title: Loss of a conserved tyrosine residue of cytochrome b induces reactive oxygen species production by cytochrome bc1.
abstract: Production of reactive oxygen species (ROS) induces oxidative damages, decreases cellular energy conversion efficiencies, and induces metabolic diseases in humans. During respiration, cytochrome bc(1) efficiently oxidizes hydroquinone to quinone, but how it performs this reaction without any leak of electrons to O(2) to yield ROS is not understood. Using the bacterial enzyme, here we show that a conserved Tyr residue of the cytochrome b subunit of cytochrome bc(1) is critical for this process. Substitution of this residue with other amino acids decreases cytochrome bc(1) activity and enhances ROS production. Moreover, the Tyr to Cys mutation cross-links together the cytochrome b and iron-sulfur subunits and renders the bacterial enzyme sensitive to O(2) by oxidative disruption of its catalytic [2Fe-2S] cluster. Hence, this Tyr residue is essential in controlling unproductive encounters between O(2) and catalytic intermediates at the quinol oxidation site of cytochrome bc(1) to prevent ROS generation. Remarkably, the same Tyr to Cys mutation is encountered in humans with mitochondrial disorders and in Plasmodium species that are resistant to the anti-malarial drug atovaquone. These findings illustrate the harmful consequences of this mutation in human diseases.
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Dong-Woo
authors: DW
authors: Lee
authors: Nur
authors: N
authors: Selamoglu
authors: Pascal
authors: P
authors: Lanciano
authors: Jason W
authors: JW
authors: Cooley
authors: Isaac
authors: I
authors: Forquer
authors: David M
authors: DM
authors: Kramer
authors: Fevzi
authors: F
authors: Daldal
mesh_terms: D019943:Amino Acid Substitution; D045303:Cytochromes b / Q000235:genetics / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics; D020125:Mutation, Missense; D010961:Plasmodium / Q000201:enzymology / Q000235:genetics; D016354:Rhodobacter capsulatus / Q000201:enzymology* / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: D029968:Escherichia coli Proteins; D014443:Tyrosine; D045303:Cytochromes b; D014450:Electron Transport Complex III