SUCLA2

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Species	Human	Mouse
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Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), is an enzyme that in humans is encoded by the SUCLA2 gene on chromosome 13.

Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinate to succinyl-CoA. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008]

Structure

SCS, also known as succinyl CoA ligase (SUCL), is a heterodimer composed of a catalytic α subunit encoded by the SUCLG1 gene and a β subunit encoded by either the SUCLA2 gene or the SUCLG2 gene, which determines the enzyme specificity for either ADP or GDP. SUCLA2 is the SCS variant containing the SUCLA2-encoded β subunit. Amino acid sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences.

SUCLA2 is located on chromosome 13 and contains 13 exons.

Function

As a subunit of SCS, SUCLA2 is a mitochondrial matrix enzyme that catalyzes the reversible conversion of succinyl-CoA to succinate and acetoacetyl CoA, accompanied by the substrate-level phosphorylation of ADP to ATP, as a step in the tricarboxylic acid (TCA) cycle. The ATP generated is then consumed in catabolic pathways. Since substrate-level phosphorylation does not require oxygen for ATP production, this reaction can rescue cells from cytosolic ATP depletion during ischemia. The reverse reaction generates succinyl-CoA from succinate to fuel ketone body and heme synthesis.

While SCS is ubiquitously expressed, SUCLA2 is predominantly expressed in catabolic tissues reliant on ATP as their main energy source, including heart, brain, and skeletal muscle. Within the brain, SUCLA2 is found exclusively in neurons; meanwhile, both SUCLA2 and SUCLG2 are absent in astrocytes, microglia, and oligodendrocytes. In order to acquire succinate to continue the TCA cycle, these cells may instead synthesize succinate through GABA metabolism of α-ketoglutarate or ketone body metabolism of succinyl-CoA.

Clinical significance

Mutations in the SUCLA2 gene are associated with mitochondrial DNA (mtDNA) depletion syndrome. Symptoms include early onset low muscle tone, severe muscular atrophy, scoliosis, movement disorders such as dystonia and hyperkinesia, epilepsy, and growth retardation. There currently is no curative therapy. Treatment is restricted to managing symptoms and includes exercises to promote mobility, respiratory assistance, baclofen to treat dystonia and hyperkinesia, and antiepileptic drugs for seizures.

There is a relatively high incidence of a specific SUCLA2 mutation in the Faroe Islands due to a founder effect. This particular mutation is often associated with early lethality. Two additional founder mutations in have been discovered in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands. These patients show a higher variability in outcomes with a number of patients with SUCLA2 missense mutation surviving into adulthood. This variability suggests that SUCLA2 missense mutations may be associated with residual enzyme activity.

Coenzyme Q10 and antioxidants have been used to treat mitochondrial DNA depletion syndrome but there is currently no evidence that these treatments result in clinical benefit.

Mutations in the SUCLA2 gene leading to SUCLA2 deficiency result in Leigh's or a Leigh-like syndrome with onset of severe hypotonia, muscular atrophy, sensorineural hearing impairment, and often death in early childhood.

See also

• Succinyl-CoA synthetase
• SUCLG1
• SUCLG2

Further reading

• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ (Nov 1999). "Antigens recognized by autologous antibody in patients with renal-cell carcinoma". International Journal of Cancer. 83 (4): 456–64. doi:10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5. PMID 10508479.
• Furuyama K, Sassa S (Mar 2000). "Interaction between succinyl CoA synthetase and the heme-biosynthetic enzyme ALAS-E is disrupted in sideroblastic anemia". The Journal of Clinical Investigation. 105 (6): 757–64. doi:10.1172/JCI6816. PMC 377455. PMID 10727444.
• Cox TC, Sadlon TJ, Schwarz QP, Matthews CS, Wise PD, Cox LL, Bottomley SS, May BK (Feb 2004). "The major splice variant of human 5-aminolevulinate synthase-2 contributes significantly to erythroid heme biosynthesis". The International Journal of Biochemistry & Cell Biology. 36 (2): 281–95. doi:10.1016/S1357-2725(03)00246-2. PMID 14643893.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (Jan 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455.
• Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, Pagnamenta A, Eshhar S, Saada A (Jun 2005). "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion". American Journal of Human Genetics. 76 (6): 1081–6. doi:10.1086/430843. PMC 1196446. PMID 15877282.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.

External links

• GeneReview/NCBI/NIH/UW entry on SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria