Identity check. The symbol, protein name, organism, family and domains all describe the same protein. SUCLA2 is the ATP-specific beta subunit of succinate–CoA ligase [ADP-forming]. It belongs to the succinate/malate CoA ligase beta family and has an ATP-grasp domain. The gene symbol is not ambiguous.
How this report was built. I ran three web searches, which returned mostly secondary sources. Those searches did not retrieve the primary papers for PMID:15877282 or PMID:40108300, or the Lambeth 2004 abstract. Claims that rest only on the UniProt annotation supplied in the task, or on my background knowledge, are marked as such.
Reaction. SUCLA2 is the beta subunit of ATP-specific succinyl-CoA synthetase (A-SCS), EC 6.2.1.5:
succinyl-CoA + ADP + Pi ⇌ succinate + CoA + ATP
This is the only substrate-level phosphorylation step of the TCA cycle. DrugBank describes the enzyme this way, and it cites PMID:15877282, PMID:34492704 and PMID:40108300 for the TCA-cycle role (DrugBank Q9P2R7). The UniProt record in the task cites PMID:15877282 as experimental support for EC 6.2.1.5.
Subunit composition. SUCLA2 forms a heterodimer with the shared alpha subunit SUCLG1.
- The beta subunit supplies nucleotide specificity (ATP) and helps bind succinate (as relayed by Wikipedia and the search summaries).
- The alternative beta subunit SUCLG2 pairs with SUCLG1 to form the GTP-specific enzyme (G-SCS). The two beta subunits are about 50% identical (Lambeth et al. 2004, J Biol Chem 279:36621, "Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues"; full text not retrieved).
- A human SUCLG1–SUCLA2 structure has been deposited at 2.59 Å (PDB 6G4Q). Its entry is listed as "To be published".
Substrate specificity and secondary activities. The UniProt entry lists two further ADP-forming ligase activities, both attributed to PMID:40108300:
- itaconyl-CoA ligase, EC 6.2.1.-
- malyl-CoA ligase, EC 6.2.1.9
These are mirrored in the mouse UniProt record (Glycosmos) and as malate-CoA ligase GO terms on DrugBank. I could not retrieve the 2025 paper, so I cannot say how efficient these side activities are or whether they matter in vivo. They fit a role in itaconate and malate/CoA-ester metabolism, but treat them as secondary to succinyl-CoA synthesis.
Biallelic SUCLA2 variants cause mitochondrial DNA depletion syndrome 5 (MTDPS5), an autosomal recessive encephalomyopathic form with mild methylmalonic aciduria (MedlinePlus condition page).
- Clinical picture. Patients have progressive, childhood-onset Leigh-like encephalomyopathy with dystonia, hypotonia, sensorineural hearing loss, basal ganglia lesions, mtDNA depletion and methylmalonic aciduria. Expression is highest in brain, which may explain the neurological predominance (PMC review).
- Key primary study. Carrozzo et al. 2007, Brain, PMID:17301081 studied 14 patients from 11 families with mild methylmalonic aciduria. It found three novel mutations and confirmed the mtDNA depletion and the protein-level defect.
- Related gene. SUCLG1 variants, in the shared alpha subunit, give a similar phenotype.
Proposed explanation for the methylmalonic aciduria: succinyl-CoA accumulation or imbalance, which is likely to affect methylmalonyl-CoA metabolism. This is my inference and I did not verify it against a primary source.
| Claim | Evidence | Strength |
|---|---|---|
| ATP-forming succinyl-CoA synthetase, EC 6.2.1.5 | UniProt, citing PMID:15877282 (experimental); DrugBank | Strong, but the primary paper was not retrieved |
| Itaconyl-CoA and malyl-CoA ligase activity | UniProt, citing PMID:40108300 | Recent; paper not read, so treat as secondary |
| Heterodimer with SUCLG1 | Structure (PDB 6G4Q), reviews | Good |
| MTDPS5 / methylmalonic aciduria | Carrozzo 2007 (PMID:17301081); MedlinePlus; PMC review | Strong |
| Tissue bias (brain, heart, muscle) | Lambeth 2004 via secondary summaries | Moderate |
Unresolved:
- The kinetics and relative efficiency of the itaconyl-CoA and malyl-CoA activities in vivo.
- The molecular mechanism linking loss of SUCLA2 to mtDNA depletion.
- The Johnson 2005 and PMID:40108300 primary papers, which should be read before the review file cites them.