title: An inhibitor of mitochondrial respiration which binds to cytochrome b and displaces quinone from the iron-sulfur protein of the cytochrome bc1 complex.
abstract: 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.
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002417:Cattle; D003573:Cytochrome b Group / Q000378:metabolism*; D003575:Cytochromes c1 / Q000378:metabolism; D014450:Electron Transport Complex III; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D007700:Kinetics; D008667:Metalloproteins / Q000378:metabolism*; D008689:Methacrylates; D008929:Mitochondria, Heart / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D011808:Quinone Reductases / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid; D013844:Thiazoles / Q000494:pharmacology; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D003573:Cytochrome b Group; D007506:Iron-Sulfur Proteins; D008667:Metalloproteins; D008689:Methacrylates; D009097:Multienzyme Complexes; D011809:Quinones; D013386:Succinates; D013844:Thiazoles; D014451:Ubiquinone; C030517:myxothiazol; D003575:Cytochromes c1; D019802:Succinic Acid; D009247:NADH, NADPH Oxidoreductases; D011808:Quinone Reductases; D014450:Electron Transport Complex III; C003741:ubiquinol