SDHA
Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.[1][2]
The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the complex, and weighs 72.7 kDA. Electrons removed from succinate transfer to SDHA, transfer across SDHB to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane.
Function of the SDHA Protein
The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain.
SDHA acts as an intermediate in the basic SDH enzyme action:
- SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2.
- Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S]. This function is part of the Respiratory chain
- Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits.
Gene that Codes for SDHA
The gene that codes for the SDHA protein is nuclear, even though the protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the fifth chromosome at p15. The gene is partitioned in 15 exons. The expressed protein has 664 amino acids.
Role in Disease
Bi-allelic mutations (i.e. both copies of the gene are mutated) have been described in Leigh syndrome.
Mutations in the SDHA subunit have a distinct pathology from mutations in the SDHB/SDHC/SDHD subunits; it is the only subunit to never have shown tumor suppressor behaviour. Heterozygous carriers of an SDHA mutation do not develop paragangliomas as has been seen for mutations in the other subunits. This appears to be due to the expression of two similar SDHA genes (Types I and II) in the paraganglia system.[3] This would require the improbable event of inactivation of all four alleles to trigger a paraganglioma.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[4]
References
- ^ "Entrez Gene: succinate dehydrogenase complex". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6389.
- ^ Hirawake H, Wang H, Kuramochi T, Kojima S, Kita K (July 1994). "Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria". J. Biochem. 116 (1): 221–7. PMID 7798181.
- ^ Brière JJ, Favier J, Bénit P, El Ghouzzi V, Lorenzato A, Rabier D, Di Renzo MF, Gimenez-Roqueplo AP, Rustin P (November 2005). "Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions". Hum. Mol. Genet. 14 (21): 3263–9. doi:10.1093/hmg/ddi359. PMID 16195397.
- ^ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78". http://www.wikipathways.org/index.php/Pathway:WP78.
Further reading
- Aboulaich N, Vainonen JP, StrÃ¥lfors P, Vener AV (2004). "Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes.". Biochem. J. 383 (Pt 2): 237–48. doi:10.1042/BJ20040647. PMC 1134064. PMID 15242332. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1134064.
- Bonache S, MartÃnez J, Fernández M, et al. (2007). "Single nucleotide polymorphisms in succinate dehydrogenase subunits and citrate synthase genes: association results for impaired spermatogenesis.". Int. J. Androl. 30 (3): 144–52. doi:10.1111/j.1365-2605.2006.00730.x. PMID 17298551.
- Horváth R, Abicht A, Holinski-Feder E, et al. (2006). "Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA).". J. Neurol. Neurosurg. Psychiatr. 77 (1): 74–6. doi:10.1136/jnnp.2005.067041. PMID 16361598.
- Kullberg M, Nilsson MA, Arnason U, et al. (2006). "Housekeeping genes for phylogenetic analysis of eutherian relationships.". Mol. Biol. Evol. 23 (8): 1493–503. doi:10.1093/molbev/msl027. PMID 16751257.
- Tomitsuka E, Kita K, Esumi H (2009). "Regulation of succinate-ubiquinone reductase and fumarate reductase activities in human complex II by phosphorylation of its flavoprotein subunit.". Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 85 (7): 258–65. PMID 19644226.
- Hao HX, Khalimonchuk O, Schraders M, et al. (2009). "SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma.". Science 325 (5944): 1139–42. doi:10.1126/science.1175689. PMID 19628817.
- Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1356129.
- González-Cabo P, Vázquez-Manrique RP, GarcÃa-Gimeno MA, et al. (2005). "Frataxin interacts functionally with mitochondrial electron transport chain proteins.". Hum. Mol. Genet. 14 (15): 2091–8. doi:10.1093/hmg/ddi214. PMID 15961414.
- Baysal BE, Lawrence EC, Ferrell RE (2007). "Sequence variation in human succinate dehydrogenase genes: evidence for long-term balancing selection on SDHA.". BMC Biol. 5: 12. doi:10.1186/1741-7007-5-12. PMID 17376234.
- Eng C, Kiuru M, Fernandez MJ, Aaltonen LA (2003). "A role for mitochondrial enzymes in inherited neoplasia and beyond.". Nat. Rev. Cancer 3 (3): 193–202. doi:10.1038/nrc1013. PMID 12612654.
- Brière JJ, Favier J, El Ghouzzi V, et al. (2005). "Succinate dehydrogenase deficiency in human.". Cell. Mol. Life Sci. 62 (19-20): 2317–24. doi:10.1007/s00018-005-5237-6. PMID 16143825.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Korsten A, de Coo IF, Spruijt L, et al. (2010). "Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation.". Biochim. Biophys. Acta 1797 (2): 197–203. doi:10.1016/j.bbabio.2009.10.003. PMID 19836344.
- Hendrickson SL, Lautenberger JA, Chinn LW, et al. (2010). "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression.". PLoS ONE 5 (9): e12862. doi:10.1371/journal.pone.0012862. PMC 2943476. PMID 20877624. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2943476.
- Van Coster R, Seneca S, Smet J, et al. (2003). "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II.". Am. J. Med. Genet. A 120A (1): 13–8. doi:10.1002/ajmg.a.10202. PMID 12794685.
- Wang L, McDonnell SK, Hebbring SJ, et al. (2008). "Polymorphisms in mitochondrial genes and prostate cancer risk.". Cancer Epidemiol. Biomarkers Prev. 17 (12): 3558–66. doi:10.1158/1055-9965.EPI-08-0434. PMC 2750891. PMID 19064571. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2750891.
- Huang G, Chen Y, Lu H, Cao X (2007). "Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer cell death.". Cell Death Differ. 14 (2): 327–37. doi:10.1038/sj.cdd.4402004. PMID 16826196.
- Sifroni KG, Damiani CR, Stoffel C, et al. (2010). "Mitochondrial respiratory chain in the colonic mucosal of patients with ulcerative colitis.". Mol. Cell. Biochem. 342 (1-2): 111–5. doi:10.1007/s11010-010-0474-x. PMID 20440543.
PDB gallery
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2h89: Avian Respiratory Complex II with Malonate Bound
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1zp0: Crystal Structure of Mitochondrial Respiratory Complex II bound with 3-nitropropionate and 2-thenoyltrifluoroacetone
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2fbw: Avian respiratory complex II with carboxin bound
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1yq4: Avian respiratory complex ii with 3-nitropropionate and ubiquinone
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1zoy: Crystal Structure of Mitochondrial Respiratory Complex II from porcine heart at 2.4 Angstroms
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1yq3: Avian respiratory complex ii with oxaloacetate and ubiquinone
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2h88: Avian Mitochondrial Respiratory Complex II at 1.8 Angstrom Resolution
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1.3.1: NAD/NADP acceptor |
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1.3.3: Oxygen acceptor |
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1.3.5: Quinone |
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1.3.99: Other acceptors |
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B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6
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Cycle |
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Anaplerotic |
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Mitochondrial
electron transport chain/
oxidative phosphorylation |
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mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
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k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
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m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
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