Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Myxothiazol, an antibiotic from Myxococcus fulvus, which inhibits mitochondrial respiration in the bc1 complex of the respiratory chain, has effects on the redox components of isolated succinate-cytochrome c reductase complex which suggest that it interacts with both cytochrome b and the iron-sulfur protein of the bc1 complex. The inhibitor appears to increase the midpoint potentials of cytochromes b-562 and b-566, as indicated by an increase in their reducibility by the succinate/fumarate couple. It also causes a red shift in the optical spectrum of ferrocytochrome b-566, as reported previously (Becker, W. F., Von Jagow , G., Anke , T., Steglisch , W. (1981) FEBS Lett. 132, 329-333). This red shift is enhanced by Triton X-100, and there is no shift in the spectrum of b-562. These results are consistent with evidence that mutations conferring myxothiazol resistance in yeast map to the mitochondrial gene for cytochrome b ( Thierbach , G., and Michaelis, G. (1982) Mol. Gen. Genet. 186, 501-506). In addition, myxothiazol has effects on reduction of the cytochromes b and c1 by succinate or ubiquinol which are identical to those caused by removal of the iron-sulfur protein from the bc1 complex. It blocks reduction of cytochrome c1 during single and multiple turnovers of the bc1 complex, but does not block reduction of the b cytochromes. In the presence of antimycin, it blocks reduction of both cytochromes b and c1. In contrast to antimycin, myxothiazol inhibits oxidant-induced reduction of both b cytochromes and does not inhibit their oxidation by fumarate. Myxothiazol also inhibits reduction of the iron-sulfur protein by ubiquinol and shifts the gx resonance in the EPR spectrum of the iron-sulfur protein from g = 1.79 to 1.76. It does not affect the midpoint potential of the iron-sulfur protein, but does eliminate the increase in midpoint potential which is caused by inhibitory hydroxyquinones which bind to the iron-sulfur protein. The effects of myxothiazol are consistent with a protonmotive Q cycle pathway of electron transfer in which myxothiazol binds to cytochrome b and displaces quinone from the iron-sulfur protein of the bc1 complex. These results suggest either that a myxothiazol-induced conformational change in cytochrome b is transmitted to a quinone binding site on the iron-sulfur protein, or that there is a quinone binding site which consists of peptide domains from both cytochrome b and iron-sulfur protein.
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PMID:An inhibitor of mitochondrial respiration which binds to cytochrome b and displaces quinone from the iron-sulfur protein of the cytochrome bc1 complex. 632 77

About 300 revertants were derived from 44 cob- mutants, mapping in the structure coding regions (exon 1, 3, 4, 5, or 6) of the mitochondrial apocytochrome b gene in Saccharomyces cerevisiae, strain 777-3A. Most of the revertants could not be distinguished from the wild-type by means of physiological properties. Twenty-two revertants different in phenotype are described here in more detail. The suppressor mutations (supa) that compensate the primary cob- mutations (i.e., restore growth on glycerol) are mitochondrially inherited. They were localized in the same cob exon regions as the respective primary mutations, except for one revertant with a primary mutation in exon 6 and a suppressor, 4.2 map units distant, which may be located either in intron 5 or downstream in exon 6. Of 21 suppressors 17 are closely coupled to the primary mutation with recombination frequencies of less than or equal to 0.1%-0.3%. An estimate predicts that in more than 80% of these revertants only one amino acid is altered at that point of the polypeptide corresponding to the cob- site in the gene. The most interesting revertant phenotypes are: reduced growth rate on glycerol. The respective cob-/supa mutations are scattered over the whole cob region and cannot be correlated exclusively with special gene regions. decreased cytochrome b content. The most extreme reductions (28% and 30% of wild-type level) were observed to be due to mutations located in the 5' proximal part of exon 1. The highest percentage of revertants with decreased cytochrome b content was predominantly found mapping in exon 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Gen Genet 1984
PMID:Cytochrome b of cob revertants in yeast. 1. Isolation and characterization of revertants derived from cob exon mutants of Saccharomyces cerevisiae. 638 25

Assimilatory nitrate reductase (NAD(P)H-nitrate oxidoreductase, EC 1.6.6.2) from the green alga Ankistrodesmus braunii can be purified to homogeneity by dye-ligand chromatography on blue-Sepharose. The purified enzyme, whose turnover number is 623 s-1, presents an optimum pH of 7.5 and Km values of 13 microM, 23 microM and 0.15 mM for NADH, NADPH and nitrate, respectively. The NADH-nitrate reductase activity exhibits an iso ping pong bi bi kinetic mechanism. The molecular weight of the native nitrate reductase is 467 400, while that of its subunits is 58 750. These values suggest an octameric structure for the enzyme, which has been confirmed by electron microscopy. As deduced from spectrophotometric and fluorimetric studies, the enzyme contains FAD and cytochrome b-557 as prosthetic groups. FAD is not covalently bound to the protein and is easily dissociated in diluted solutions from the enzyme. Its apparent Km value is 4 nM, indicative of a high affinity of the enzyme for FAD. The results of the quantitative analyses of prosthetic groups indicate that nitrate reductase contains four molecules of flavin, four heme irons, and two atoms of molybdenum. The three components act sequentially transferring electrons from reduced pyridine nucleotides to nitrate, thus forming a short electron transport chain along the protein. A mechanism is proposed for the redox interconversion of the nitrate reductase activity. Inactivation seems to occur by formation of a stable complex of reduced enzyme with cyanide or superoxide, while reactivation is a consequence of reoxidation of the inactive enzyme. Both reactions imply the transfer of only one electron.
Mol Cell Biochem 1983
PMID:Assimilatory nitrate reductase from the green alga Ankistrodesmus braunii. 668 79

The effect of the association of gossypol and Lonidamine on the electron transport in Ehrlich ascites tumor mitochondria has been investigated by addition of drugs to isolated mitochondria. The results may be summarized as follows. (1) Low concentrations of gossypol increase the rate of oxygen consumption at the level of three energy-conserving sites of the respiratory chain. Higher concentrations result in an inhibition of oxygen consumption at (or near) both energy-conserving sites 1 and 2, while energy-conserving site 3 is unaffected. (2) Gossypol, at concentrations at which it exerts its uncoupling effect, stimulates ATPase activity. Higher concentrations inhibit the enzyme activity. (3) The addition of gossypol to mitochondria respiring on pyruvate plus malate or succinate induces a more oxidized state of NAD+ and cytochrome b, respectively. (4) Gossypol enhances the effect of Lonidamine on oxygen consumption. Lonidamine does not affect state 4 respiration, but in the presence of gossypol, it determines a marked decrease in the rate of oxygen consumption. The inhibition of oxidation of NAD-linked substrates is greater than that of FAD-linked substrates. (5) It may be concluded that gossypol is very effective in potentiating the effect of Lonidamine. Moreover, it may be suggested that the antitumor activity of Lonidamine is enhanced if it is used in combination with other drugs and/or treatments, such as hyperthermia, which modify the energy status of mitochondria.
Exp Mol Pathol 1984 Apr
PMID:The effect of gossypol and Lonidamine on electron transport in Ehrlich ascites tumor mitochondria. 670 94

Mitochondrial and nuclear mutants resistant to myxothiazol were isolated and characterized. The mitochondrial mutants could be assigned to two loci, myx1 and myx2, by allelism tests. The two loci map in the box region, the split gene coding for apocytochrome b. Locus myx1 maps in the first exon (box4/5) whereas myx2 maps in the last exon (box6). The nuclear mutants could be divided into three groups: two groups of recessive mutations and one of dominant mutations. Respiration of isolated mitochondria from mitochondrial mutants is resistant to myxothiazol. These studies support the conclusion that myxothiazol is an inhibitor of the respiratory chain of yeast mitochondria. The site of action of myxothiazol is mitochondrial cytochrome b.
Mol Gen Genet 1982
PMID:Mitochondrial and nuclear myxothiazol resistance in Saccharomyces cerevisiae. 675 59

NADPH oxidase from stimulated guinea pig granulocytes was extracted with deoxycholate. The solubilized enzyme was stable in 20% glycerol. Solubilized enzyme was free of myeloperoxidase activity. The properties of the deoxycholate solubilized enzyme indicated that it is a high molecular weight complex with a flavoprotein, calmodulin and cytochrome b possibly forming part of the complex. Maximum activity was between pH 7.0 and 7.5. The Km value was 15.8 microM for NADPH and 434 microM for NADH indicating that NADPH is the preferential substrate.
Mol Cell Biochem 1983
PMID:The NADPH oxidase of guinea pig polymorphonuclear leucocytes. Properties of the deoxycholate extracted enzyme. 686 30

We have undertaken a systematic examination of the polypeptides accumulating in thirteen (out of 23) mutants in the intron cluster box7 and its flanking clusters box2 and box9 of the cob-box (cytochrome b) region of the mitochondrial genome of Saccharomyces cerevisiae. We have subjected these polypeptides to fingerprint analysis, both sequential and in parallel, with two proteases in order to disclose sequence homologies and differences between the different novel polypeptides themselves, and between them and the wild type product of the gene, i.e. apocytochrome b. One of our aims has been to establish the existence of possible correlations between the nature of the novel polypeptides and the fine structure genetic map of that segment of the mitochondrial genome. Our results show that all box7 mutants accumulate the following set of polypeptides not seen in wild type cells: a) a characteristic set of "large" polypeptides consisting of three species: p56, p42 and p35 or p34.5; b) a polypeptides p23; c) a much shorter fragment (of which the apparent molecular weight varies from 12.5 to 13, according to the mutation) with the exception of two mutants; d) in addition, the majority accumulate in varying amounts a polypeptide p30 closely related to but not identical with apocytochrome b. Moreover only two box7 mutants accumulate a polypeptide in the range of mobilities corresponding to 25-27 Kd (referred to as class p26) while such a polypeptide is seen in all box9 and box2 mutants examined with one exception in box2.
Mol Gen Genet 1980 Feb
PMID:Mutations within an intron and its flanking sites: patterns of novel polypeptides generated by mutants in one segment of the cob-box region of yeast mitochondrial DNA. 699 Feb 1

Antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide, two specific inhibitors of the b-c1 segment of the respiratory chain, affected the respiration of Trypanosoma cruzi epimastigote forms. The half-maximum inhibitory concentrations were about 0.05 and 4.0 micrograms/mg cells (dry wt.), respectively. The maximum effect of antimycin (about 80% inhibition of respiration) was at about 0.1 microgram antimycin/mg cells. Differential spectrophotometry of T. cruzi epimastigotes in the presence of antimycin, cyanide (or sulfide) and uncouplers, revealed the presence of functional cytochromes aa3, b and c558. In the stationary growth phase respiration by T. cruzi was completely inhibited by cyanide and effectively inhibited by sulfide, but in the exponential growth phase respiration was about 20% insensitive to 5 mM cyanide. Cyanide- and antimycin-insensitive respiration was completely inhibited by salicylhydroxamic acid (2 mM). Antimycin inhibited the operation of the tricarboxylic acids cycle in T. cruzi, as shown by the lesser production of 14CO2 and by the modification of 14C distribution in epimastigotes incubated with [1-14C]glucose, [2-14C]acetate or NaH14CO3. The inhibition of electron transport by antimycin increased the rate of the fumarate reductase reaction, an alternative electron pathway for the oxidation of reduced pyridine nucleotides. Addition of carbonyl cyanide 3-chlorophenylhydrazone to epimastigotes increased the rate of respiration and promoted the oxidation of reduced cytochrome b components, thus showing that these components are subject to respiratory (acceptor) control. Pentachlorophenol similarly affected the cytochrome b redox level but did not modify the rate of respiration. The uncouplers released N,N'-dicyclohexylcarbodiimide inhibition of respiration, and uncouplers and cyanide significantly decreased the ATP level in epimastigotes. The combined effects of the assay inhibitors on respiration, cytochrome b redox level, ATP content and energy charge confirmed the operation of oxidative phosphorylation in T. cruzi epimastigotes. Antimycin, uncouplers and N,N'-dicyclohexylcarbodiimide inhibited growth of T. cruzi, thus proving the essential role of oxidative phosphorylation for the parasite.
Mol Biochem Parasitol 1980 Oct
PMID:Effect of inhibitors of electron transport and oxidative phosphorylation on Trypanosoma cruzi respiration and growth. 700 81

In the preceding paper of this series (Dujardin et al. 1980 a) we described general methods of selecting and genetically characterizing suppressor mutations that restore the respiratory capacity of mit- mitochondrial mutations. Two dominant nuclear (NAM1-1 and NAM2-1) and one mitochondrial (mim2-1) suppressors are more extensively studied in this paper. We have analysed the action spectrum of these suppressors on 433 mit- mutations located in various mitochondrial genes and found that they preferentially alleviate the effects of mutations located within intron open reading frames of the cob-box gene. We conclude that these suppressors permit the maturation of cytochrome b mRNA by restoring the synthesis of intron encoded protein(s) catalytically involved in splicing i.e. mRNA-maturase(s) (cf. Lazowska et al. 1980). NAM1-1 is allele specific and gene non-specific; it suppresses mutations located within different introns. NAM2-1 and mim2-1 are intron-specific: they suppress mutations all located in the same (box7) intron of the cob-box gene. Analyses of cytochrome absorption spectra and mitochondrial translation products of cells in which the suppressors are associated with various other mit- mutations show that the suppressors restore cytochrome b and/or cytochrome oxidase (cox I) synthesis, as expected from their growth phenotype. This suppression is, however, only partial: some new polypeptides characteristic of the mit- mutations can be still detected in the presence of suppressor. Interestingly enough when box7 specific suppressors NAM2-1 and mim2-1 are associated with a complete cob-box deletion (leading to a total deficiency of cytochrome b and oxidase) partial restoration of cox I synthesis is observed while cytochrome b is still totally absent. These results show that in strains carrying NAM2-1 or mim2-1 the presence of cytochrome b gene is no longer required for the expression of the oxi3 gene pointing out to the possibility of a mutational switch-on of silent genes, whether mitochondrial, mim2-1, or nuclear, NAM2-1. This switch-on would permit the synthesis of an active maturase acting as a substitute for the box7 maturase in order to splice the cytochrome b and oxidase mRNAs.
Mol Gen Genet 1981
PMID:Long range control circuits within mitochondria and between nucleus and mitochondria. II. Genetic and biochemical analyses of suppressors which selectively alleviate the mitochondrial intron mutations. 703 98

Recessive suppressor mutations in yeast Saccharomyces cerevisiae alter a component of the cytoplasmic ribosomes, relaxing the control of translational fidelity. As a consequence ribosomes can misread nonsense codons as amino acids (Surguchov et al. 1980a). The suppressor mutants are often respiratory deficient, being unable to grow on non-fermentable substrates. The study of the cytochrome spectra has revealed that the cytochrome b and aa3 contents were lower in the mutants than in the parent strains. Furthermore, the suppressor mutations often cause hypersensitivity to paromomycin and neomycin on media with a non-fermentable source of carbon. Some of the suppressor mutants exhibited both erythromycin and chloramphenicol-dependent growth on media containing ethanol or glycerol as a sole carbon source. These results suggest that the mutations altering cytoplasmic ribosomes may simultaneously impair the mitochondrial translation. A coupling of cytoplasmic and mitochondrial protein synthesis in yeast cells is proposed. The existence of a common protein component participating both in mitochondrial and cytoplasmic protein synthesis apparatus is discussed.
Mol Gen Genet 1982
PMID:Ribosomal recessive suppressors cause a respiratory deficiency in yeast Saccharomyces cerevisiae. 704 87


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