SDHA

Succinate dehydrogenase complex, subunit A, flavoprotein (Fp)
250px PDB rendering based on 2h89.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1yq3, 1yq4, 1zoy, 1zp0, 2fbw, 2h88, 2h89
Identifiers
Symbols	SDHA ; CMD1GG; FP; PGL5; SDH1; SDH2; SDHF
External IDs	OMIM: 600857 MGI: 1914195 HomoloGene: 3073 ChEMBL: 5758 GeneCards: SDHA Gene
EC number	1.3.5.1
Gene ontology Molecular function • succinate dehydrogenase activity • protein binding • succinate dehydrogenase (ubiquinone) activity • flavin adenine dinucleotide binding Cellular component • mitochondrion • mitochondrial inner membrane • mitochondrial respiratory chain complex II, succinate dehydrogenase complex (ubiquinone) • myelin sheath Biological process • tricarboxylic acid cycle • succinate metabolic process • nervous system development • respiratory electron transport chain • cellular metabolic process • small molecule metabolic process • oxidation-reduction process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6389	66945
Ensembl	ENSG00000073578	ENSMUSG00000021577
UniProt	P31040	Q8K2B3
RefSeq (mRNA)	NM_001294332	NM_023281
RefSeq (protein)	NP_001281261	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. 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.

Structure

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

Function

File: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.

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

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.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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TCA Cycle edit