Succinate dehydrogenase
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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. It is the only enzyme that participates in both the citric acid cycle and the mitochondrial electron transport chain (in this role it is often called Complex II). It is the only citric acid cycle 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.
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 several iron-sulfur centers which relay electrons from SDHA to the membrane domains: a [2Fe-2S] cluster, a [4Fe-4S] cluster and a [3Fe-4S] cluster.
- These tunnelling electrons are transferred to Coenzyme Q, first to a ubiquinone 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.
Role in Disease
The fundamental role of succinate-coenzyme Q reductase in the electron transfer chain of mitochondria makes it vital in most multicellular organisms, removal of this enzyme from the genome has also been shown to be lethal at the embryonic stage in mice.
SDHB, SDHC and SDHD exhibit classic tumor suppressor gene behavior. SDHA has never been reported to be a tumor suppressor. 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. Other diseases linked to succinate dehydrogenase include hereditary paraganglioma, obsessive compulsive disorder, generation of aromatic flatulants, and dwarfism.
Additional images
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External links
- Interactive Molecular model of succinate dehydrogenase (Requires MDL Chime)
- Weiner Web page describing research on Complex II Homologs
- UMich Orientation of Proteins in Membranes families/superfamily-3 - Calculated spatial positions of succinate dehydrogenase and related proteins in membranes
- MeSH Succinate+dehydrogenase
Metabolism: Citric acid cycle enzymes | |
|---|---|
| Cycle | Citrate synthase - Aconitase - Isocitrate dehydrogenase - Oxoglutarate dehydrogenase - Succinyl CoA synthetase Succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD) - Fumarase - Malate dehydrogenase |
| Anaplerotic | to acetyl-CoA: Pyruvate dehydrogenase complex (regulated by Pyruvate dehydrogenase kinase and Pyruvate dehydrogenase phosphatase)
to ketoglutaric acid: Glutamate dehydrogenase to succinyl-CoA: Methylmalonyl-CoA mutase to oxaloacetate: Pyruvate carboxylase - Aspartate transaminase |
Mitochondrial electron transport chain/oxidative phosphorylation | |
|---|---|
| Primary | Complex I/NADH dehydrogenase - Complex II/Succinate dehydrogenase - Coenzyme Q - Complex III/Coenzyme Q - cytochrome c reductase - Cytochrome c - Complex IV/Cytochrome c oxidase |
| Other | Alternative oxidase - Electron-transferring-flavoprotein dehydrogenase |
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
