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)

We describe the purification of a H2O-producing NADH oxidase from the protozoan parasite Giardia duodenalis. The enzyme is a monomeric flavoprotein containing flavin adenine dinucleotide in a 1:1 molar ratio with the polypeptide. The NADH oxidase has an apparent molecular mass of 46 kDa and was homogenous as determined by denaturing gel electrophoresis and N-terminal amino acid sequencing. NADPH could substitute for NADH as an electron donor with a K(m) value of 4.2 microM for NADH and 16 microM for NADPH (pH 7.8 at room temperature). With oxygen as the primary electron acceptor under aerobic conditions, the pure enzyme did not produce O.-2 nor H2O2 as stoichiometric products of oxygen reduction, implicating H2O as the end product and obviating the need for superoxide dismutase. The ability to utilise oxygen explains the apparent respiration of the amitochondrial fermentative metabolism of Giardia. Mercurials, flavoantagonists and heavy metals (Cu2+ and Zn2+) inhibited this activity. Under anaerobic conditions the enzyme catalysed electron transfer at lower efficiencies to other electron acceptors including nitroblue tetrazolium, potassium ferricyanide, FAD and FMN, using either NADH or NADPH as electron donors. NADPH, however, was a more efficient electron donor. Cytochrome c was not reduced under any assay conditions used. The enzyme reduced the nitrofuran drugs, furazolidone (an antigiardial) and nitrofurantoin, to their toxic radical forms as determined by EPR. Metronidazole, a nitroimidazole, was not reduced. Pure NADH oxidase did not demonstrate ferredoxin:NAD(P)1 oxidoreductase activity since it could not accept electrons from reduced ferredoxin to regenerate NAD(P)H. The G. duodenalis NADH oxidase may, therefore, function as a terminal oxidase, similar to the mitochondrial cytochrome oxidase, and in the maintenance of an optimum intracellular redox ratio. This report of a flavoenzyme from Giardia places Giardia close to the anaerobic bacteria in evolutionary terms.
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PMID:A H2O-producing NADH oxidase from the protozoan parasite Giardia duodenalis. 889 1

Mitochondrial mRNAs encoding subunits of respiratory-chain complexes in kinetoplastids are post-transcriptionally edited by uridine insertion and deletion. In order to identify the proteins encoded by these mRNAs, we have analyzed respiratory-chain complexes from cultured cells of Crithidia fasciculata with the aid of 2D polyacrylamide gel electrophoresis (PAGE). The subunit composition of F0F1-ATPase (complex V), identified on the basis of its activity as an oligomycin-sensitive ATPase, is similar to that of bovine mitochondrial F0F1-ATPase. Amino acid sequence analysis, combined with binding studies using dicyclohexyldiimide and azido ATP allowed the identification of two F0 subunits (b and c) and all of the F1 subunits. The F0 b subunit has a low degree of similarity to subunit b from other organisms. The F1 alpha subunit is extremely small making the beta subunit the largest F1 subunit. Other respiratory-chain complexes were also analyzed. Interestingly, an NADH: ubiquinone oxidoreductase (complex I) appeared to be absent, as judged by electron paramagnetic resonance (EPR), enzyme activity and 2D PAGE analysis. Cytochrome c oxidase (complex IV) displayed a subunit pattern identical to that reported for the purified enzyme, whereas cytochrome c reductase (complex III) appeared to contain two extra subunits. A putative complex II was also identified. The amino acid sequences of the subunits of these complexes also show a very low degree of similarity (if any) to the corresponding sequences in other organisms. Remarkably, peptide sequences derived from mitochondrially encoded subunits were not found in spite of the fact that sequences were obtained of virtually all subunits of complex III, IV and V.
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PMID:Characterization of the respiratory chain from cultured Crithidia fasciculata. 910 91

Cytochrome c oxidase (COX, EC 1.9.3.1), the last component of the mitochondrial electron transfer chain, is built up by 13 polypeptides; 3 of them are encoded by the mitochondrial genome while the 10 smaller subunits are encoded by the nuclear genome. Several nuclear-encoded subunits occur in two different tissue-specific isoforms, a constitutive "L"-form and an "M"-form specific for skeletal and heart muscle. In this article, we describe the genomic sequence and organization of the human gene for COX subunit VIIa-M (COX7A1) located on chromosome 19q13.1 and compare it to its bovine homologue. The coding region of the gene extends over 1.45 kb of genomic sequence, organized in four exons. Intron-exon boundaries are well conserved between cattle and humans. Although it is a gene for a tissue-specific isoform, it has some features of a housekeeping gene: it is located in a CpG island, like its bovine homologue, and no TATA or CCAAT boxes were found in the 5' flanking sequence. Southern hybridization of COX7A1 to human genomic DNA revealed no pseudogenes. Putative binding sites for ubiquitous transcription factors like Sp1 and specific expression in skeletal as well as in heart muscle have been found. In contrast to the bovine gene, the human gene contains putative binding sites for nuclear respiratory factor 2 (NRF-2), which is implicated in the activation of other respiratory enzymes. Therefore, the human and the bovine genes, although well conserved in their coding regions, could differ in the tissue-specific regulation of gene expression. Knowledge of the gene structure will facilitate the analysis of the involvement of subunit VIIa in mitochondrial myopathies and may provide clues to the function of this subunit in a multicomponent enzyme.
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PMID:Genomic sequence and organization of the human gene for cytochrome c oxidase subunit (COX7A1) VIIa-M. 934 74

Recent progress in studies on apoptosis has revealed that cytochrome c is a pro-apoptotic factor. It is released from its places on the outer surface of the inner mitochondrial membrane at early steps of apoptosis and, combining with some cytosolic proteins, activates conversion of the latent apoptosis-promoting protease pro-caspase-9 to its active form. Cytochrome c release can be initiated by the pro-apoptotic protein Bax. This process is blocked by the anti-apoptotic proteins Bcl-2 and Bcl-xL. The role of cytochrome c in apoptosis may be understood within the framework of the concept assuming that the evolutionary primary function of apoptosis was to purify tissues from ROS-overproducing cells. In this context, the pro-apoptosis activity of cytochrome c might represent one of the anti-oxidant functions inherent in this cytochrome. Among other cytochrome c-linked antioxidant mechanisms, the following systems can be indicated. (1) Cytochrome c released from the inner mitochondrial membrane to the intermembrane space can operate as an enzyme oxidizing O2.- back to O2. The reduced cytochrome c is oxidized by cytochrome oxidase (or in yeasts and bacteria, by cytochrome c peroxidase). (2) The intermembrane cytochrome c can activate the electron transport chain in the outer mitochondrial membrane. This bypasses the initial and middle parts of the main respiratory chain, which produce, as a rule, the major portion of ROS in the cell. (3) The main respiratory chain losing its cytochrome c is inhibited in such a fashion that antimycin-like agents fail to stimulate ROS production.
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PMID:Cytochrome c in the apoptotic and antioxidant cascades. 951 23

The formation of sanazole (drug AK-2123) radicals by the xanthine--xanthine oxidase system was studied by spectrophotometry in hypoxygenic (pO2 = 45 +/- 5 mm Hg) and normoxygenic (pO2 = 150 +/- 4 mm Hg) media. At concentrations from 0.1 to 10.5 mM, sanazole dose-dependently increased the rate of cytochrome c reduction in hypoxygenic medium but had no effect on the reaction rate under normoxygenic conditions. The activating influence of sanazole depended on xanthine concentration. At xanthine concentrations from 0.08 to 0.1 mM in hypoxygenic medium, the rate of cytochrome c reduction was increased twofold after the addition of sanazole. Reduction of cytochrome c in the medium without sanazole was completely blocked by superoxide dismutase; addition of sanazole partially restored the blocked reaction. Cytochrome c reduced in the presence of superoxide dismutase and sanazole was oxidized by cytochrome oxidase. The data indicate that in the presence of the xanthine--xanthine oxidase system under hypoxygenic conditions, sanazole can accept electrons and generate nitro radicals which donate electrons to cytochrome c or oxygen.
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PMID:Generation of sanazole nitro radicals by xanthine oxidase. 991 54

Cytochrome c (cyt c) release was investigated in cerebellar granule cells used as an in vitro neuronal model of apoptosis. We have found that cyt c is released into the cytoplasm as an intact, functionally active protein, that this event occurs early, in the commitment phase of the apoptotic process, and that after accumulation, this protein is progressively degraded. Degradation, but not release, is fully blocked by benzyloxycarbonyl-Val-Ala-Asp-fluoromethylchetone (z-VAD-fmk). On the basis of previous findings obtained in the same neuronal population undergoing excitotoxic death, it is hypothesized that release of cyt c may be part of a cellular attempt to maintain production of ATP via cytochrome oxidase, which is reduced by cytosolic NADH in a cytochrome b5-soluble cyt c-mediated fashion.
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PMID:Early release and subsequent caspase-mediated degradation of cytochrome c in apoptotic cerebellar granule cells. 1048 78

Cytochrome c oxidase was purified from control and CCl4 treated rats and its kinetic properties were studied. The activity of the enzyme was inhibited by 51% in CCl4 (4 g per kg body weight for 24 hr) treated rats. Studies on the kinetic properties showed that the K(m) of the enzyme increased by 60% while Vmax decreased by 44% in CCl4 treated rats compared to controls. The content of cytochrome aa3 was decreased by 34% while cytochrome b and c were not affected by CCl4 treatment. Phosphatidylcholine, phosphatidylethanolamine and cardiolipin were decreased significantly by 40%, 49% and 60% respectively in CCl4 treated rats. A decrease in the cytochrome aa3 content and a change in the lipid environment of the membrane are probably responsible for a decreased rate of electron transfer from cytochrome c to oxygen.
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PMID:Studies on cytochrome oxidase in carbon tetrachloride treated rats. 1078 47

Two enzymes, the soluble guanylate cyclase and cytochrome c oxidase, have been shown to be exquisitely sensitive to nitric oxide (NO) at low physiological concentrations. Activation of the soluble guanylate cyclase by endogenous NO and the consequent increase in the second messenger cyclic GMP are now known to control a variety of biological functions. Cytochrome c oxidase (complex IV, the terminal enzyme of the mitochondrial respiratory chain) is inhibited by NO. We have shown that NO generated by vascular endothelial cells under basal and stimulated conditions modulates the respiration of these cells in response to acute changes in oxygen concentration. This action occurs at the level of complex IV and depends on influx of calcium. Thus, NO plays a physiological role in adjusting the capacity of this enzyme to use oxygen, allowing endothelial cells to adapt to acute changes in their environment. We have, in addition, studied the effect of long-term exposure to NO on different enzymes of the respiratory chain in a variety of cell lines. Our results show that, although NO inhibits complex IV in a way that is always reversible, prolonged exposure to NO results in a gradual and persistent inhibition of complex I that is concomitant with a reduction in the intracellular concentration of reduced glutathione. This inhibition appears to result from S-nitrosylation of critical thiols in the enzyme complex because it can be immediately reversed by exposing the cells to high intensity light or by replenishment of intracellular reduced glutathione. Furthermore, decreasing the concentration of reduced glutathione accelerates the process of persistent inhibition. Our results suggest that, although NO may regulate cell respiration physiologically by its action on complex IV, long-term exposure to NO leads to persistent inhibition of complex I and potentially to cell pathology.
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PMID:Nitric oxide and cell respiration: physiology and pathology. 1090 18

Beta amyloid (Abeta) peptides accumulate in Alzheimer's disease and are neurotoxic possibly through the production of oxygen free radicals. Using brain microdialysis we characterized the ability of Abeta to increase oxygen radical production in vivo. The 1-40 Abeta fragment increased 2,3-dehydroxybenzoic acid efflux more than the 1-28 fragment, in a manner dependent on nitric oxide synthase and NMDA receptor channels. We then examined the effects of Abeta peptides on mitochondrial function in vitro. Induction of the mitochondrial permeability transition in isolated rat liver mitochondria by Abeta(25-35) and Abeta(35-25) exhibited dose dependency and required calcium and phosphate. Cyclosporin A prevented the transition as did ruthenium red, chlorpromazine, or N-ethylmaleimide. ADP and magnesium delayed the onset of mitochondrial permeability transition. Electron microscopy confirmed the presence of Abeta aggregates and swollen mitochondria and preservation of mitochondrial structure by inhibitors of mitochondrial permeability transition. Cytochrome c oxidase (COX) activity was selectively inhibited by Abeta(25-35) but not by Abeta(35-25). Neurotoxic Abeta peptide can increase oxidative stress in vivo through mechanisms involving NMDA receptors and nitric oxide sythase. Increased intracellular Abeta levels can further exacerbate the genetically driven complex IV defect in sporadic Alzheimer's disease and may precipitate mitochondrial permeability transition opening. In combination, our results provide potential mechanisms to support the feed-forward hypothesis of Abeta neurotoxicity.
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PMID:Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. 1118 24

Three cases of Leigh disease are described. In all three, symptoms began in the first months of life, with muscle hypotonia, lactic acidosis, and psychomotor delay. The diagnosis was made on the basis of the clinical characteristics, biochemical abnormalities, and typical brain magnetic resonance imaging with symmetric lesions suggesting bilateral necrosis at the level of the basal ganglia and of the midbrain. Cytochrome c oxidase (complex IV of the mitochondrial respiratory chain) deficiency was demonstrated in muscle tissue in all patients and confirmed in skin fibroblasts in patient 3. A genetic heterogeneity was present in these patients since only one had a SURF-1 gene mutation. The clinical, biochemical, and neuroradiologic aspects are discussed. Finally, the finding of facial dysmorphisms in the cytochrome c oxidase deficiency observed in one of the described cases is of extreme interest; to our knowledge, this association has never been reported in the literature.
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PMID:Leigh disease: clinical, neuroradiologic, and biochemical study of three new cases with cytochrome c oxidase deficiency. 1151 Sep 37


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