Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parasites have developed a wide variety of physiological functions to survive within the specialized environments of the host. Regarding energy metabolism, which represents an essential factor for survival, parasites adapt low oxygen tension in host mammals using metabolic systems that differ substantially from those of the host. Most parasites do not use free oxygen available within the host, but employ systems other than oxidative phosphorylation for ATP synthesis. Furthermore, parasites display marked changes in mitochondrial morphology and components during the life cycle, and these represent very interesting elements of biological processes such as developmental control and environmental adaptation. The enzymes in parasite-specific pathways offer potential targets for chemotherapy. Cyanide-insensitive trypanosome alternative oxidase (TAO) is the terminal oxidase of the respiratory chain of long slender bloodstream forms of the African trypanosome, which causes sleeping sickness. Recently, the most potent inhibitor of TAO to date, ascofuranone, was isolated from the phytopathogenic fungus, Ascochyta visiae. The inhibitory mechanisms of ascofuranone have been revealed using recombinant enzyme. Parasite-specific respiratory systems are also found in helminths. The NADH-fumarate reductase system in mitochondria form a final step in the phosphoenolpyruvate carboxykinase (PEPCK)-succinate pathway, which plays an important role in anaerobic energy metabolism for the Ascaris suum adult. Enzymes in this system, such as NADH-rhodoquinone reductase (complex I) and rhodoquinol-fumarate reductase (complex II), form promising targets for chemotherapy. In fact, a specific inhibitor of nematode complex I, nafuredin, has been found in mass-screening using parasite mitochondria.
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PMID:Parasite mitochondria as drug target: diversity and dynamic changes during the life cycle. 1452 69

Two main entry points for electrons into the mitochondrial respiratory chain are NADH:ubiquinone oxidoreductase (complex I) and succinate:ubiquinone oxidoreductase (complex II). Metabolic regulation of these two respiratory complexes is not understood in detail. It has been suggested that the Krebs cycle metabolic intermediate oxaloacetate (OAA) inhibits complex II in vivo, whereas complex I undergoes a reversible active/de-active transition. In normoxic and anoxic hearts it has been shown that the proportion of complex I in the active and de-active states is different suggesting a possible mode of regulation of the enzyme by oxygen concentration. In the current studies rapid isolation of mitochondrial membranes in a state that preserves the activity of both complex I and complex II has been achieved using Langendorff perfused rat hearts. The findings indicate that the state of activation of complex I is controlled by the oxygen saturation in the perfusate. In addition, these studies show that complex II is fully active in the mitochondrion and not inhibited by OAA regardless of the oxygen concentration.
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PMID:Effect of oxygen on activation state of complex I and lack of oxaloacetate inhibition of complex II in Langendorff perfused rat heart. 1470 27

A phenolic antioxidant 3-tert-butyl-4-hydroxyanisole (BHA) is a widely used food additive. BHA had cytotoxicity in human monocytic leukemia U937 cells. BHA at 0.75 mM caused nuclear condensation and fragmentation, structural damage in mitochondria, decrease in mitochondrial transmembrane potential, and internucleosomal DNA cleavage. It induced the activities of caspase-3 and/or -7, -6, -8 and -9, especially high when DEVD-MCA was the substrate (caspase-3 and/or -7). DEVDase activity increased in time- and dose-dependent manner and high activity was observed in lysates of cells treated for 3 h at 0.75 mM. Addition of GSH (reduced glutathione) during the treatment of cells with BHA inhibited the induction of DEVDase activity, and the intracellular GSH level decreased as the concentration of BHA was raised. Intracellular ATP levels decreased in time- and dose-dependent manner when the cells were treated with BHA in the presence or absence of glucose. Enzyme activities involved in the respiratory chain were assayed with the mitochondrial fraction prepared from U937 cells. BHA distinctly inhibited NADH-ubiquinone oxidoreductase (complex I) and cytochrome c oxidase (complex IV) at low concentrations. Succinate-ubiquinone oxidoreductase (complex II) was also inhibited, but to somewhat less extent. Without mitochondrial enzymes, BHA stimulated the ubiquinol-dependent reduction of cytochrome c (complex III), but it might have some detrimental effects on the mitochondrial enzyme reaction of complex III. The inhibition of mitochondrial oxidative phosphorylation might corroborate the mechanistic evidence for apoptosis of leukemia cells by BHA. Cell death induced by BHA is primarily ascribable to apoptosis.
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PMID:Molecular mechanism of cell death induced by the antioxidant tert-butylhydroxyanisole in human monocytic leukemia U937 cells. 1499 91

Since the bitter taste of enrofloxacin apparently limit the patient compliance in the oral formulations of the antibacterial agent, the masking of the taste is essential for the improvement of the therapeutic effectiveness. Therefore, this study was carried out to examine the feasibility of taste masking of enrofloxacin by the retardation of its dissolution rate using the formation of complex between the drug and Carbopol. The complexation between Carbopol and enrofloxacin was confirmed by turbidity, UV spectrophotometry, wide angle X-ray diffraction, and differential scanning calorimetry. The enrofloxacin content in the complexes was 34% (Carbo-enrofloxacin complex I) and 57% (Carbo-enrofloxacin complex II) depending on the preparation method. The dissolution rate of enrofloxacin from the complex increased as the pH was reduced. The dissolution rate of enrofloxacin from the Carbo-enrofloxacin complex I was significantly lower than that of the enrofloxacin powder. Therefore, these observations suggest that Carbo-enrofloxacin complex I can be used to mask the taste of enrofloxacin.
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PMID:Preparation and characterization of enrofloxacin/carbopol complex in aqueous solution. 1528 71

Brain-derived neurotrophic factor (BDNF) governs both the selective survival of neurons during development and the experience-based regulation of synaptic strength throughout life. BDNF produced a concentration-dependent increase in the respiratory control index (RCI, a measure of the efficiency of respiratory coupling, ATP synthesis and organelle integrity) of rat brain mitochondria. This effect was mediated via a MAP kinase pathway and highly specific for oxidation of glutamate plus malate (complex I) by brain mitochondria. The oxidation by brain mitochondria of the complex II substrate succinate was unaffected by BDNF. The failure of BDNF to modify respiratory activity associated with mitochondrial preparations isolated from rat liver indicates that the actions of the neurotrophin are tissue specific. BDNF also increased the RCI values associated with Ca2+ -induced respiration to a similar extent. This is the first demonstration that BDNF, in addition to modifying neuronal plasticity, can modify brain metabolism and the efficiency of oxygen utilization. The finding that neurotrophins can alter mitochondrial oxidative efficiency has important implications for neurodegenerative and psychiatric diseases.
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PMID:BDNF increases rat brain mitochondrial respiratory coupling at complex I, but not complex II. 1534 90

Oxidative stress has been implicated in neuronal death caused by cerebral ischemia or some neurologic disorders. Chemical hypoxia (term defining the simulation by using respiratory inhibitors) chosen as in vitro ischemic model, was induced in primary cultures of rat cerebellar granule neurons by inhibitors of mitochondrial electron transport such as rotenone or paraquat (complex I), 3-nitropropionic acid (3-NPA, complex II), antimycin A (complex III), or sodium azide (complex IV). All compounds caused neuronal death determined by trypan blue staining and MTT-test. On the other hand, neurotoxicity of rotenone and paraquat but not of 3-NPA, antimycin or azide was significantly abolished by menadione (vitamin K3, 2-methyl-1,4-naphthoquinone). This neuroprotective effect of menadione was associated with a decrease of rotenone-induced free radical production.
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PMID:Menadione reduces rotenone-induced cell death in cerebellar granule neurons. 1537 39

Mitochondria of the malaria parasite Plasmodium falciparum are morphologically different between the asexual and sexual blood stages (gametocytes). In this paper recent findings of mitochondrial heterogeneity are reviewed based on their ultrastructural characteristics, metabolic activities and the differential expression of their genes in these 2 blood stages of the parasite. The existence of NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), cytochrome c reductase (complex III) and cytochrome c oxidase (complex IV) suggests that the biochemically active electron transport system operates in this parasite. There is also an alternative electron transport branch pathway, including an anaerobic function of complex II. One of the functional roles of the mitochondrion in the parasite is the coordination of pyrimidine biosynthesis, the electron transport system and oxygen utilization via dihydroorotate dehydrogenase and coenzyme Q. Complete sets of genes encoding enzymes of the tricarboxylic acid cycle and the ATP synthase complex are predicted from P. falciparum genomics information. Other metabolic roles of this organelle include membrane potential maintenance, haem and coenzyme Q biosynthesis, and oxidative phosphorylation. Furthermore, the mitochondrion may be a chemotherapeutic target for antimalarial drug development. The antimalarial drug atovaquone targets the mitochondrion.
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PMID:The multiple roles of the mitochondrion of the malarial parasite. 1555 97

The whole extract of the fresh berries of Hippophae rhamnoides L. (RH-3), which has been reported to provide protection to whole mice, various tissues, cells and cell organelles against lethal irradiation, was further investigated for its effects on mitochondria isolated from mouse liver. Superoxide anion, reduced (GSH) and oxidized glutathione (GSSG) levels, NADH-ubiquinone oxidoreductase (complex I), NADH-cytochrome c oxidoreductase (complex I/II), succinate-cytochrome c oxidoreductase (complex II/III), mitochondrial membrane potential (MMP), lipid peroxidation (LPx) and protein oxidation (PO) were determined for RH-3-mediated radioprotective manifestation. Pre-irradiation treatment of mice with RH-3 (30 mg kg(-1,) i. p.; single dose; -30 min) significantly inhibited the radiation-induced increase in superoxide anions, GSSG, thiobarbituric acid reactive substances (TBARS), complex I, complex I/III activity and MMP maximally at 4 h (P < 0.05). This treatment inhibited the oxidation of proteins (P < 0.05) at all the time periods studied here. This study suggests that pre-irradiation treatment of mice with RH-3 protects the functional integrity of mitochondria from radiation-induced oxidative stress.
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PMID:Protection of mitochondrial system by Hippophae rhamnoides L. against radiation-induced oxidative damage in mice. 1563 1

Mitochondria are central to the efficient provision of energy for eukaryotic cells. The oxidative-phosphorylation system of mitochondria consists of a series of five major membrane complexes: NADH-ubiquinone oxidoreductase (commonly known as complex I), succinate-ubiquinone oxidoreductase (complex II), ubiquinol-cytochrome c oxidoreductase (cytochrome bc1 complex or complex III), cytochrome c-O2 oxidoreductase (complex IV), and F1F0-ATP synthase (complex V). Several lines of evidence have recently suggested that complexes I and III-V might interact to form supercomplexes. However, because of their fragility, the structures of these supercomplexes are still unknown. A stable supercomplex consisting of complex I and dimeric complex III was purified from plant mitochondria. Structural characterization by single-particle EM indicates a specific type of interaction between monomeric complex I and dimeric complex III in a 1:1 ratio. We present a model for how complexes I and III are spatially organized within the I+III2 supercomplex.
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PMID:Structure of a mitochondrial supercomplex formed by respiratory-chain complexes I and III. 1571 2

Variations in broiler growth and efficiency have been explained in part by differences in mitochondrial function and biochemistry in broilers. To further our knowledge in this regard, 2 experiments were carried out to determine the relationships of a) mitochondrial function and activities of various electron transport chain (ETC) complexes; b) production of H2O2, a reactive oxygen species (ROS), and its association with protein oxidation; and c) mitochondrial protein expression in liver of a single line male broilers with low or high feed efficiency (FE, n = 5 to 8 per group). Mitochondrial function and complex activities were measured polarographically and spectrophotometrically, respectively. H2O2 was measured fluorimetrically, whereas oxidized protein (carbonyls) and specific mitochondrial proteins were analyzed using Western blots. Mitochondrial function (ETC coupling) and activities of ETC complexes (I, II, III, and IV) were higher in high FE compared with low FE broilers. H2O2 and protein carbonyls were higher in the livers of low FE broilers than in high FE broilers. Whereas the expression of 4 immunoreactive proteins [NAD3 (complex I), subunit VII (complex III), cytochrome c oxidase subunits (COX) II, and COX IVb (complex IV)] were higher in low FE liver mitochondria and 2 proteins [subunit 70 (complex II) and a-ATP synthase (complex V)] were higher in high FE birds, there were no differences between groups in the expression of 18 other mitochondrial proteins. In conclusion, increases in oxidative stress in low FE broilers were caused by or may contribute to differences in mitochondrial function (ETC coupling and complex activities) or the differential expression of steady-state levels of some mitochondrial proteins in the liver. Understanding the role of oxidative stress in Low FE broilers will provide clues in understanding the cellular basis of feed efficiency.
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PMID:Compromised liver mitochondrial function and complex activity in low feed efficient broilers are associated with higher oxidative stress and differential protein expression. 1597 33


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