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The structure of Escherichia coli succinate dehydrogenase (SQR), analogous to the mitochondrial respiratory complex II, has been determined, revealing the electron transport pathway from the electron donor, succinate, to the terminal electron acceptor, ubiquinone. It was found that the SQR redox centers are arranged in a manner that aids the prevention of reactive oxygen species (ROS) formation at the flavin adenine dinucleotide. This is likely to be the main reason SQR is expressed during aerobic respiration rather than the related enzyme fumarate reductase, which produces high levels of ROS. Furthermore, symptoms of genetic disorders associated with mitochondrial SQR mutations may be a result of ROS formation resulting from impaired electron transport in the enzyme.
Succinate dehydrogenase (complex II; or succinate:ubiquinone oxidoreductase, SQR) is a functional member of both the Krebs cycle and the aerobic respiratory chain. Complex II couples the oxidation of succinate to fumarate in the mitochondrial matrix (or cytoplasm in bacteria) with the reduction of ubiquinone in the membrane (1). Mammalian mitochondrial and many bacterial SQRs are composed of two hydrophilic subunits, a flavoprotein (SdhA) and iron-sulfur protein (SdhB) subunit, and two hydrophobic membrane anchor subunits, SdhC and SdhD, which contain one heme b and provide the binding site for ubiquinone (1).
In eukaryotes, mutations of nuclear-encoded SQR genes can manifest themselves with a wide variety of clinical phenotypes, including optic atrophy, tumor formation, myopathy, and encephalopathy (2). Mutations in the SQR genes have been classified into two categories: (i) mutations in SdhA that cause disorders displaying a phenotype resembling other Krebs cycle gene defects, including Leigh syndrome (3); and (ii) those in SdhB, SAC, and SdhD that cause the tumors observed in hereditary paraganglioma and/or pheochromocytoma (4, 5). In Caenorhabditis elegans, the mev-1 mutant, which has a point mutation in the SdhC subunit, is reported to be hypersensitive to oxygen and to develop a premature aging phenotype (6, 7). Although it has been suggested that these disorders can be caused by oxidative stress produced by complex II itself (2), no detailed molecular mechanism has been proposed.
Succinate dehydrogenase is closely related to fumarate reductase (menaquinol:fumarate oxidoreductase or QFR), which catalyzes the opposite reaction to that of SQR during anaerobic respiration in bacteria (8). SQR and QFR are suggested to have evolved...