SUCLG1 encodes the alpha subunit of mitochondrial succinyl-CoA synthetase (succinate-CoA ligase), the matrix enzyme that carries out the only substrate-level phosphorylation of the tricarboxylic acid cycle by converting succinyl-CoA, a nucleoside diphosphate and phosphate to succinate, CoA and a nucleoside triphosphate. The alpha subunit binds CoA and phosphate and carries the phosphohistidine intermediate; it is shared by two enzymes that differ in their beta subunit, the ADP-forming enzyme with SUCLA2 and the GDP-forming enzyme with SUCLG2. The alpha subunit is required for the stability of both beta subunits. The enzyme also forms malyl-CoA as a side reaction; formation of itaconyl-CoA has been reported but is contested. Biallelic loss-of-function variants cause mitochondrial DNA depletion syndrome 9, an encephalomyopathy with methylmalonic aciduria. SUCLG1 is the ortholog of yeast LSC1 and bacterial SucD; having two beta partners is a feature of animals and a few other lineages.
Definition: Catalysis of the reaction: itaconate + a nucleoside triphosphate + CoA = itaconyl-CoA + a nucleoside diphosphate + phosphate.
Justification: UniProt records itaconyl-CoA ligase as an alternative activity of the succinyl-CoA synthetase subunits and cites PMID:40108300 for it. Only the abstract of that paper is cached; its bioRxiv preprint (doi 10.1101/2024.09.25.614871, version 1) reports that the recombinant human enzymes form itaconyl-CoA with catalytic efficiencies 30-fold (ADP-forming) and 15-fold (GDP-forming) lower than with succinate. The activity is contested, because an earlier study found that neither recombinant SCS-A nor pig heart SCS-G converted itaconate at 10 mM and that itaconate inhibits the enzyme (PMID:34492704). A search of GO found no term for this activity, so it is currently carried only under the parent GO:0016878 acid-thiol ligase activity. It is a side activity of the enzyme, so the term would be used as non-core. The parent is GO:0016878 and not GO:0016405 CoA-ligase activity, because GO:0016405 is defined as forming AMP and diphosphate.
Parent term: acid-thiol ligase activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: Detection in a UV-crosslinking mRNA interactome capture of HeLa cells. Reason: A proteome-wide capture. SUCLG1 is listed in Table 1 of the paper in the mRNA interactome class, with 16 other enzymes of intermediary metabolism. No RNA target, binding site or RNA-dependent function has been shown for SUCLG1. The observation may be real, but as a molecular function of the gene it is unsupported beyond the screen. Supporting Evidence: PMID:22658674 We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: Root molecular-function term from InterPro signatures. Reason: True but uninformative: GO:0004775 succinate-CoA ligase (ADP-forming) activity and GO:0004776 succinate-CoA ligase (GDP-forming) activity, both accepted in this review, entail it. Supporting Evidence: PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0004774 succinate-CoA ligase activity | IMP PMID:27484306 Expanding the phenotypic spectrum of Succinyl-CoA ligase def... | TOO GENERAL | Summary: Patient fibroblasts lacking SUCLG1 protein have essentially undetectable succinyl-CoA synthetase activity, restored by wild-type SUCLG1. Reason: True, and the experiment is sound, but the term is uninformative here: its two children GO:0004775 and GO:0004776 are both accepted on EXP rows in this review and are the core activities, and together they entail it. The same reasoning is applied to the root term catalytic activity above. The paper assayed ADP-dependent and GDP-dependent activity separately, and both were lost and both were restored by wild-type SUCLG1, so the result is kept as evidence for both children in core_functions. Supporting Evidence: PMID:27484306 The patient's cells lack the SUCLG1 protein, with significantly reduced levels of SUCLA2 and SUCLG2 protein. PMID:27484306 This leads to essentially undetectable SCS enzyme activity, mtDNA depletion, and cellular respiration defects. PMID:27484306 These abnormal phenotypes are rescued upon ectopic expression of wild-type SUCLG1 in the patient's fibroblasts PMID:27484306 Both ADP and GDP-specific SCS activities are completely restored in the patientβs cells with ectopic expression of SUCLG1 (Figure 1B) |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | EXP PMID:34492704 The immunometabolite itaconate inhibits heme synthesis and r... | ACCEPT | Summary: Recombinant ADP-forming succinyl-CoA synthetase (SCS-A) converted succinate. Itaconate was not a substrate in this assay and inhibited the enzyme. Reason: Core activity. SUCLG1 is the single alpha subunit shared by both human succinyl-CoA synthetases; with the ATP-specific beta subunit SUCLA2 it forms the ADP-forming enzyme. The full text reports assays of recombinant SCS-A, which metabolised succinate; the curator annotation is accepted. The source of the recombinant enzyme is given only in the supplemental Methods, which were not read. Supporting Evidence: PMID:34492704 Succinate but not itaconate at 10 mM concentrations is metabolized by pig heart SCS-GTP (SCS-G) (A) and recombinant SCS-ATP (SCS-A) (B). PMID:34492704 Pig heart SCS-G (Sigma) and recombinant SCS-A were assayed for reverse activity (GTP or ATP consumption as appropriate) with succinate and/or itaconate as substrate(s) PMID:32627745 These isoforms share the same Ξ±-subunit but have different Ξ²-subunits, which determine the nucleotide specificity |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | EXP PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | ACCEPT | Summary: ADP-forming succinyl-CoA synthetase activity in the study of malyl-CoA formation by citric acid cycle enzymes. Reason: Core activity. SUCLG1 is the single alpha subunit shared by both human succinyl-CoA synthetases; with the ATP-specific beta subunit SUCLA2 it forms the ADP-forming enzyme. Only the abstract of the published paper is cached, and it does not mention the enzyme. The bioRxiv preprint of the study (doi 10.1101/2024.09.25.614871, version 1) was read. It reports assays of recombinant human SUCLG1/SUCLA2 with succinate, malate and itaconate. UniProt cites this paper for the reaction and the curator annotation is accepted. Supporting Evidence: file:human/SUCLG1/SUCLG1-uniprot.txt Reaction=succinate + ATP + CoA = succinyl-CoA + ADP + phosphate; |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the LUCA node of the alpha-subunit family (PTN000122012); SUCLG1 is itself one of the seeds. Reason: Core activity. SUCLG1 is the single alpha subunit shared by both human succinyl-CoA synthetases; with the ATP-specific beta subunit SUCLA2 it forms the ADP-forming enzyme. SUCLG1 appears in the with/from because its own experimental annotation helped place the node; every succinyl-CoA synthetase outside the animal G-type clade that has been assayed uses ADP (E. coli, S. cerevisiae, the animal A-type enzyme, tobacco, Blastocystis, Trypanosoma brucei, Trichomonas vaginalis). In patient fibroblasts the ADP-dependent activity is lost with SUCLG1 and restored by it. Supporting Evidence: PMID:27484306 Both ADP and GDP-specific SCS activities are completely restored in the patientβs cells with ectopic expression of SUCLG1 (Figure 1B) PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. PMID:32627745 These isoforms share the same Ξ±-subunit but have different Ξ²-subunits, which determine the nucleotide specificity |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation from Rhea, EC 6.2.1.5, UniRule and the mouse ortholog. Reason: Core activity. SUCLG1 is the single alpha subunit shared by both human succinyl-CoA synthetases; with the ATP-specific beta subunit SUCLA2 it forms the ADP-forming enzyme. Supporting Evidence: PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0004776 succinate-CoA ligase (GDP-forming) activity | EXP PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | ACCEPT | Summary: GDP-forming succinyl-CoA synthetase activity (SUCLG1/SUCLG2). Reason: Core activity. With the GTP-specific beta subunit SUCLG2, SUCLG1 forms the GDP-forming enzyme. The alpha subunit binds CoA and phosphate and carries the phosphohistidine; it is nucleotide-agnostic, and the term holds because the human genome encodes a G-type beta partner. Only the abstract of the published paper is cached, and it does not mention the enzyme. The bioRxiv preprint of the study (doi 10.1101/2024.09.25.614871, version 1) was read. It reports assays of recombinant human SUCLG1/SUCLG2 with succinate, malate and itaconate. UniProt cites this paper for the GTP reaction and the curator annotation is accepted. Direct human evidence for the GDP-dependent activity also comes from patient fibroblasts, where it is lost with SUCLG1 and restored by it. Supporting Evidence: PMID:27484306 Both ADP and GDP-specific SCS activities are completely restored in the patientβs cells with ectopic expression of SUCLG1 (Figure 1B) file:human/SUCLG1/SUCLG1-uniprot.txt Reaction=GTP + succinate + CoA = succinyl-CoA + GDP + phosphate; PMID:32627745 Human GTP-specific SCS (GTPSCS), an Ξ±Ξ²-heterodimer, was produced in Escherichia coli |
| GO:0004776 succinate-CoA ligase (GDP-forming) activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the LUCA node of the alpha-subunit family (PTN000122012); SUCLG1 is one of the seeds. Reason: Core activity. With the GTP-specific beta subunit SUCLG2, SUCLG1 forms the GDP-forming enzyme. The alpha subunit binds CoA and phosphate and carries the phosphohistidine; it is nucleotide-agnostic, and the term holds because the human genome encodes a G-type beta partner. This is a lineage for which the placement is right. The same node also sends the term to the fungal alpha subunits in the tree, whose genomes lack a G-type beta gene; that over-propagation is recorded in the family review (NEEDS_PRUNING at the fungal branch) and does not affect the human gene. Supporting Evidence: PMID:27484306 Both ADP and GDP-specific SCS activities are completely restored in the patientβs cells with ectopic expression of SUCLG1 (Figure 1B) PMID:32627745 Human GTP-specific SCS (GTPSCS), an Ξ±Ξ²-heterodimer, was produced in Escherichia coli PMID:9765290 Because the two succinyl-CoA synthetases incorporate the same alpha-subunit, the determinants of nucleotide specificity must reside within the beta-subunit file:yeast/LSC2/LSC2-bioinformatics/RESULTS.md The 15 fungal genomes in the PANTHER tree (14 Dikarya and the chytrid Batrachochytrium dendrobatidis) have an A-type beta gene and no G-type beta gene. |
| GO:0004776 succinate-CoA ligase (GDP-forming) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation from Rhea and EC 6.2.1.4. Reason: Core activity. With the GTP-specific beta subunit SUCLG2, SUCLG1 forms the GDP-forming enzyme. The alpha subunit binds CoA and phosphate and carries the phosphohistidine; it is nucleotide-agnostic, and the term holds because the human genome encodes a G-type beta partner. Supporting Evidence: PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Affinity-purification mass spectrometry interaction with SUCLG2 (BioPlex). Reason: The alpha/beta interaction is genuine: SUCLG1 and SUCLG2 form the GDP-forming succinyl-CoA synthetase heterodimer. Removal follows the protein-binding policy and does not mean the interaction is false; it is captured by part_of succinate-CoA ligase complex (GDP-forming), GO:0045244, which this review accepts. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. Reactome:R-HSA-71775 The enzyme is a heterodimer containing SUCLG1 and SUCLG2 monomers. |
| GO:0005515 protein binding | IPI PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | REMOVE | Summary: SUCLG1 and SUCLG2 co-purify and co-crystallise as the human GTP-specific succinyl-CoA synthetase. Reason: The alpha/beta interaction is genuine: SUCLG1 and SUCLG2 form the GDP-forming succinyl-CoA synthetase heterodimer. Removal follows the protein-binding policy and does not mean the interaction is false; it is captured by part_of succinate-CoA ligase complex (GDP-forming), GO:0045244, which this review accepts. Supporting Evidence: PMID:32627745 Human GTP-specific SCS (GTPSCS), an Ξ±Ξ²-heterodimer, was produced in Escherichia coli |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Affinity-purification mass spectrometry interaction with SUCLG2 (BioPlex 3). Reason: The alpha/beta interaction is genuine: SUCLG1 and SUCLG2 form the GDP-forming succinyl-CoA synthetase heterodimer. Removal follows the protein-binding policy and does not mean the interaction is false; it is captured by part_of succinate-CoA ligase complex (GDP-forming), GO:0045244, which this review accepts. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Reactome:R-HSA-71775 The enzyme is a heterodimer containing SUCLG1 and SUCLG2 monomers. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-confidence human mitochondrial proteome (MitoCoP). Reason: SUCLG1 is a subunit of a mitochondrial matrix enzyme of the TCA cycle. The term stops at the organelle because the assay does not resolve the sub-compartment; matrix is asserted on separate rows. Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the eukaryotic alpha-subunit clade (PTN000122014). Reason: SUCLG1 is a subunit of a mitochondrial matrix enzyme of the TCA cycle. The row stops at the organelle because PAINT placed the organelle term at the eukaryotic node, from experimental mitochondrion annotations of Arabidopsis, mouse, yeast and human alpha subunits among the seeds; the organelle claim holds and matrix is asserted on separate rows. The node is the eukaryotic clade, which branches from within the bacterial alpha subunits, so bacterial members do not inherit the location. Supporting Evidence: PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0005739 mitochondrion | IDA PMID:15877282 Deficiency of the ADP-forming succinyl-CoA synthase activity... | ACCEPT | Summary: Mitochondrial location, annotated from the paper that described SUCLA2 deficiency. Reason: SUCLG1 is a subunit of a mitochondrial matrix enzyme of the TCA cycle. The term stops at the organelle because the assay does not resolve the sub-compartment; matrix is asserted on separate rows. The cached title and abstract concern SUCLA2, the beta subunit; the full text describes the heterodimeric matrix enzyme, and the curator annotation of the alpha subunit is accepted. Supporting Evidence: PMID:15877282 This mitochondrial matrix enzyme catalyzes the formation of succinate and ATP from succinyl-CoA and ADP in the tricarboxylic acid (TCA) cycle in a reversible manner. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping. Reason: SUCLG1 is a subunit of a mitochondrial matrix enzyme of the TCA cycle. The row stops at the organelle because its source, the UniProt subcellular location line assigned by HAMAP rule MF_03222, names the mitochondrion only; the organelle claim holds and matrix is asserted on separate rows. Supporting Evidence: file:human/SUCLG1/SUCLG1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000255|HAMAP-Rule:MF_03222}. PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0005739 mitochondrion | NAS PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: Author statement in the structure paper for human GTP-specific succinyl-CoA synthetase. Reason: SUCLG1 is a subunit of a mitochondrial matrix enzyme of the TCA cycle. The row stops at the organelle because the author statement it rests on names the mitochondrion only; matrix is asserted on separate rows. Supporting Evidence: PMID:32627745 In mammals, SCS is a mitochondrial enzyme and is an Ξ±,Ξ²-heterodimer with different isoforms |
| GO:0005739 mitochondrion | TAS PMID:9128182 The molecular basis for cross-reaction of an anti-dystrophin... | ACCEPT | Summary: A human muscle cDNA clone was identified as the mitochondrial succinyl-CoA synthetase alpha subunit in an antibody epitope study. Reason: SUCLG1 is a subunit of a mitochondrial matrix enzyme of the TCA cycle. The row stops at the organelle because the statement it rests on names the mitochondrial enzyme only; matrix is asserted on separate rows. The paper is about an anti-dystrophin antibody and mentions the enzyme only to identify a cross-reacting clone; the location is right but this reference is weak support for it. Supporting Evidence: PMID:9128182 contain part of the out-of-frame human mitochondrial succinyl CoA synthetase (alpha-subunit) cDNA sequence PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: Matrix location transferred from the mouse ortholog. Reason: The enzyme acts on matrix metabolites of the TCA cycle and the heterodimer is described as a matrix enzyme. Supporting Evidence: PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. PMID:15877282 This mitochondrial matrix enzyme catalyzes the formation of succinate and ATP from succinyl-CoA and ADP in the tricarboxylic acid (TCA) cycle in a reversible manner. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70997 | ACCEPT | Summary: Reactome places the SUCLG1:SUCLA2 ADP-forming enzyme in the mitochondrial matrix. Reason: Matrix is where the reaction takes place. Supporting Evidence: Reactome:R-HSA-70997 The enzyme catalyzing the reaction in vertebrates is a heterodimer of SUCLG1 and SUCLA2 that occurs in two isoforms. PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-71775 | ACCEPT | Summary: Reactome places the SUCLG1:SUCLG2 GDP-forming enzyme in the mitochondrial matrix. Reason: Matrix is where the reaction takes place. Supporting Evidence: Reactome:R-HSA-71775 The enzyme is a heterodimer containing SUCLG1 and SUCLG2 monomers. PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0006099 tricarboxylic acid cycle | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the LUCA node of the alpha-subunit family (PTN000122012). Reason: Core process: the enzyme carries out the substrate-level phosphorylation step of the TCA cycle, a role conserved from bacteria to animals. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. |
| GO:0006099 tricarboxylic acid cycle | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation from UniRule, UniPathway and the mouse ortholog. Reason: Core process. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. |
| GO:0006099 tricarboxylic acid cycle | NAS PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: Author statement. Reason: Core process. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. |
| GO:0006108 malate metabolic process | IDA PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | KEEP AS NON CORE | Summary: Succinyl-CoA synthetase converts malate to malyl-CoA as a side reaction. Reason: The enzyme does act on malate, so the term is true; it is peripheral because the reaction is a low-level side activity of a promiscuous enzyme whose product is removed by CLYBL. In the preprint of the study the catalytic efficiency with malate was 340-fold (ADP-forming enzyme) and 540-fold (GDP-forming enzyme) lower than with succinate. Kept as non-core, as for the beta subunit SUCLA2. Supporting Evidence: file:human/SUCLG1/SUCLG1-uniprot.txt Reaction=(S)-malate + ATP + CoA = (S)-malyl-CoA + ADP + phosphate; file:human/SUCLG1/SUCLG1-uniprot.txt Also able to act as an itaconyl- and malyl-CoA synthetase (PubMed:40108300). PMID:40108300 Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. |
| GO:0009361 succinate-CoA ligase complex (ADP-forming) | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the LUCA node of the alpha-subunit family (PTN000122012), seeded by E. coli SucD. Reason: SUCLG1 with SUCLA2 is the ADP-forming complex. A single bacterial seed is enough: an ADP-forming complex is found by assay in bacteria and in fungi, plants and animals. Supporting Evidence: Reactome:R-HSA-70997 The enzyme catalyzing the reaction in vertebrates is a heterodimer of SUCLG1 and SUCLA2 that occurs in two isoforms. PMID:30470562 Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. |
| GO:0009361 succinate-CoA ligase complex (ADP-forming) | NAS PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: Author statement. Reason: SUCLG1 with SUCLA2 is the ADP-forming complex. Supporting Evidence: PMID:32627745 These isoforms share the same Ξ±-subunit but have different Ξ²-subunits, which determine the nucleotide specificity Reactome:R-HSA-70997 The enzyme catalyzing the reaction in vertebrates is a heterodimer of SUCLG1 and SUCLA2 that occurs in two isoforms. |
| GO:0016878 acid-thiol ligase activity | IDA PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | KEEP AS NON CORE | Summary: The heterodimer forms other acyl-CoA thioesters. Malyl-CoA formation is established; itaconyl-CoA formation is reported but contested. Reason: Malyl-CoA formation is covered by the specific descendant GO:0050074 malate-CoA ligase activity, which is kept on this gene. The row is retained because itaconate-CoA ligase activity, also reported for the enzyme, has no GO term (see proposed_new_terms). When that term exists, this row becomes TOO_GENERAL or a MODIFY to it. Itaconyl-CoA formation is contested, with a negative result in PMID:34492704 and a positive one in PMID:40108300. Non-core because the promiscuity is peripheral to the succinyl-CoA reaction. Supporting Evidence: PMID:40108300 Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. file:human/SUCLG1/SUCLG1-uniprot.txt Also able to act as an itaconyl- and malyl-CoA synthetase (PubMed:40108300). |
| GO:0045244 succinate-CoA ligase complex (GDP-forming) | IPI PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: Crystal structure of the human SUCLG1/SUCLG2 heterodimer. Reason: Direct structural evidence that SUCLG1 is part of the GDP-forming complex, with CoA bound in the alpha subunit. Supporting Evidence: PMID:32627745 Human GTP-specific SCS (GTPSCS), an Ξ±Ξ²-heterodimer, was produced in Escherichia coli PMID:32627745 The CoA portion binds in the CoA-binding site located in the amino-terminal domain of the Ξ±-subunit |
| GO:0050074 malate-CoA ligase activity | EXP PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | KEEP AS NON CORE | Summary: Malate-CoA ligase activity of succinyl-CoA synthetase. Reason: A measured side activity that produces a damaged metabolite, malyl-CoA, which CLYBL removes. In the preprint of the study the catalytic efficiency with malate was 340-fold (ADP-forming enzyme) and 540-fold (GDP-forming enzyme) lower than with succinate. A genuine secondary activity, not what the enzyme evolved to do. Supporting Evidence: file:human/SUCLG1/SUCLG1-uniprot.txt Reaction=(S)-malate + ATP + CoA = (S)-malyl-CoA + ADP + phosphate; file:human/SUCLG1/SUCLG1-uniprot.txt Also able to act as an itaconyl- and malyl-CoA synthetase (PubMed:40108300). PMID:40108300 Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. |
| GO:0050074 malate-CoA ligase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation from Rhea and EC 6.2.1.9. Reason: Same judgement as the experimental row: a promiscuous side activity. Supporting Evidence: file:human/SUCLG1/SUCLG1-uniprot.txt Reaction=(S)-malate + ATP + CoA = (S)-malyl-CoA + ADP + phosphate; file:human/SUCLG1/SUCLG1-uniprot.txt Also able to act as an itaconyl- and malyl-CoA synthetase (PubMed:40108300). PMID:40108300 Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. |
| GO:0110052 toxic metabolite repair | IDA PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | UNDECIDED | Summary: Annotated from the study of malyl-CoA repair by CLYBL. The published full text was not read, so the basis of the curator annotation could not be checked. Reason: The published full text of PMID:40108300 was not accessible; only its abstract is cached. The abstract and the bioRxiv preprint of the study (version 1) present succinyl-CoA synthetase as a source of malyl-CoA, the damaged metabolite, and CLYBL as the enzyme that removes it. On that reading the process term belongs to CLYBL and this row is an over-annotation. The preprint also names succinyl-CoA synthetase, with AUH and CLYBL, as an enzyme of itaconate catabolism, in which it would form itaconyl-CoA. If the curator annotated that activating step as part of a disposal route, the gene product does some of the work and the row could stand. The row is left undecided until the published paper is read. The same action is used for SUCLA2. Supporting Evidence: PMID:40108300 Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. |
| GO:1901289 succinyl-CoA catabolic process | NAS PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: Author statement. Reason: In the oxidative direction of the TCA cycle the enzyme converts succinyl-CoA to succinate. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. |
| GO:1902494 catalytic complex | IDA PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | TOO GENERAL | Summary: Membership of a catalytic complex, without naming which. Reason: True but uninformative: GO:0009361 and GO:0045244, both accepted in this review, entail it. Supporting Evidence: Reactome:R-HSA-70997 The enzyme catalyzing the reaction in vertebrates is a heterodimer of SUCLG1 and SUCLA2 that occurs in two isoforms. Reactome:R-HSA-71775 The enzyme is a heterodimer containing SUCLG1 and SUCLG2 monomers. |
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Download this section (compressed HTML)Q: Is the reported restriction of POLRMT succinylation by SUCLG1 a direct, local effect, or a general consequence of the succinyl-CoA pool that any change in succinyl-CoA synthetase flux would produce?
Q: Does acylation of SUCLG1 (for example the reported butyrylation of Lys90) regulate the enzyme in normal physiology?
Q: Does the single alpha subunit partition between SUCLA2 and SUCLG2 simply by their abundance, or is assembly of the two enzymes regulated?
Q: Does the published version of the CLYBL study (PMID:40108300) present succinyl-CoA synthetase only as a source of malyl-CoA, or also as the itaconate-activating step of a disposal route? The answer decides whether the toxic metabolite repair annotation (GO:0110052) on SUCLG1 and SUCLA2 stands.
Q: Does human succinyl-CoA synthetase form itaconyl-CoA at physiological itaconate concentrations? One study found no conversion at 10 mM itaconate (PMID:34492704) and another measured the activity with the recombinant human enzymes (PMID:40108300).
Experiment: In SUCLG1-null fibroblasts, compare rescue of mtDNA copy number by wild-type SUCLG1, by a catalytically dead alpha subunit (phosphohistidine substitution) that still stabilises the beta subunits, and by lowering succinyl-CoA independently (SIRT5 overexpression or reduced 2-oxoglutarate dehydrogenase flux).
Hypothesis: mtDNA depletion in succinyl-CoA synthetase deficiency is caused by loss of matrix GTP supply or of NDPK coupling, not by succinyl-CoA accumulation.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: How loss of succinyl-CoA synthetase causes mitochondrial DNA depletion is not established. It is unknown whether the cause is loss of a physical or functional coupling to mitochondrial nucleoside diphosphate kinase, loss of matrix GTP, or a consequence of succinyl-CoA accumulation such as protein hypersuccinylation.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Established: patient fibroblasts lacking SUCLG1 lose both beta subunits and succinyl-CoA synthetase activity and show mtDNA depletion, all rescued by wild-type SUCLG1; knockdown of SUCLG2 lowers mtDNA content and NDPK activity. Not established: the molecular step that links the enzyme to mtDNA copy number.
Provenance (the field's own admissions):
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