SDHA

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Succinate dehydrogenase complex, subunit A, flavoprotein (Fp)
SuccDeh.svg
PDB rendering based on 2h89.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SDHA ; CMD1GG; FP; PGL5; SDH1; SDH2; SDHF
External IDs OMIM600857 MGI1914195 HomoloGene3073 ChEMBL: 5758 GeneCards: SDHA Gene
EC number 1.3.5.1
Orthologs
Species Human Mouse
Entrez 6389 66945
Ensembl ENSG00000073578 ENSMUSG00000021577
UniProt P31040 Q8K2B3
RefSeq (mRNA) NM_004168 NM_023281
RefSeq (protein) NP_004159 NP_075770
Location (UCSC) Chr 5:
0.22 – 0.26 Mb
Chr 13:
74.32 – 74.35 Mb
PubMed search [1] [2]

Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.[1] This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[2]

Structure[edit]

The SDHA gene is located on the p arm of chromosome 5 at locus 15 and is comprised of 16 exons.[2] The SDHA protein encoded by this gene is 664 amino acids long and weighs 72.7 kDA.[3][4]

Function[edit]

SuccDeh.svg

The SDH complex is located on the inner membrane of the mitochondria and participates in both the citric acid cycle and the respiratory chain. The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). Electrons removed from succinate transfer to SDHA, transfer across SDHB through iron sulphur clusters to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane.

Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in the SDHB subunit until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol.[5]

SDHA acts as an intermediate in the basic SDH enzyme action:

  1. SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2.
  2. 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
  3. Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits.

Clinical significance[edit]

Bi-allelic mutations (i.e. both copies of the gene are mutated) have been described in Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder. The SDHA gene mutations responsible for Leigh syndrome change single amino acids in the SDHA protein or result in an abnormally short protein. These genetic changes disrupt the activity of the SDH enzyme, impairing the ability of mitochondria to produce energy. It is not known, however, how mutations in the SDHA gene are related to the specific features of 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 behavior. 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. This would require the improbable event of inactivation of all four alleles to trigger a paraganglioma.[6]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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TCACycle_WP78 go to article go to article go to article go to article go to HMDB go to article go to article go to article Go to article go to article go to article go to article go to article go to article Go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to HMDB go to article go to article go to HMDB go to article go to article go to HMDB go to article go to article go to HMDB go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article
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  1. ^ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78". 

References[edit]

  1. ^ Hirawake H, Wang H, Kuramochi T, Kojima S, Kita K (Jul 1994). "Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria". Journal of Biochemistry 116 (1): 221–7. PMID 7798181. 
  2. ^ a b "Entrez Gene: succinate dehydrogenase complex". 
  3. ^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS et al. (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338. 
  4. ^ "SDHA - Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  5. ^ Horsefield, R; Yankovskaya, V; Sexton, G; Whittingham, W; Shiomi, K; Omura, S; Byrne, B; Cecchini, G; Iwata, S (17 March 2006). "Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction.". The Journal of biological chemistry 281 (11): 7309–16. doi:10.1074/jbc.m508173200. PMID 16407191. 
  6. ^ Brière JJ, Favier J, Bénit P, El Ghouzzi V, Lorenzato A, Rabier D et al. (Nov 2005). "Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions". Human Molecular Genetics 14 (21): 3263–9. doi:10.1093/hmg/ddi359. PMID 16195397.  Vancouver style error (help)

Further reading[edit]