Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dihydroorotate dehydrogenase (EC 1.3.3.1 or EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. In eukaryotes it is located in the inner mitochondrial membrane, with ubiquinone as the proximal and cytochrome oxidase as the ultimate electron transfer system, whereas the rest of pyrimidine biosynthesis takes place in the cytosol. Here, the distribution of dihydroorotate dehydrogenase activity in cryostat sections of various rat tissues, and tissue samples of human skin and kidney, was visualized by light microscopy using the nitroblue tetrazolium technique. In addition, a hydrogen peroxide-producing oxidase side-reactivity of dihydroorotate dehydrogenase could be visualized by trapping the peroxide with cerium-diaminobenzidine. The pattern of activity was similar to that of succinate dehydrogenase, but revealed a less intensive staining. High activities of dihydroorotate dehydrogenase were found in tissues with known proliferative, regenerative, absorptive or excretory activities, e.g., mucosal cells of the ileum and colon crypts in the gastrointestinal tract, cultured Ehrlich ascites tumor cells, and proximal tubules of the kidney cortex, whilst lower activities were present in the periportal area of the liver, testis and spermatozoa, prostate and other glands, and skeletal muscle. Dihydroorotate dehydrogenase and succinate dehydrogenase activity in Ehrlich ascites tumor cells grown in suspension culture were quantified by application of nitroblue tetrazolium or cyanotolyl tetrazolium and subsequent extraction of the insoluble formazans with organic solvents. The ratio of dihydroorotate dehydrogenase to succinate dehydrogenase activity was 1:4. This was in accordance with that of 1:5 obtained from oxygen consumption measurement of isolated mitochondria on addition of dihydroorotate or succinate. The ratio determined with mitochondria from animal tissues was up to 1:15 (rat liver, bovine heart). The application of the enzyme inhibitors brequinar sodium and toltrazuril verified the specificity of the histochemical and biochemical methods applied.
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PMID:Catalytic enzyme histochemistry and biochemical analysis of dihydroorotate dehydrogenase/oxidase and succinate dehydrogenase in mammalian tissues, cells and mitochondria. 885 33

Mitochondrially bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyses the fourth sequential step in the de novo synthesis of uridine monophosphate; this enzyme uses ubiquinone as the proximal and cytochrome oxidase as is the ultimate electron transfer system. Here, seven compounds with proven antiproliferative activity and in vitro antipyrimidine effects were investigated with isolated functional mitochondria of rat tissues in order to differentiate their anti-dihydroorotate dehydrogenase potency versus putative effects on the respiratory chain enzymes. Ten microM of brequinar sodium, the leflunomide derivatives A77-1726, [2-cyano-3-cyclopropyl-3-hydroxy-enoic acid (4-trifluoromethylphenyl)-amide], MNA 279, (2-cyano-N-(4-cyanophenyl)-3-cyclopropyl-3-oxo-propanamide), MNA715 (2-cyano-3-hydroxy-N-(4-(trifluoromethyl)-phenyl-6-heptanamide), HR325 (2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ]-propenamide), and the diazine toltrazuril completely inhibited the dihydroorotate-induced oxygen consumption of liver mitochondria. Succinate and NADH oxidation were found to be influenced only at elevated drug concentration (100 microM), with the exception of HR325, 10 microM of which caused a 70% inhibition of NADH and 50% inhibition of succinate oxidation. This was comparable to the effects of toltrazuril, which caused an approximate 75% inhibition of NADH oxidation. Ciprofloxacin was shown here to have only marginal effects on the redox activities of the inner mitochondrial membrane. This differentiation of drug effects on mitochondrial functions will contribute to a better understanding of the in vivo pharmacological activity of these drugs, which are presently in clinical trials because of their immunosuppressive, cytostatic or anti-parasitic activity. A comparison of the influence of A77-1726, HR325, brequinar and 2,4-dinitrophenol on energetically coupled rat liver mitochondria revealed only a weak uncoupling potential of A77-1726 and brequinar. In addition, a modeling study was raised to search for common spatial arrangements of functional groups essential for binding of inhibitors to dihydroorotate dehydrogenase. From the structural comparison of different metabolites and inhibitors of pyrimidine metabolism, a 6-point model was obtained by conformational analysis for the drugs tested on mitochondrial functions, pharmacophoric perception and mapping. We propose our model in combination with kinetic data for a rational design of highly specific inhibitors of dihydroorotate dehydrogenase.
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PMID:Structural and functional comparison of agents interfering with dihydroorotate, succinate and NADH oxidation of rat liver mitochondria. 977 18

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

It has been hypothesized that mitochondrial respiratory chain dysfunction leads to a pyrimidine deficiency since the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase is coupled to the electron transport chain. The uridine prodrug triacetyluridine (PN401) is neuroprotective in several models of neurodegenerative disease involving respiratory chain toxins. Therefore, the therapeutic effects of PN401 might involve the correction of a pyrimidine deficiency secondary to respiratory chain impairment. We infused mice with the cytochrome c oxidase inhibitor azide, which inhibited brain complex IV activity. Chronic infusion of azide for 2 or 14 days induced significant toxicity and mortality but did not cause a pyrimidine deficit in the brain. In contrast, the pyrimidine synthesis inhibitor N-phosphonoacetyl-l-aspartate (PALA) produced a pyrimidine deficit with minimal mortality. Treatment with 6% PN401 decreased mortality and cerebrocortical apoptosis caused by azide. Previously, we found that optimal neuroprotection against mitochondrial complex II inhibition required 4-6% PN401. PN401 at 1, 3, 6 and 10% in chow induced nonlinear increases in plasma uridine with 6% PN401 elevating plasma uridine up to 80 muM, and these higher micromolar uridine levels were also required for neuroprotection in chemical hypoxia models in vitro. Our results indicate that severe complex IV inhibition in vivo does not lead to a pyrimidine deficiency, and therefore the protective effect of PN401 in the azide toxin model is not mediated through the correction of a pyrimidine deficiency. Furthermore, supraphysiological levels of uridine are required to produce optimal protective effects in disorders involving impairment of mitochondrial respiratory complex II or IV.
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PMID:Severe cytochrome c oxidase inhibition in vivo does not induce a pyrimidine deficiency; neuroprotective action of oral uridine prodrug PN401 requires supraphysiological levels of uridine. 1633