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. SUCLG2 is the SCS variant containing the SUCLG2-encoded β subunit.[2][3][4]Amino acid sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences.[5]
SUCLG2 is located on chromosome 3 and contains 14 exons.[1]
Function
As a subunit of SCS, SUCLG2 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 GDP to GTP, as a step in the tricarboxylic acid (TCA) cycle.[2][3][4][6] The GTP generated is then consumed in anabolic pathways.[3][5] However, since GTP is not transported through the inner mitochondrial membrane in mammals and other higher organisms, it must be recycled within the matrix.[4] In addition, SUCLG2 may function in ATP generation in the absence of SUCLA2 by complexing with the mitochondrial nucleotide diphosphate kinase, nm23-H4, and thus compensate for SUCLA2 deficiency.[2][4] The reverse reaction generates succinyl-CoA from succinate to fuel ketone body and heme synthesis.[2][4]
While SCS is ubiquitously expressed, SUCLG2 is predominantly expressed in tissues involved in biosynthesis, including liver and kidney.[4][5][7] SUCLG2 has also been detected in the microvasculature of the brain, likely to support its growth.[3] Notably, both SUCLA2 and SUCLG2 are absent in astrocytes, microglia, and oligodendrocytes in the brain; thus, 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.[3][4]
Clinical significance
Though mitochondrial DNA (mtDNA) depletion syndrome has been largely attributed to SUCLA2 deficiency, SUCLG2 may play a more crucial role in mtDNA maintenance, as it functions to compensate for SUCLA2 deficiency and its absence results in decreased mtDNA and OXPHOS-dependent growth.[2] Moreover, no mutations in the SUCLG2 gene have been reported, indicating that such mutations are lethal and selected against.[4]
↑ 2.02.12.22.32.4Miller C, Wang L, Ostergaard E, Dan P, Saada A (May 2011). "The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion". Biochimica et Biophysica Acta. 1812 (5): 625–9. doi:10.1016/j.bbadis.2011.01.013. PMID21295139.
↑ 3.03.13.23.33.4Dobolyi A, Bagó AG, Gál A, Molnár MJ, Palkovits M, Adam-Vizi V, Chinopoulos C (April 2015). "Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain". Journal of Bioenergetics and Biomembranes. 47 (1–2): 33–41. doi:10.1007/s10863-014-9586-4. PMID25370487.
↑ 4.04.14.24.34.44.54.64.7Dobolyi A, Ostergaard E, Bagó AG, Dóczi T, Palkovits M, Gál A, Molnár MJ, Adam-Vizi V, Chinopoulos C (January 2015). "Exclusive neuronal expression of SUCLA2 in the human brain". Brain Structure & Function. 220 (1): 135–51. doi:10.1007/s00429-013-0643-2. PMID24085565.
↑ 5.05.15.2Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO (October 1998). "Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes". The Journal of Biological Chemistry. 273 (42): 27580–6. doi:10.1074/jbc.273.42.27580. PMID9765291.