“…In complex III these are cytochromes b 566 , b 562 and c 1 , the Rieske Fe-S centre, and the quinones at centres ‘ i ’ and ‘ o ’ (Zhang et al, 2000). The main reductant is the semiquinone at centre o (IIIQo) (Boveris and Chance, 1973; Cadenas et al, 1977; Turrens et al, 1985), consistent with a Q cycle mechanism (Turrens, 2003).…”
Section: Sites Of Mitochondrial Ros Productionmentioning
Mitochondrial superoxide production is an important source of reactive oxygen species in cells, and may cause or contribute to ageing and the diseases of ageing. Seven major sites of superoxide production in mammalian mitochondria are known and widely accepted. In descending order of maximum capacity they are the ubiquinone binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, the flavin in complex I (site IF), the electron transferring flavoprotein:Q oxidoreductase (ETFQOR) of fatty acid beta oxidation, and pyruvate and 2-oxoglutarate dehydrogenases. None of these sites is fully characterized and for some we only have sketchy information. The topology of the sites is important because it determines whether or not a site will produce superoxide in the mitochondrial matrix and be able to damage mitochondrial DNA. All sites produce superoxide in the matrix; site IIIQo and glycerol 3-phosphate dehydrogenase also produce superoxide to the intermembrane space. The relative contribution of each site to mitochondrial reactive oxygen species generation in the absence of electron transport inhibitors is unknown in isolated mitochondria, in cells or in vivo, and may vary considerably with species, tissue, substrate, energy demand and oxygen tension.
“…In complex III these are cytochromes b 566 , b 562 and c 1 , the Rieske Fe-S centre, and the quinones at centres ‘ i ’ and ‘ o ’ (Zhang et al, 2000). The main reductant is the semiquinone at centre o (IIIQo) (Boveris and Chance, 1973; Cadenas et al, 1977; Turrens et al, 1985), consistent with a Q cycle mechanism (Turrens, 2003).…”
Section: Sites Of Mitochondrial Ros Productionmentioning
Mitochondrial superoxide production is an important source of reactive oxygen species in cells, and may cause or contribute to ageing and the diseases of ageing. Seven major sites of superoxide production in mammalian mitochondria are known and widely accepted. In descending order of maximum capacity they are the ubiquinone binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, the flavin in complex I (site IF), the electron transferring flavoprotein:Q oxidoreductase (ETFQOR) of fatty acid beta oxidation, and pyruvate and 2-oxoglutarate dehydrogenases. None of these sites is fully characterized and for some we only have sketchy information. The topology of the sites is important because it determines whether or not a site will produce superoxide in the mitochondrial matrix and be able to damage mitochondrial DNA. All sites produce superoxide in the matrix; site IIIQo and glycerol 3-phosphate dehydrogenase also produce superoxide to the intermembrane space. The relative contribution of each site to mitochondrial reactive oxygen species generation in the absence of electron transport inhibitors is unknown in isolated mitochondria, in cells or in vivo, and may vary considerably with species, tissue, substrate, energy demand and oxygen tension.
“…In general, the protein structure that Gao et al (47) described was relatively indifferent to occupancy, with the vacant structure showing only 0.24Å rmsd from the quinone-occupied structure. The inhibitor binding in all structures reported (2,39,47,89,(149)(150)(151) showed volumes of occupancy that impinge on the surfaces at which mutational changes (152) lead to resistance.…”
Section: Quinone Reduction At the Q I -Sitementioning
The bc1 complexes are intrinsic membrane proteins that catalyze the oxidation of ubihydroquinone and the reduction of cytochrome c in mitochondrial respiratory chains and bacterial photosynthetic and respiratory chains. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. Genetic defects leading to mutations in proteins of the respiratory chain, including the subunits of the bc1 complex, result in mitochondrial myopathies, many of which are a direct result of dysfunction at catalytic sites. Some myopathies, especially those in the cytochrome b subunit, exacerbate free-radical damage by enhancing superoxide production at the ubihydroquinone oxidation site. This bypass reaction appears to be an unavoidable feature of the reaction mechanism. Cellular aging is largely attributable to damage to DNA and proteins from the reactive oxygen species arising from superoxide and is a major contributing factor in many diseases of old age. An understanding of the mechanism of the bc1 complex is therefore central to our understanding of the aging process. In addition, a wide range of inhibitors that mimic the quinone substrates are finding important applications in clinical therapy and agronomy. Recent structural studies have shown how many of these inhibitors bind, and have provided important clues to the mechanism of action and the basis of resistance through mutation. This paper reviews recent advances in our understanding of the mechanism of the bc1 complex and their relation to these physiologically important issues in the context of the structural information available.
“…Many membrane protein pseudogenes are also present in the mammalian genomes. A good example is cytochrome b (cytb), which is a ubiquitous 8-TM protein that catalyzes a crucial step in the mitochondrial oxidative phosphorylation process (Zhang et al 1998(Zhang et al , 2000. The functional gene of this protein is in the mitochondrial genome, but more than 70 copies of its cytb pseudogenes are present in the nuclear genome due to a DNA-mediated process (Tourmen et al 2002 ;Woischnik & Moraes, 2002).…”
Section: Membrane Proteins and Pseudogenesmentioning
We review recent computational advances in the study of membrane proteins, focusing on those that have at least one transmembrane helix. Transmembrane protein regions are, in many respects, easier to investigate computationally than experimentally, due to the uniformity of their structure and interactions (e.g. consisting predominately of nearly parallel helices packed together) on one hand and presenting the challenges of solubility on the other. We present the progress made on identifying and classifying membrane proteins into families, predicting their structure from amino-acid sequence patterns (using many different methods), and analyzing their interactions and packing The total result of this work allows us for the first time to begin to think about the membrane protein interactome, the set of all interactions between distinct transmembrane helices in the lipid bilayer.
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