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: UNIPROT:Q16795 (ubiquinone)
5,455 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chloroplast genomes of Marchantia polymorpha, Nicotiana tabacum, and Oryza sativa contain open reading frames (ORFs or potential genes) encoding homologues of some of the subunits of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Seven of these subunits (ND1-ND4, ND4L, ND5, and ND6) are products of the mitochondrial genome, and two others (the 49- and 30-kDa components of the iron-sulfur protein fraction) are nuclear gene products. These findings have been taken to indicate the presence in chloroplasts of an enzyme related to complex I, possibly an NAD(P)H:plastoquinone oxidoreductase, participating in chlororespiration. This view is reinforced by the present work in which we have shown that chloroplast genomes encode a homologue of the 23-kDa subunit, another nuclear-encoded component of bovine complex I. The 23-kDa subunit is in the hydrophobic protein fraction of the enzyme, the residuum after removal of the flavoprotein and iron-sulfur protein fractions. The sequence motif CysXXCysXXCysXXXCysPro, which provides ligands for tetranuclear iron-sulfur centers in ferredoxins, occurs twice in its polypeptide chain and is evidence of two associated 4Fe-4S clusters. This is the only iron-sulfur protein identified so far in the hydrophobic protein fraction of complex I, and so it is possible that one of these centers is that known as N-2, the donor of electrons to ubiquinone. The sequence of the 23-kDa subunit is closely related to potential proteins, which also contain the cysteine-rich sequence motifs, encoded in the frxB ORFs in chloroplast genomes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A homologue of a nuclear-coded iron-sulfur protein subunit of bovine mitochondrial complex I is encoded in chloroplast genomes. 190 Oct 22

We report the electron transfer properties of the NADH:ubiquinone oxidoreductase complex of the respiratory chain (Complex I) in mitochondria of cells derived from LHON patients with two different mutations in mitochondrial DNA (mtDNA). The mutations occur in the mtDNA genes coding for the ND1 and ND4 subunits of Complex I. The ND1/3460 mutation exhibits 80% reduction in rotenone-sensitive and ubiquinone-dependent electron transfer activity, whereas the proximal NADH dehydrogenase activity of the Complex is unaffected. This is in accordance with the proposal that the ND1 subunit interacts with rotenone and ubiquinone. In contrast, the ND4/11778 mutation had no effect on electron transfer activity of the Complex in inner mitochondrial membrane preparations; also Km for NADH and NADH dehydrogenase activity were unaffected. However, in isolated mitochondria with the ND4 mutation, the rate of oxidation of NAD-linked substrates, but not of succinate, was significantly decreased. This suggests that the ND4 subunit might be involved in specific aggregation of NADH-dependent dehydrogenases and Complex I, which may result in fast ('solid state') electron transfer from the former to the latter.
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PMID:Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). 195 19

Short-chain ubiquinone analogues act as electron acceptors and as inhibitors in the lymphoblast mitochondria of ND1/3460 mutants, which indicates structural changes in the ubiquinone-binding domain of Complex I in this mutant. The ND4/11778 mutant and two secondary ND5 mutants studied are associated with reductions of at least 50, 35 and 30% in the catalytic rate constant, respectively. However, the efficiency of oxidative phosphorylation is unaffected in all these ND mutants. The rate of respiration is only slightly limited by Complex I in lymphoblast mitochondria. Consequently, there is a 30-35% reduction in the electron flow through Complex I compared with that through Complex II, and an increased lactate/pyruvate ratio, in the ND1 and ND4 mutants, but these factors were unaffected in the secondary ND5 mutants. Energy metabolism is thus less severely affected in the secondary mutants than in the primary mutants, which supports the division into these two categories. An increased ubiquinone-10 content in the mitochondrial membrane of all the mutants, and enhanced succinate dehydrogenase and citrate synthase activities in the ND4 mutant, are proposed to be compensatory changes. The efficiency of these changes and the level of kinetic limitation of respiration by Complex I in each tissue are proposed to determine the clinical development of the disease.
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PMID:Catalytic activity of complex I in cell lines that possess replacement mutations in the ND genes in Leber's hereditary optic neuropathy. 870 9

The human mitochondrial ND1/3460 mutation changes Ala52 to Thr in the ND1 subunit of Complex I, and causes Leber's hereditary optic neuropathy (LHON) [Huoponen et al. (1991) Am. J. Hum. Genet. 48, 1147]. We have used a bacterial counterpart of Complex I, NDH-1 from Paracoccus denitrificans, for studying the effect of mutations in the ND1 subunit on the enzymatic activity. The LHON mutation as well as several other mutations in strictly conserved amino acids in its vicinity were introduced into the NQO8 subunit of NDH-1, a bacterial homologue of ND1. The enzymatic activity of the mutants in the presence of hexammineruthenium (rotenone-insensitive) and ubiquinone-1 (rotenone-sensitive) were assayed. In addition, the kinetics of the interaction of selected mutant enzymes with ubiquinone-1, ubiquinone-2, and decylubiquinone was studied. The results suggest that the mutated residues play an important role in ubiquinone reduction by Complex I.
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PMID:Analysis of the pathogenic human mitochondrial mutation ND1/3460, and mutations of strictly conserved residues in its vicinity, using the bacterium Paracoccus denitrificans. 971 1

The authors report the clinical features and the results of genetic and biochemical studies of a child affected by ND1/3460 Leber's hereditary optic neuropathy, who demonstrates a persistent visual recovery after protracted monitoring. A 10-year-old male suffered from a severe right visual impairment that was incidentally detected. Within 2 months the left eye was also seriously involved, and visual acuity worsened to 20/300 in both eyes, associated with bilateral cecocentral scotomas and dyschromatopsia. During the following months a progressive visual improvement occurred, and 2 years later the visual acuity was 20/20 OU. After 9 years of follow-up the clinical status is unchanged. The mutation at np ND1/3460 was found to be virtually homoplasmic in the proband's mtDNA, which was extracted either from platelets or leukocytes, whereas the mother and the sister tested heteroplasmic for the same mutation. The specific activity of complex I in platelets was reduced in the proband and normal in his relatives. An abnormal resistance of NADH:ubiquinone reductase to the inhibitory effect of rotenone was found in platelet mitochondria from the proband and family members and was consistent with the degree of heteroplasmy. This pattern of biochemical abnormalities suggests a cumulative effect of the increasing percentage of mutated mtDNA on complex I function, which involves the interaction between complex I and its substrate ubiquinone in the heteroplasmic condition (asymptomatic state), and the catalytic function of complex I, as mutated mDNA turns toward the homoplasmic condition (symptomatic state).
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PMID:Childhood Leber's hereditary optic neuropathy (ND1/3460) with visual recovery. 983 Oct 4

Complex I is the largest of the mitochondrial respiratory chain proteins, and contains subunits encoded by both mitochondrial and nuclear genomes. Leber's hereditary optic neuropathy has been clearly linked to mutations of mitochondrial DNA complex I genes, and variable complex I functional defects have been reported. We have confirmed an approximate 60% defect in mitochondrial NADH CoQ1 reductase activity in cultured fibroblasts bearing the 3460-bp G to A mutation within the ND1 gene. However complex I-linked ATP synthesis was found to be normal in these fibroblasts. A 60% rotenone-induced decrease in complex I activity was shown to reduce ATP synthesis in normal fibroblasts, indicating that this level of complex I activity was below the threshold required to affect ATP synthesis. Although 3460 LHON mitochondria were less sensitive to rotenone inhibition, this did not explain the decreased complex I activity as the rotenone insensitive activity was not increased, nor did the inhibitor diphenyleneiodonium inhibit the NADH CoQ1 reductase activity to a greater extent. Decreased NADH cytochrome c reductase activity in cybrids homoplasmic for the 3460 LHON mtDNA mutation confirmed that the decrease in complex I activity was not specific to the assay used and was not caused by inhibitory effects of ubiquinone analogues used in the NADH CoQ1 reductase assay. These findings have important implications for our understanding of complex I dysfunction in the pathogenesis of 3460 Leber's hereditary optic neuropathy.
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PMID:Functional consequences of the 3460-bp mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. 1042 38

We report an unusual molecular defect in the mitochondrially encoded ND1 subunit of NADH ubiquinone oxidoreductase (complex I) in a patient with mitochondrial myopathy and isolated complex I deficiency. The mutation is an inversion of seven nucleotides within the ND1 gene, which maintains the reading frame. The inversion, which alters three highly conserved amino acids in the polypeptide, was heteroplasmic in the patient's muscle but was not detectable in blood. This is the first report of a pathogenic inversion mutation in human mtDNA.
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PMID:Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. 1077 30

Steady-state kinetics of the H(+)-translocating NADH:ubiquinone reductase (complex I) were analyzed in membrane samples from bovine mitochondria and the soil bacterium Paracoccus denitrificans. In both enzymes the calculated K(m) values, in the membrane lipid phase, for four different ubiquinone analogues were in the millimolar range. Both the structure and size of the hydrophobic side chain of the acceptor affected its affinity for complex I. The ND1 subunit of bovine complex I is a mitochondrially encoded protein that binds the inhibitor dicyclohexylcarbodiimide (DCCD) covalently [Yagi and Hatefi (1988) J. Biol. Chem. 263, 16150-16155]. The NQO8 subunit of P. denitrificans complex I is a homologue of ND1, and within it three conserved Glu residues that could bind DCCD, E158, E212, and E247, were changed to either Asp or Gln and in the case of E212 also to Val. The DCCD sensitivity of the resulting mutants was, however, unaffected by the mutations. On the other hand, the ubiquinone reductase activity of the mutants was altered, and the mutations changed the interactions of complex I with short-chain ubiquinones. The implications of the results for the location of the ubiquinone reduction site in this enzyme are discussed.
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PMID:Mutagenesis of three conserved Glu residues in a bacterial homologue of the ND1 subunit of complex I affects ubiquinone reduction kinetics but not inhibition by dicyclohexylcarbodiimide. 1106 86

LHON (Leber hereditary optic neuropathy) is a maternally inherited disease that leads to sudden loss of central vision at a young age. There are three common primary LHON mutations, occurring at positions 3460, 11778 and 14484 in the human mtDNA (mitochondrial DNA), leading to amino acid substitutions in mitochondrial complex I subunits ND1, ND4 and ND6 respectively. We have now examined the effects of ND6 mutations on the function of complex I using the homologous NuoJ subunit of Escherichia coli NDH-1 (NADH:quinone oxidoreductase) as a model system. The assembly level of the NDH-1 mutants was assessed using electron transfer from deamino-NADH to the 'shortcut' electron acceptor HAR (hexammine ruthenium), whereas ubiquinone reductase activity was determined using DB (decylubiquinone) as a substrate. Mutant growth in minimal medium with malate as the main carbon source was used for initial screening of the efficiency of energy conservation by NDH-1. The results indicated that NuoJ-M64V, the equivalent of the common LHON mutation in ND6, had a mild effect on E. coli NDH-1 activity, while nearby mutations, particularly NuoJ-Y59F, NuoJ-V65G and NuoJ-M72V, severely impaired the DB reduction rate and cell growth on malate. NuoJ-Met64 and NuoJ-Met72 position mutants lowered the affinity of NDH-1 for DB and explicit C-type inhibitors, whereas NuoJ-Y59C displayed substrate inhibition by oxidized DB. The results are compatible with the notion that the ND6 subunit delineates the binding cavity of ubiquinone substrate, but does not directly take part in the catalytic reaction. How these changes in the enzyme's catalytic properties contribute to LHON pathogenesis is discussed.
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PMID:Leber hereditary optic neuropathy mutations in the ND6 subunit of mitochondrial complex I affect ubiquinone reduction kinetics in a bacterial model of the enzyme. 1789 48

125I-labeled (trifluoromethyl)phenyldiazirinyl acetogenin, [125I]TDA, a photoaffinity labeling probe of acetogenin, photo-cross-links to the ND1 subunit of bovine heart mitochondrial NADH-ubiquinone oxidoreductase (complex I) with high specificity [M. Murai, A. Ishihara, T. Nishioka, T. Yagi, and H. Miyoshi, (2007) The ND1 subunit constructs the inhibitor binding domain in bovine heart mitochondrial complex I, Biochemistry 46 6409-6416.]. To identify the binding site of [125I]TDA in the ND1 subunit, we carried out limited proteolysis of the subunit cross-linked by [125I]TDA using various proteases and carefully analyzed the fragmentation patterns. Our results revealed that the cross-linked residue is located within the region of the 4th to 5th transmembrane helices (Val144-Glu192) of the subunit. It is worth noting that an excess amount of short-chain ubiquinones such as ubiquinone-2 (Q2) and 2-azido-Q2 suppressed the cross-linking by [125I]TDA in a concentration-dependent way. Although the question of whether the binding sites for ubiquinone and different inhibitors in complex I are identical remains to be answered, the present study provided, for the first time, direct evidence that an inhibitor (acetogenin) and ubiquinone competitively bind to the enzyme. Considering the present results along with earlier photoaffinity labeling studies, we propose that not all inhibitors acting at the terminal electron transfer step of complex I necessarily bind to the ubiquinone binding site itself.
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PMID:Exploring the binding site of acetogenin in the ND1 subunit of bovine mitochondrial complex I. 1926 69


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