Succinate - coenzyme Q reductase
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Succinate-coenzyme Q reductase (EC 1.3.5.1 ; succinate dehydrogenase) is an enzyme complex bound to the inner mitochondrial membrane. The enzyme functions at the crossroads of the citric acid cycle and the electron transport chain, and is the only enzyme that is membrane-bound. It is found in many aerobic and anaerobic organisms including Escherichia coli. The enzyme complex is a heterotetramer divided into three domains: SDHA, the catalytic domain; SDHB, the electron transfer subunit; SDHC/SDHD, the dimeric membrane anchor that contains β -type heme.
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[edit] Function of the Succinate-coenzyme Q Reductase Complex
The function of the enzyme is illustrated by following the transfer of electrons from succinate to ubiquinol. The electron path is shown in the diagram by the red arrows.
- Succinate is oxidized to fumarate by the SDHA subunit. SDHA contains a flavin adenine dinucleotide (FAD) cofactor that is covalently linked to a conserved histidine residue. This causes the oxidized FAD to be reduced to FADH2 in a two electron process. This is part of the citric acid cycle.
- The electron transfer subunit (SDHB) contains a [2Fe-4S] cluster, a [4Fe-4S] cluster and a [3Fe-4S] cluster which help relay electrons from SDHA to the membrane domains.
- These tunnelling electrons invariably go on to reduce a ubiquinone (Q) molecule bound to the SDHC/SDHD dimer, reducing it to ubiquinol (QH2). Quinone reduction is a two-electron process and requires the formation of a ubisemiquinone radical intermediate.
- The resulting ubiquinol molecule is released, free to diffuse through the inner mitochondrial membrane to interact with subsequent enzymes of the mitochondrial respiratory chain (electron transport chain). A heme cofactor is also found within the membrane domain but its function has yet to be discovered.
[edit] Role in Disease
Generally, the genes have classic tumor suppressor gene behaviour. The resulting disease depends on which gene is mutated.
- SDHA mutations can lead to Leigh syndrome.
- SDHB mutations can lead to tumorogenesis in chromaffin cells, causing hereditary paraganglioma and hereditary pheochromocytoma. Tumors tend to be malignant.
- SDHC mutations can lead to hereditary paraganglioma and hereditary pheochromocytoma. Tumors tend to be benign. These mutations are uncommon.
- SDHD mutations can lead to hereditary paraganglioma and hereditary pheochromocytoma. Tumors tend to be benign, and occur often in the head and neck regions.
The precise mechanism for each of these disease pathways is still being determined. See the specific gene for more details. Removal of this enzyme from the genome has also been shown to be embryonic lethal.
[edit] Research on Succinate-coenzyme Q Reductase Complex
This protein is quickly becoming one of the hottest topics of research due to its crucial role in cellular metabolism. Joel Weiner, professor at the University of Alberta in Canada, is a leading expert on succinate dehydrogenase and bioenergetics in general.
The ability of the iron-sulfur clusters to transfer electrons is a major focus for the semiconductor industry where biomolecules may one day be used to replace copper wires. Flavin flourescence is also at the forefront of industry research where it may be used to diagnose particluar disease states as well as their progressions. However, research in Sdh FAD fluorescence remains an elusive mystery and may never be fully deconvoluted.
