 and 54.1 +/- 5.5% respectively of the total respiration. Activities of lactate dehydrogenase, NAD(+)-linked malic enzyme and pyruvate kinase were less than 6 nanomoles/min/mg protein suggesting that they play a minor role in energy metabolism of the parasite. Phosphoenolpyruvate carboxykinase, pyruvate dehydrogenase, succinate dehydrogenase, NADP(+)-linked malic enzyme, NADH fumarate reductase, malate dehydrogenase, and alpha-ketoglutarate dehydrogenase and glycerol kinase on the other hand had specific activities greater than 60 nanomoles/min/mg protein. These enzyme activities could account for the production of pyruvate, acetate, succinate and glycerol. The results further show that the amount of glycerol produced was 35-48% of the combined total of pyruvate, acetate and succinate produced. It is apparent that some of the glycerol 3-phosphate produced in glycolysis in the presence of salicylhydroxamic acid is dephosphorylated to form glycerol while the rest is oxidised via cytochrome aa3 to form acetate, succinate and pyruvate.
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PMID:Pathways of glucose catabolism in procyclic Trypanosoma congolense. 1084 79

The major initial product of the oxidation of norepinephrine (NE) in the presence of L-cysteine is 5-S-cysteinylnorepinephrine which is then further easily oxidized to the dihydrobenzothiazine (DHBT) 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-NE-1). When incubated with intact rat brain mitochondria, DHBT-NE-1 evokes rapid inhibition of complex I respiration without affecting complex II respiration. DHBT-NE-1 also evokes time- and concentration-dependent irreversible inhibition of NADH-coenzyme Q(1) (CoQ(1)) reductase, the pyruvate dehydrogenase complex (PDHC), and alpha-ketoglutarate dehydrogenase (alpha-KGDH) when incubated with frozen and thawed rat brain mitochondria (mitochondrial membranes). The time dependence of the inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by DHBT-NE-1 appears to be related to its oxidation, catalyzed by an unknown component of the inner mitochondrial membrane, to electrophilic intermediates which bind covalently to active site cysteinyl residues of these enzyme complexes. The latter conclusion is based on the ability of glutathione to block inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by scavenging electrophilic intermediates, generated by the mitochondrial membrane-catalyzed oxidation of DHBT-NE-1, forming glutathionyl conjugates, several of which have been isolated and spectroscopically identified. The possible implications of these results to the degeneration of neuromelanin-pigmented noradrenergic neurons in the locus ceruleus in Parkinson's disease are discussed.
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PMID:Oxidative metabolites of 5-S-cysteinylnorepinephrine are irreversible inhibitors of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes: possible implications for neurodegenerative brain disorders. 1095 63

A characteristic change in the substantia nigra of Parkinson's disease patients is an apparent accelerated rate of dopamine oxidation as evidenced by an increased 5-S-cysteinyldopamine (5-S-CyS-DA) to dopamine ratio. However, 5-S-CyS-DA is more easily oxidized than dopamine to give 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Previous studies have demonstrated that DHBT-1 can be accumulated by intact rat brain mitochondria and inhibits complex I but not complex II respiration. In this study, it is shown that DHBT-1 also inhibits the alpha-ketoglutarate dehydrogenase complex (alpha-KGDH) but not cytochrome c oxidase (complex IV). The inhibition of alpha-KGDH is dependent on the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an electrophilic o-quinone imine that covalently modifies active site sulfhydryl residues. The latter conclusion is based on the ability of > or = equimolar glutathione to block the inhibition of alpha-KGDH by DHBT-1, without altering its rate of mitochondrial membrane-catalyzed oxidation, by scavenging the electrophilic o-quinone intermediate forming glutathionyl conjugates which have been isolated and spectroscopically characterized. Activities of mitochondrial alpha-KGDH and complex I, but not other respiratory complexes, are decreased in the parkinsonian substantia nigra. Such changes together with evidence for accelerated dopamine oxidation, increased formation of 5-S-CyS-DA and the ease of oxidation of this conjugate to DHBT-1 which inhibits alpha-KGDH and complex I, without affecting other respiratory enzyme complexes, suggests that the latter putative metabolite might be an endotoxin that contributes to the alpha-KGDH and complex I defects in Parkinson's disease.
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PMID:Oxidative metabolites of 5-S-cysteinyldopamine inhibit the alpha-ketoglutarate dehydrogenase complex: possible relevance to the pathogenesis of Parkinson's disease. 1104 Dec 75

We have studied cultured skin fibroblasts from three siblings and one unrelated individual, all of whom had fatal mitochondrial disease manifesting soon after birth. After incubation with 1 mM glucose, these four cell strains exhibited lactate/pyruvate ratios that were six times greater than those of controls. On further analysis, enzymatic activities of the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, NADH cytochrome c reductase, succinate dehydrogenase, and succinate cytochrome c reductase were severely deficient. In two of the siblings the enzymatic activity of cytochrome oxidase was mildly decreased (by approximately 50%). Metabolite analysis performed on urine samples taken from these patients revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of both the glycine-cleavage system and branched-chain alpha-ketoacid dehydrogenase. In contrast, the activities of fibroblast pyruvate carboxylase, mitochondrial aconitase, and citrate synthase were normal. Immunoblot analysis of selected complex III subunits (core 1, cyt c(1), and iron-sulfur protein) and of the pyruvate dehydrogenase complex subunits revealed no visible changes in the levels of all examined proteins, decreasing the possibility that an import and/or assembly factor is involved. To elucidate the underlying molecular defect, analysis of microcell-mediated chromosome-fusion was performed between the present study's fibroblasts (recipients) and a panel of A9 mouse:human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells from both families and the mouse:human hybrid clone carrying human chromosome 2. These results indicate that the underlying defect in our patients is under the control of a nuclear gene, the locus of which is on chromosome 2. A 5-cM interval has been identified as potentially containing the critical region for the unknown gene. This interval maps to region 2p14-2p13.
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PMID:A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. 1115 34

During normal cellular metabolism, mitochondrial electron transport results in the formation of superoxide anion (O(2)) and subsequently hydrogen peroxide (H(2)O(2)). Because H(2)O(2) increases in concentration under certain physiologic and pathophysiologic conditions and can oxidatively modify cellular components, it is critical to understand the response of mitochondria to H(2)O(2). In the present study, treatment of isolated rat heart mitochondria with H(2)O(2) resulted in a decline and subsequent recovery of state 3 NADH-linked respiration. Alterations in NADH levels induced by H(2)O(2) closely paralleled changes in the rate of state 3 respiration. Assessment of electron transport chain complexes and Krebs cycle enzymes revealed that alpha-ketoglutarate dehydrogenase (KGDH), succinate dehydrogenase (SDH), and aconitase were susceptible to H(2)O(2) inactivation. Of particular importance, KGDH and SDH activity returned to control levels, concurrent with the recovery of state 3 respiration. Inactivation is not because of direct interaction of H(2)O(2) with KGDH and SDH. In addition, removal of H(2)O(2) alone is not sufficient for reactivation. Enzyme activity does not recover unless mitochondria remain intact. The sensitivity of KGDH and SDH to H(2)O(2)-mediated inactivation and the reversible nature of inactivation suggest a potential role for H(2)O(2) in the regulation of KGDH and SDH.
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PMID:Modulation of mitochondrial function by hydrogen peroxide. 1128 20

The activity level and some physico-chemical properties of enzymes of the tricarboxylic acid cycle (TCA cycle) and the associated enzymes isocitrate lyase and glutamate dehydrogenase of cyanobacterium Spirulina platensis grown under illumination of 5000 lk in batch conditions, have been studied. High activities of most of the studied enzymes except for alpha-ketoglutarate dehydrogenase (alpha-KGDH) and succinate dehydrogenase have been estimated. In some cases the activities were by an order higher than that of similar enzymes in other cyanobacteria. This reflects the microorganism ability to synthesize intensively organic substances and first of all protein. Absence of alpha-KGDH activity proves that TCA cycle of spirulina has a limited value for energy generation and mainly performs the biosynthetic function.
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PMID:[Activity of tricarboxylic acid cycle enzymes in cyanobacteria Spirulina platensis]. 1130 83

In crude cell extracts of the ectomycorrhizal fungus, Suillus bovinus, activities of citrate synthase, aconitase, isocitrate dehydrogenase, succinate dehydrogenase, fumarase, and malate dehydrogenase have been proved and analyzed. Citrate synthase exhibited high affinities for both its substrates: oxaloacetate (Km = 0.018 mM) and acetyl-CoA (Km = 0.014 mM). Aconitase showed better affinity for isocitrate (Km = 0.62 mM) than for citrate (Km = 3.20 mM). Analysis of isocitrate dehydrogenase revealed only small maximum activity (60 nmol x mg protein(-1) x min(-1)), the enzyme being exclusively NADP+-dependent. Using the artificial electron acceptor dichlorophenol indophenol, activity and substrate affinity of succinate dehydrogenase were rather poor. Fumarase proved Fe2+-independent. Its affinity for malate was found higher (Km = 1.19 mM) than that for fumarate (Km = 2.09 mM). High total activity of malate dehydrogenase could be separated by native PAGE into a slowly running species of (mainly) cytosolic (about 80%) and a faster running species of (mainly) mitochondrial origin. Affinities for oxaloacetate of the two enzyme species were found identical within limits of significance (Km = 0.24 mM and 0.22 mM). The assumed cytosolic enzyme exhibited affinity for malate (Km = 5.77 mM) more than one order of magnitude lower than that for oxaloacetate. FPLC on superose 12 revealed only one activity band at a molecular mass of 100 +/- 15 kDa. Activities of 2-oxoglutarate dehydrogenase and of succinyl-CoA synthetase could not be found. Technical problems in their detection, but also existence of an incomplete tricarboxylic acid cycle are considered. Metabolite affinities, maximum activities and pH-dependences of fumarase and of malate dehydrogenase allow the assumption of a reductive instead of oxidative function of these enzymes in vivo.
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PMID:Tricarboxylic acid cycle enzymes of the ectomycorrhizal basidiomycete, Suillus bovinus. 1142 46

Mitochondrial dysfunction appears to contribute to some of the loss of function accompanying ageing. Mitochondria from aged tissue use oxygen inefficiently impairing ATP synthesis and results in increased oxidant production. A high flux of oxidants not only damages mitochondria, but other important cell biomolecules as well. In the present investigation, the levels of lipid peroxidation, oxidized glutathione, non-enzymatic antioxidants and the activities of mitochondrial enzymes were measured in liver and kidney mitochondria of young and aged rats before and after lipoic acid supplementation. In both liver and kidney increase in the levels of mitochondrial lipid peroxidation and oxidized glutathione and decrease in the levels of antioxidants and the activities of mitochondrial enzymes were observed in aged rats. DL-alpha-lipoic acid supplemented aged rats showed a decrease in the levels of lipid peroxidation and oxidized glutathione and increase in the levels of reduced glutathione, vitamins C and E and the activities of mitochondrial enzymes like isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, NADH-dehydrogenase and cytochrome-c-oxidase. Thus, lipoic acid reverses the age-associated decline in endogenous low molecular weight antioxidants and mitochondrial enzymes and, therefore, may lower the increased risk of oxidative damage that occurs during ageing. From our results it can be concluded that lipoic acid supplementation enhances the activities of mitochondrial enzymes and antioxidant status and thereby protects mitochondria from ageing.
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PMID:Effect of DL-alpha-lipoic acid on mitochondrial enzymes in aged rats. 1167


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