SUCLG2

Succinate-CoA ligase, GDP-forming, beta subunit
Identifiers
Symbols SUCLG2 ; GBETA
External IDs OMIM: 603922 GeneCards: SUCLG2 Gene
EC number 6.2.1.4
Orthologs
Species Human Mouse
Entrez 8801 n/a
Ensembl ENSG00000172340 n/a
UniProt Q96I99 n/a
RefSeq (mRNA) NM_001177599 n/a
RefSeq (protein) NP_001171070 n/a
Location (UCSC) Chr 3:
67.36 – 67.65 Mb		 n/a
PubMed search n/a
Succinate-CoA ligase, ADP-forming, beta subunit
Identifiers
Symbols SUCLA2 ; A-BETA; MTDPS5; SCS-betaA
External IDs OMIM: 603921 MGI: 1306775 HomoloGene: 2856 GeneCards: SUCLA2 Gene
EC number 6.2.1.5
Orthologs
Species Human Mouse
Entrez 8803 20916
Ensembl ENSG00000136143 ENSMUSG00000022110
UniProt Q9P2R7 Q9Z2I9
RefSeq (mRNA) NM_003850 NM_011506
RefSeq (protein) NP_003841 NP_035636
Location (UCSC) Chr 13:
47.94 – 48 Mb		 Chr 14:
73.53 – 73.6 Mb
PubMed search

Succinyl-CoA ligase [GDP-forming] subunit beta, mitochondrial is an enzyme that in humans is encoded by the SUCLG2 gene on chromosome 3.[1]

This gene encodes a GTP-specific beta subunit of succinyl-CoA synthetase. Succinyl-CoA synthetase catalyzes the reversible reaction involving the formation of succinyl-CoA and succinate. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 5 and 12. [provided by RefSeq, Apr 2010][1]

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. 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]

SUCLG2 may also play a role in clearing cerebrospinal fluid amyloid-beta 1–42 (Aβ1–42) in Alzheimer's disease (AD) and, thus, reducing neuronal death.[6]

See also

References

  1. 1 2 3 "Entrez Gene: SUCLA2 succinate-CoA ligase, GDP-forming, beta subunit".
  2. 1 2 3 4 5 Miller, 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. PMID 21295139.
  3. 1 2 3 4 5 Dobolyi, 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. PMID 25370487.
  4. 1 2 3 4 5 6 7 8 Dobolyi, 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. PMID 24085565.
  5. 1 2 3 Johnson, JD; Mehus, JG; Tews, K; Milavetz, BI; Lambeth, DO (16 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. PMID 9765291.
  6. 1 2 Ramirez, A; van der Flier, WM; Herold, C; Ramonet, D; Heilmann, S; Lewczuk, P; Popp, J; Lacour, A; Drichel, D; Louwersheimer, E; Kummer, MP; Cruchaga, C; Hoffmann, P; Teunissen, C; Holstege, H; Kornhuber, J; Peters, O; Naj, AC; Chouraki, V; Bellenguez, C; Gerrish, A; International Genomics of Alzheimer's Project, (IGAP); Alzheimer's Disease Neuroimaging Initiative, (ADNI); Heun, R; Frölich, L; Hüll, M; Buscemi, L; Herms, S; Kölsch, H; Scheltens, P; Breteler, MM; Rüther, E; Wiltfang, J; Goate, A; Jessen, F; Maier, W; Heneka, MT; Becker, T; Nöthen, MM (15 December 2014). "SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.". Human molecular genetics 23 (24): 6644–58. PMID 25027320.
  7. ↑ Matilainen, S; Isohanni, P; Euro, L; Lönnqvist, T; Pihko, H; Kivelä, T; Knuutila, S; Suomalainen, A (March 2015). "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion.". European journal of human genetics : EJHG 23 (3): 325–30. PMID 24986829.
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