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)

Malonic acidaemia is an inborn error of metabolism that accumulates malonate, a competitive succinate dehydrogenase (SDH; EC 1.3.99.1) inhibitor. The present study investigated the behavioural effects of unilateral intrastriatal administration of malonate (0.6, 1.8 or 6 micromol) in adult male Wistar rats (n=10-13). Low doses of malonate (1.8 micromol) decreased exploratory activity and caused ipsiversive rotational behaviour. High doses of malonate (6 micromol) induced contralateral rotational behaviour and convulsive episodes. Malonate competitively inhibited SDH in mitochondrion-enriched fractions from striatum ( Ki=0.034+/-0.008 mmol/L). Interestingly, methylmalonate, which is a weaker SDH inhibitor than malonate (Ki=4.22+/-1.3 mmol/L), induced more convulsions than malonate at equimolar doses and did not cause ipsiversive rotational behaviour. It is suggested that the potency of SDH inhibition in vitro does not correlate positively with the convulsant potential of these inhibitors in vivo.
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PMID:Intrastriatal malonate administration induces convulsive behaviour in rats. 1515 52

The antiepileptic drug valproate (VPA) may be neuroprotective. We treated rats with VPA for 14 days (300 mg/kg twice daily) before intrastriatal injection of 1.5 micromol (1 M) of the succinate dehydrogenase inhibitor malonate. VPA-treated animals developed smaller lesions than control animals: 10 +/- 2 mm(3) versus 26 +/- 8 mm(3) (means +/- SD; P = 10(-4). Injection of NaCl that was equiosmolar with 1 M malonate caused lesions of only 1.2 +/- 0.4 mm(3) in control animals, whereas physiologic saline produced no lesion. VPA pretreatment reduced the malonate-induced extracellular accumulation of glutamate. This effect paralleled an increase in the striatal level of the glutamate transporter GLT, which augmented high-affinity glutamate uptake by 25%, as determined from the uptake of [(3)H] glutamate into striatal proteoliposomes. Malonate caused a 76% reduction in striatal adenosine triphosphate (ATP) content, but the glial, ATP-dependent formation of glutamine from radiolabeled glucose or glutamate was intact, indicating that glial ATP production supported uptake of glutamate. Striatal levels of HSP-70 and fos were reduced, and the levels of bcl-2 and phosphorylated extracellular signal-regulated kinase remained unaffected, but histone acetylation was increased by VPA treatment. The results suggest that augmentation of glutamate uptake may contribute importantly to VPA-mediated neuroprotection in striatum.
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PMID:Valproate is neuroprotective against malonate toxicity in rat striatum: an association with augmentation of high-affinity glutamate uptake. 1554 16

1. Herein we study the effects of the mitochondrial complex II inhibitor malonate on its primary target, the mitochondrion. 2. Malonate induces mitochondrial potential collapse, mitochondrial swelling, cytochrome c (Cyt c) release and depletes glutathione (GSH) and nicotinamide adenine dinucleotide coenzyme (NAD(P)H) stores in brain-isolated mitochondria. 3. Although, mitochondrial potential collapse was almost immediate after malonate addition, mitochondrial swelling was not evident before 15 min of drug presence. This latter effect was blocked by cyclosporin A (CSA), Ruthenium Red (RR), magnesium, catalase, GSH and vitamin E. 4. Malonate added to SH-SY5Y cell cultures produced a marked loss of cell viability together with the release of Cyt c and depletion of GSH and NAD(P)H concentrations. All these effects were not apparent in SH-SY5Y cells overexpressing Bcl-xL. 5. When GSH concentrations were lowered with buthionine sulphoximine, cytoprotection afforded by Bcl-xL overexpression was not evident anymore. 6. Taken together, all these data suggest that malonate causes a rapid mitochondrial potential collapse and reactive oxygen species production that overwhelms mitochondrial antioxidant capacity and leads to mitochondrial swelling. Further permeability transition pore opening and the subsequent release of proapoptotic factors such as Cyt c could therefore be, at least in part, responsible for malonate-induced toxicity.
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PMID:Malonate induces cell death via mitochondrial potential collapse and delayed swelling through an ROS-dependent pathway. 1565 18

A study was made of respiration, output of K+ and ultrastructure of wheat root cells treated for 6 h with malonic acid (MA) (15 mM), an inhibitor of succinate dehydrogenase. After a 1 h treatment, on the background of a decrease in respiration, and output of K+ an increased number of lumens of smooth endoplasmic reticulum was observed. These changes may be the result of lipid biosynthesis. Within first hours of treatment with MA, the mitochondrial matrix was becoming more brightened, and after 3 h all organelles became transparent. Moreover, mitochondria increased in size and almost lacked cristae. After 4 h mitochondria assumed their normal sizes due, presumably, to a competitive action of malonate. After 5 h the matrix was brightened again, mitochondria augmented in size, several organelles acquired torus shapes, and their outer area was eventually increased. We found contacts of endoplasmic reticulum lumens with mitochondria, which may suggest the synthesis of an enzyme, able to transform to malonate. After a 6 h exposure of MA, we observed the increase of respiration, re-entry of K+ and normal ultrastructure of mitochondria. Based on our experiments, we conclude that adaptation of root cells may be a result of external NADPH-dehydrogenase activity and MA detoxification.
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PMID:[Effect of malonate on the structural and functional changes of wheat Triticum aestivum L. root cells]. 1570 78

Malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, is frequently used as a model neurotoxin to produce lesion of the nigrostriatal dopaminergic system in animals due to particular sensitivity of dopamine neurons to mild energy impairment. This model of neurotoxicity was applied in our study to explore neuroprotective potential of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance whose function in the mammalian brain, despite extensive studies, has not been elucidated so far. Injection of malonate at a dose of 3 mumol unilaterally into the rat left medial forebrain bundle resulted in the 54% decrease in dopamine (DA) concentration in the ipsilateral striatum and, depending on the examined striatum regions, caused 24-44% reduction in [3H]GBR12,935 binding to the dopamine transporter (DAT). TIQ (50 mg/kg i.p.) administered 4 h before malonate infusion and next once daily for successive 7 days prevented both these effects of malonate. Such TIQ treatment restored DA content and DAT binding almost to the control level. The results of the present study indicate that TIQ may act as a neuroprotective agent in the rat brain. An inhibition of the enzymatic activities of monoamine oxidase and gamma-glutamyl transpeptidase as well as an increase in the striatal levels of glutathione and nitric oxide found after TIQ administration and reported in our earlier studies are considered to be potential factors that may be involved in the TIQ-mediated protection of dopamine terminals from malonate toxicity.
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PMID:1,2,3,4-Tetrahydroisoquinoline protects terminals of dopaminergic neurons in the striatum against the malonate-induced neurotoxicity. 1600 76

The mechanism of fumarate reduction in Geobacter sulfurreducens was investigated. The genome contained genes encoding a heterotrimeric fumarate reductase, FrdCAB, with homology to the fumarate reductase of Wolinella succinogenes and the succinate dehydrogenase of Bacillus subtilis. Mutation of the putative catalytic subunit of the enzyme resulted in a strain that lacked fumarate reductase activity and was unable to grow with fumarate as the terminal electron acceptor. The mutant strain also lacked succinate dehydrogenase activity and did not grow with acetate as the electron donor and Fe(III) as the electron acceptor. The mutant strain could grow with acetate as the electron donor and Fe(III) as the electron acceptor if fumarate was provided to alleviate the need for succinate dehydrogenase activity in the tricarboxylic acid cycle. The growth rate of the mutant strain under these conditions was faster and the cell yields were higher than for wild type grown under conditions requiring succinate dehydrogenase activity, suggesting that the succinate dehydrogenase reaction consumes energy. An orthologous frdCAB operon was present in Geobacter metallireducens, which cannot grow with fumarate as the terminal electron acceptor. When a putative dicarboxylic acid transporter from G. sulfurreducens was expressed in G. metallireducens, growth with fumarate as the sole electron acceptor was possible. These results demonstrate that, unlike previously described organisms, G. sulfurreducens and possibly G. metallireducens use the same enzyme for both fumarate reduction and succinate oxidation in vivo.
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PMID:Genetic characterization of a single bifunctional enzyme for fumarate reduction and succinate oxidation in Geobacter sulfurreducens and engineering of fumarate reduction in Geobacter metallireducens. 1638 34

Chlorella vulgaris Beyerinck (Emerson's strain), fails to grow in the dark even when sugars are provided. This phenomenon was clearly demonstrated in the alga, C. vulgaris, for which the growth rate in darkness on a glucose medium remained constant for 2 days and then declined to approach zero. Pigment concentrations also declined in darkness. Changes in flow rate of 1% CO(2)-in-air from zero to 7 ml per minute caused a progressive increase in the dark growth rate over a 5-day period, but did not maintain growth in the dark. Rates above 7 ml per minute produced no changes in growth rates.White light intensities below the compensation point of the alga maintained heterotrophic growth. The saturation value for this response was 0.8 muw/cm(2). White light also initiated growth in nongrowing cultures transferred from darkness to light.The action spectrum for heterotrophic growth indicated a porphyrin as the active pigment. Light in the 425 mmu region was 4 times as effective as white light in stimulating heterotrophic growth. A secondary peak of growth stimulation occurred in the 575 mmu region.The respiration of glucose by the alga was stimulated by low intensities of white light. This response was not immediate, but was clearly present after the third day of incubation.Malonate and cyanide were inhibitory to growth of C. vulgaris on inorganic medium or glucose medium under 300 ft-c of white light. These data suggested that succinic dehydrogenase and cytochrome oxidase systems were present.Substances inhibitory to growth were excreted into the medium under dark-growth conditions, and 2 of these substances were indentified as formic and acetic acids.The evidence suggested that respiration of glucose cannot proceed for an extended period of time in darkness. The reason for this is postulated to be the lack of a cytochrome or a cytochrome precursor.
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PMID:Responses of Heterotrophic Cultures of Chlorella vulgaris Beyerinck to Darkness and Light. II. Action Spectrum for and Mechanism of the Light Requirement for Heterotrophic Growth. 1665 34

A method for isolating intact chloroplasts from Chlamydomonas reinhardtii F-60 was developed from the Klein, Chen, Gibbs, Platt-Aloia procedure ([1983] Plant Physiol 72: 481-487). Protoplasts, generated by treatment with autolysine, were lysed with a solution of digitonin and fractionated on Percoll step gradients. The chloroplasts were assessed to be 90% intact (ferricyanide assay) and free from cytoplasmic contamination (NADP isocitrate dehydrogenase activity) and to range from 2 to 5% in mitochondrial contamination (cytochrome c oxidase activity). About 25% of the cellular succinate dehydrogenase activity (21.6 micromoles per milligram chlorophyll per hour, as determined enzymically) was placed within the chloroplast. Chloroplastic succinate dehydrogenase had a K(m) for succinate of 0.55 millimolar and was associated with the thylakoidal material derived from the intact chloroplasts. This same thylakoidal material, with an enzymic assay of 21.6 micromoles per milligram chlorophyll per hour was able to initiate a light-dependent uptake of oxygen at a rate of 16.4 micromoles per milligram chlorophyll per hour when supplied with succinate and methyl viologen. Malonate was an apparent competitive inhibitor of this reaction. The succinate dehydrogenase activity present in the chloroplast was sufficient to account for the photoanaerobic rate of acetate dissimilation in H(2) adapted Chlamydomonas (M Gibbs, RP Gfeller, C Chen [1986] Plant Physiol 82: 160-166).
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PMID:Evidence for Chloroplastic Succinate Dehydrogenase Participating in the Chloroplastic Respiratory and Photosynthetic Electron Transport Chains of Chlamydomonas reinhardtii. 1666 55

Methylmalonic acidemia (MMAemia) is an inherited metabolic disorder of branched amino acid and odd-chain fatty acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Systemic and neurological manifestations in this disease are thought to be associated with the accumulation of methylmalonate (MMA) in tissues and biological fluids with consequent impairment of energy metabolism and oxidative stress. In the present work we studied the effect of MMA and two other inhibitors of mitochondrial respiratory chain complex II (malonate and 3-nitropropionate) on the activity of lactate dehydrogenase (LDH) in tissue homogenates from adult rats. MMA potently inhibited LDH-catalyzed conversion of lactate to pyruvate in liver and brain homogenates as well as in a purified bovine heart LDH preparation. LDH was about one order of magnitude less sensitive to inhibition by MMA when catalyzing the conversion of pyruvate to lactate. Kinetic studies on the inhibition of brain LDH indicated that MMA inhibits this enzyme competitively with lactate as a substrate (K (i)=3.02+/-0.59 mM). Malonate and 3-nitropropionate also strongly inhibited LDH-catalyzed conversion of lactate to pyruvate in brain homogenates, while no inhibition was observed by succinate or propionate, when present in concentrations of up to 25 mM. We propose that inhibition of the lactate/pyruvate conversion by MMA contributes to lactate accumulation in blood, metabolic acidemia and inhibition of gluconeogenesis observed in patients with MMAemia. Moreover, the inhibition of LDH in the central nervous system may also impair the lactate shuttle between astrocytes and neurons, compromising neuronal energy metabolism.
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PMID:Lactate dehydrogenase activity is inhibited by methylmalonate in vitro. 1675 63

Most Candida albicans cells cultured in RPMI1640 medium at 37 degrees C grow in hyphal form in aerobic conditions, but they grow in yeast form in anaerobic conditions. The hyphal growth of C. albicans was inhibited in glucose-deficient conditions. Malonic acid, an inhibitor of succinate dehydrogenase, enhanced the yeast proliferation of C. albicans, indicating that the hyphal-formation signal was derived from the glycolysis system and the signal was transmitted to the electron transfer system via the citric acid cycle. Thenoyl trifluoro acetone (TTFA), an inhibitor of the signal transmission between complex II and Co Q, significantly inhibited the hyphal growth of C. albicans. Antimycin, KCN, and oligomycin, inhibitors of complex III, IV, and V, respectively, did not inhibit the hyphal growth of C. albicans. The production of mRNAs for the hyphal formation signal was completely inhibited in anaerobic conditions. These results indicate that the electron transfer system functions upstream of the RAS1 signal pathway and activates the expression of the hyphal formation signal. Since the electron transfer system is inactivated in anaerobic conditions, C. albicans grew in yeast form in this condition.
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PMID:Hyphal formation of Candida albicans is controlled by electron transfer system. 1687 61


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