Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A male infant with an atypical form of Menkes kinky hair disease showed mitochondrial NADH-CoQ reductase (complex I) deficiency in a femoris muscle biopsy. His clinical features consisted of hypotonicity of the upper limbs, hyper-reflexia of the lower extremities, abnormal hair and fine myoclonic movement of the hands. The serum levels of copper and ceruloplasmin were just below normal range, and the copper concentration in fibroblastic cells was much increased (101.2 ng/mg of protein). The occurrence of this case suggests that there may be a mild form of Menkes disease with a NADH-CoQ reductase deficiency or other mitochondrial enzyme defects.
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PMID:Atypical form of Menkes kinky hair disease with mitochondrial NADH-CoQ reductase deficiency. 245 75

Primary biliary cirrhosis (PBC)-specific antigens were purified from beef heart mitochondria by immunoaffinity chromatography. Three major polypeptides (75, 60, and 40 kDa) were detected in the purified antigen fraction both by Coomassie blue staining and by western blot analysis. The 75 kDa antigen was identified as a subunit of Complex I (NADH-ubiquinone reductase) by the following criteria: (1) antibodies against the purified 75 kDa subunit of beef heart Complex I react with the immunoaffinity-purified 75 kDa antigen. (2) the 75 kDa subunit present in isolated Complex I, like that in the immunoaffinity-purified antigen, reacts with PBC sera only after reduction with mercaptoethanol, and (3) the 75 kDa antigen is enriched in isolated Complex I. A relationship between the 75 kDa and the 60 and 40 kDa antigens is suggested, since optimal binding of anti-mitochondrial autoantibodies (AMA) to the latter antigens also requires prior reduction with mercaptoethanol. A fourth major antigen (70 kDa) was also detected by western blot analysis, but only in samples that had not been boiled prior to electrophoresis. This antigen, which is also present in isolated Complex I, resembles the 75, 60, and 40 kDa antigens in its response to mercaptoethanol and its reaction with antibodies against the 75 kDa subunit of Complex I. A scheme is presented which relates all of the PBC antigens to the parent 75 kDa subunit of Complex I, probably as proteolytic products of the latter.
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PMID:Evidence that the major primary biliary cirrhosis-specific mitochondrial autoantigen is a subunit of complex I of the respiratory chain. 245 35

A monoclonal antibody specific for the major primary biliary cirrhosis (PBC)-associated mitochondrial antigen (subunit I of NADH-ubiquinone reductase) was produced and used to study the binding sites recognized by anti-mitochondrial autoantibodies (AMA) in PBC sera. Immunization of mice with purified beef heart mitochondrial inner membranes resulted in one monoclonal antibody which reacted with mitochondrial proteins. This antibody (PBC-MoAb), which was of the IgG2b subclass with kappa light chains, exhibited a pattern of immunofluorescence reactivity with rat kidney, human thyroid, and cultured human epithelial cells (Hep-2) similar to that obtained with sera from PBC patients. Similar binding patterns between PBC-MoAb and AMA were also found in western blot analysis using mitochondria as antigen. Both types of antibodies revealed a major antigen of 75 kDa, a minor antigen of 60 kDa, and a third antigen (70 kDa), which was detected only in samples that had not been boiled prior to electrophoresis. Furthermore, optimal binding of the PBC-MoAb and AMA to the 75 and 70 kDa antigens required reduction of the antigen with mercaptoethanol prior to electrophoresis. Competition ELISA experiments were conducted to compare the epitopes recognized by PBC-MoAb and AMA. Of 28 PBC sera tested, 27 inhibited the binding of PBC-MoAb to mitochondrial inner membranes by almost 100% and one serum inhibited binding by 50%, indicating that most PBC sera contain autoantibodies reactive with the same or a closely related antibody binding site as the PBC-MoAb. PBC-MoAb inhibited AMA binding to the inner membrane by more than 80% in 10 sera, 60-80% in 11 sera, and 40-59% in seven sera, with an average inhibition of 71%. Our observations strongly indicate that anti-mitochondrial autoantibody binding sites are restricted to a highly immunogenic epitope on the major PBC-specific antigen (NADH-ubiquinone reductase subunit I), and that the anti-mitochondrial monoclonal antibody obtained has a specificity identical with the human PBC-specific M2 type anti-mitochondrial autoantibody.
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PMID:Primary biliary cirrhosis: indication for a single mitochondrial antigenic epitope detected by patient autoantibodies and a novel monoclonal antibody. 246 83

A catalytic component of the bovine mitochondrial NADH:ubiquinone oxidoreductase complex (Complex I) is a soluble NADH dehydrogenase iron-sulfur flavoprotein (FP). FP is composed of three subunits of Mr 51,000, 24,000, and 9,000, and contains FMN and two iron-sulfur clusters. Previous studies by others with the use of various chemical probes had suggested that, except for an access for NADH to the 51-kDa subunit, the FP polypeptides are buried within Complex I and shielded from the medium. In the present study, monospecific antibodies were raised to each of the three FP subunits, and used in conjunction with Complex I, submitochondrial particles (SMP), mitoplasts, and intact mitochondria as sources of antigens. Results of enzyme-linked immunosorbent assays and 125I-protein A labeling experiments indicated that epitopes from the 51-, 24-, and 9-kDa subunits of FP are exposed to the medium in Complex I and SMP, but not in mitoplasts and mitochondria. Appropriate enzymatic assays showed that none of the antibodies inhibited the NADH dehydrogenase activity of isolated FP or the NADH oxidase activity of SMP. These results have been discussed in relation to the structure of Neurospora Complex I deduced from membrane crystals of the isolated enzyme complex by Leonard et al. [K. Leonard, H. Haiker, and H. Weiss (1987) J. Mol. Biol. 194, 277-286].
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PMID:Studies on the structure of NADH:ubiquinone oxidoreductase complex: topography of the subunits of the iron-sulfur flavoprotein component. 246 82

Anti-mitochondrial autoantibodies (AMA) from patients with primary biliary cirrhosis (PBC) were analysed for fine specificity by immunoblotting and enzyme-linked immunosorbent assay (ELISA). Inhibition ELISA showed that complex I (NADH-ubiquinone reductase) from beef heart mitochondria completely inhibited the binding of AMA to mitochondrial inner membranes (SMP), indicating that the major mitochondrial antigens are located in complex I. Immunoblot analysis of beef heart SMP, complex I and the iron sulphur (IP) subfraction of complex I revealed several antigens, one of which (75 kDa) reacted with all PBC sera but not with the additional autoimmune sera tested. Resolution of SMP or complex I by two-dimensional electrophoresis yielded in both preparations a polypeptide of 75 kDa with an isoelectric point of 6.4, which reacted with PBC serum and with rabbit antisera raised against the 75,000 subunit of complex I. In immunoblot experiments, the antigenicity of the 75,000 polypeptide in SMP, complex I, and the IP subfraction is increased by prior reduction of the sample with mercaptoethanol. This suggests a similarity to the PBC-specific 'M-2' antigen, which is also sensitive to sulphur reagents. The data indicate that the 75 kDa polypeptide of complex I is a major mitochondrial antigen binding AMA in PBC sera, and allows us to identify the location and probable function of the PBC antigen.
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PMID:Mitochondrial autoantigens in primary biliary cirrhosis. Association of disease-specific determinants with a subunit of complex I (NADH-ubiquinone reductase) of the inner mitochondrial membrane. 246 24

Capsaicin and its analogs with different acyl moieties were found to inhibit the electron-transfer activity of NADH-coenzyme Q oxidoreductase isolated from beef heart mitochondria. The inhibitory potency of capsaicin was lower than those of dihydrocapsaicin and analogs with heptanoyl, capryl, undecanoyl, and lauroyl moieties, but was higher than those of analogs with palmitoyl and stearoyl moieties. The analog with the lauroyl moiety showed the strongest inhibition. These results suggest that hydrophobicity and the appropriate carbon chain length of the acyl moiety are important for the binding of compounds to the enzyme. On the other hand, capsaicin and its analogs did not interrupt rotenone-insensitive electron transfer from NADH to menadione. Furthermore, these compounds had almost no effect on the spectral properties and EPR signals arising from iron-sulfur clusters of the NADH-treated enzyme. Kinetic analyses with double-reciprocal plots showed that these compounds were competitive inhibitors with respect to coenzyme Q1, an electron acceptor. These results strongly suggest that capsaicin and its analogs bind to the coenzyme Q1 binding site of the enzyme.
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PMID:Capsaicin and its analogs inhibit the activity of NADH-coenzyme Q oxidoreductase of the mitochondrial respiratory chain. 249 67

The mitochondrial NADH-ubiquinone reductase (complex I) is an assembly of approximately 26 different polypeptides. In vertebrates and invertebrates, seven of its subunits are the products of genes in the mitochondrial DNA, and homologues of these genes have been found previously in the chloroplast genomes of Marchantia polymorpha and Nicotiana tabacum, although their function in the chloroplast is unknown. The remainder of the subunits of the mitochondrial complex are nuclear gene products that are imported into the organelle, amongst them the 49 kd subunit, a component of the iron--sulphur subcomplex of the enzyme. In the present work, the N-terminal sequence of this protein has been determined, and this has been used to design two mixtures of synthetic oligonucleotides, each containing 32 different sequences 17 bases long. These mixtures have been used as hybridization probes to isolate cDNA clones from a bovine library. The DNA sequences of these clones have been determined and they encode the mature 49 kd protein, with the exception of amino acids 1 and 2. The protein sequence of 430 amino acids is closely related to those of proteins that are encoded in open reading frames (ORFs) present in the chloroplast genomes of M.polymorpha and N.tabacum. Only one cysteine is conserved and the sequences provide no indication that the 49 kd protein contains iron--sulphur centres. These ORFs are found in the single copy regions of chloroplast DNA in close proximity to four of the homologues of the mammalian mitochondrial genes that encode subunits of complex I.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A homologue of the nuclear coded 49 kd subunit of bovine mitochondrial NADH-ubiquinone reductase is coded in chloroplast DNA. 249 81

The 24-kDa subunit of mitochondrial NADH-ubiquinone reductase (complex I) is an iron-sulfur protein that is present in the flavoprotein or NADH dehydrogenase II subcomplex. It is a nuclear gene product and is imported into the organelle. A group of human patients with mitochondrial myopathy have been shown to have reduced levels of subunits of complex I in skeletal muscle mitochondria, and in one patient the 24-kDa subunit appears to be absent (Schapira et al., 1988). To investigate the genetic basis of this type of myopathy, cDNA clones have been isolated from a bovine library derived from heart and liver mRNA by hybridization with two mixtures of 48 synthetic oligonucleotides 17 bases in length that were designed on the basis of known protein sequences. The recombinant DNA sequence has been determined, and it encodes a precursor of the mature 24-kDa protein. The N terminus of the mature protein is preceded by a presequence of 32 amino acids that has properties that are characteristic of mitochondrial import sequences. The sequence of the mature protein deduced from the cDNA contains a segment of nine amino acids that was not determined in an earlier partial protein sequence analysis. The bovine clone has been employed as a hybridization probe to identify cDNA clones of the human homologue of the 24-kDa protein. Its DNA sequence has also been determined, and it codes for a protein that is closely related to the bovine protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitochondrial NADH-ubiquinone reductase: complementary DNA sequences of import precursors of the bovine and human 24-kDa subunit. 250 Sep 70

The yeast C. parapsilosis CBS7157 is strictly dependent on oxidative metabolism for growth since it lacks a fermentative pathway. It is nevertheless able to grow on high glucose concentrations and also on a glycerol medium supplemented with antimycin A or drugs acting at the level of mitochondrial protein synthesis. Besides its normal respiratory chain C. parapsilosis develops a second electron transfer chain antimycin A-insensitive which allows the oxidation of cytoplasmic NAD(P)H resulting from glycolytic and hexose monophosphate pathways functioning through a route different from the NADH-coenzyme Q oxidoreductase described in S. cerevisiae or from the alternative pathways described in numerous plants and microorganisms. The second respiratory chain of C. parapsilosis involves 2 dehydrogenases specific for NADH and NADPH respectively, which are amytal and mersalyl sensitive and located on the outer face of the inner membrane. Since this antimycin A-insensitive pathway is fully inhibited by myxothiazol, it was hypothesized that electrons are transferred to a quinone pool that is different from the classical coenzyme Q-cytochrome b cycle. Two inhibitory sites were evidenced with myxothiazol, one related to the classical pathway, the other to the second pathway and thus, the second quinone pool could bind to a Q-binding protein at a specific site. Elimination of this second pool leads to a fully antimycin A-sensitive NADH oxidation, whereas its reincorporation in mitochondria allows recovery of an antimycin A-insensitive, myxothiazol sensitive NADH oxidation. The third step in this second respiratory chain involves a specific pool of cytochrome c which can deliver electrons either to a third phosphorylation site or to an alternative oxidase, cytochrome 590. This cytochrome is inhibited by high cyanide concentrations and salicylhydroxamates.
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PMID:The second respiratory chain of Candida parapsilosis: a comprehensive study. 250 62

Resolution of the mitochondrial NADH:ubiquinone oxidoreductase complex (Complex I) by chaotropic agents result in the separation of three building blocks of the enzyme, designated FP (flavoprotein), IP (iron-sulfur protein), and HP (hydrophobic protein). FP contains three subunits of Mr 51, 24, and 9 kDa; one FMN; and two iron-sulfur clusters. Immunochemical studies with monospecific antibodies to the FP subunits have indicated that all three subunits of FP protrude from the inner mitochondrial membrane on the matrix side, whereas no reactive epitopes from these subunits were found exposed on the cytosolic side [A.-L. Han, T. Yagi, and Y. Hatefi (1988) Arch. Biochem. Biophys. 267, 490-496]. IP contains six subunits of Mr 75, 49, 30, 18, 15, and 13 kDa and four iron-sulfur clusters. In the present study, immunochemical experiments (enzyme-linked immunosorbent assays and 125I-protein A labeling) were carried out with monospecific antibodies to the above IP subunits and with bovine Complex I, submitochondrial particles, mitoplasts, and intact mitochondria as sources of antigens. Results have indicated that all six IP subunits protrude from the inner mitochondrial membrane into the matrix, and that the 75-kDa subunit, and possibly the 15-kDa subunit, protrude in mitoplasts from the cytosolic side as well. No epitopes reactive toward the monospecific antibodies to the 49-, 30-, 18-, and 13-kDa subunits were detected in mitoplasts.
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PMID:Studies on the structure of NADH: ubiquinone oxidoreductase complex: topography of the subunits of the iron-sulfur protein component. 251 Jun 1


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