SUCLA2 encodes the beta subunit of the ATP-specific (ADP-forming) succinyl-CoA synthetase, a mitochondrial matrix heterodimer formed with the alpha subunit SUCLG1. The enzyme converts succinyl-CoA to succinate and CoA while phosphorylating ADP to ATP, the only substrate-level phosphorylation step of the tricarboxylic acid cycle; the beta subunit determines nucleotide specificity, and a paralogous GTP-specific beta subunit (SUCLG2) forms the GTP-forming isoenzyme. SUCLA2 is highly expressed in brain and skeletal muscle. The enzyme associates with mitochondrial nucleoside diphosphate kinase, which has been proposed to link it to mitochondrial dNTP salvage. As a promiscuous enzyme it also forms malyl-CoA; formation of itaconyl-CoA has been reported but is contested. Biallelic SUCLA2 loss-of-function variants cause an encephalomyopathic mtDNA depletion syndrome with mildly elevated methylmalonic acid, deafness, dystonia and Leigh-like lesions (MTDPS5).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: Magnesium ion binding, from an InterPro-derived electronic inference. Reason: Succinyl-CoA synthetase binds one Mg2+ per subunit as part of its catalytic mechanism; correct but a cofactor detail of the core activity. Supporting Evidence: file:human/SUCLA2/SUCLA2-uniprot.txt Binds 1 Mg(2+) ion per subunit. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: Catalytic activity, the root of the molecular-function branch, from an InterPro-derived electronic inference. Reason: True but uninformative: GO:0004775 succinate-CoA ligase (ADP-forming) activity, accepted in this review, entails it. Supporting Evidence: PMID:15877282 Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | EXP PMID:15877282 Deficiency of the ADP-forming succinyl-CoA synthase activity... | ACCEPT | Summary: A SUCLA2 loss-of-function variant markedly decreases succinyl-CoA synthetase activity in patient muscle mitochondria. Reason: A SUCLA2 loss-of-function variant markedly decreases succinyl-CoA synthetase activity in patient muscle mitochondria. Succinate-CoA ligase (ADP-forming) activity is the core MF of the SUCLA2-containing enzyme. Supporting Evidence: PMID:15877282 Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. |
| 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) metabolised succinate in this study; itaconate was not a substrate and inhibited the enzyme. Reason: Succinate-CoA ligase (ADP-forming) activity is the core MF of SUCLA2; the curator-assigned EXP annotation from this study is consistent with the established biochemistry. The full text reports that recombinant SCS-A metabolised succinate. Supporting Evidence: PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. 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 itaconate causes global alterations in cellular metabolite pools, resulting in elevated levels of succinate |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | EXP PMID:40108300 CLYBL averts vitamin B(12) depletion by repairing malyl-CoA. | ACCEPT | Summary: Succinate-CoA ligase (ADP-forming) activity is the core MF; the curator-assigned EXP annotation from this study (which also characterises malyl-CoA side products of TCA enzymes) is consistent with the established biochemistry. Reason: Succinate-CoA ligase (ADP-forming) activity is the core MF; the curator-assigned EXP annotation from this study (which also characterises malyl-CoA side products of TCA enzymes) is consistent with the established biochemistry. 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. Supporting Evidence: PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. file:human/SUCLA2/SUCLA2-uniprot.txt Reaction=succinate + ATP + CoA = succinyl-CoA + ADP + phosphate; |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core MF; IBA consistent with experimental and genetic data in human. Reason: Core MF; IBA consistent with experimental and genetic data in human. Supporting Evidence: PMID:15877282 Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core MF; combined IEA consistent with experimental data. Reason: Core MF; combined IEA consistent with experimental data. Supporting Evidence: PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. |
| GO:0004775 succinate-CoA ligase (ADP-forming) activity | TAS PMID:10727444 Interaction between succinyl CoA synthetase and the heme-bio... | ACCEPT | Summary: SUCLA2 (SCS-betaA) is the ATP-specific beta subunit of succinyl-CoA synthetase; core MF. Reason: SUCLA2 (SCS-betaA) is the ATP-specific beta subunit of succinyl-CoA synthetase; core MF. Supporting Evidence: PMID:10727444 we verified that mitochodrially expressed SCS-betaA associates specifically with ALAS-E and not with ALAS-N PMID:9765291 Highly ATP- and GTP-specific isoforms of succinyl-CoA synthetase in pigeon incorporate the same alpha-subunit, but different beta-subunits |
| GO:0005515 protein binding | IPI PMID:10727444 Interaction between succinyl CoA synthetase and the heme-bio... | REMOVE | Summary: Protein binding to ALAS2 (ALAS-E) from yeast two-hybrid and co-immunoprecipitation. Reason: Protein binding to ALAS2 (ALAS-E) from yeast two-hybrid and co-immunoprecipitation. The proposed functional role (channelling succinyl-CoA to heme synthesis) remains speculative, and protein binding is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:10727444 our findings suggest that appropriate association of SCS-betaA and ALAS-E promotes efficient use of succinyl CoA by ALAS-E or helps translocate ALAS-E into mitochondria PMID:10727444 we verified that mitochodrially expressed SCS-betaA associates specifically with ALAS-E and not with ALAS-N |
| GO:0005515 protein binding | IPI PMID:14643893 The major splice variant of human 5-aminolevulinate synthase... | REMOVE | Summary: Protein binding to the ALAS2 splice variant. Reason: Protein binding to the ALAS2 splice variant. Protein binding is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:14643893 with affinity for the ATP-specific, beta subunit of succinyl CoA synthase, comparable to that of mature ALAS2 |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: A physical interaction detected by isoform-resolved interactome profiling, recorded as bare protein binding. Reason: Protein binding from isoform-resolved interactome profiling is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:26871637 we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: A physical interaction detected by isoform-resolved interactome profiling, recorded as bare protein binding. Reason: Protein binding from isoform-resolved interactome profiling is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:26871637 we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: A physical interaction detected by isoform-resolved interactome profiling, recorded as bare protein binding. Reason: Protein binding from isoform-resolved interactome profiling is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:26871637 we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A physical interaction detected in the HuRI binary interactome screen, recorded as bare protein binding. Reason: Protein binding from the HuRI binary interactome screen is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: A physical interaction detected in a neurodegeneration-focused yeast two-hybrid interactome, recorded as bare protein binding. Reason: Protein binding from a neurodegeneration-focused yeast two-hybrid interactome is uninformative about SUCLA2 function; removal does not imply the interaction is false. Supporting Evidence: PMID:32814053 Here, we report on an interactome map that focuses on neurodegenerative disease (ND) |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: ATP binding, from an InterPro-derived electronic inference. Reason: ATP binding is part of the ATP-specific reaction, since the beta subunit determines nucleotide specificity, which is why this row is non-core rather than a function in its own right. It is not a refinement target or an ancestor of the core molecular function - GO:0005524 and GO:0004775 are in different branches, confirmed in both directions - so no more specific binding term replaces it. Supporting Evidence: file:human/SUCLA2/SUCLA2-uniprot.txt The beta subunit provides nucleotide specificity of the enzyme and binds the substrate succinate |
| GO:0005739 mitochondrion | EXP PMID:17287286 Mitochondrial encephalomyopathy with elevated methylmalonic ... | ACCEPT | Summary: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Reason: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. |
| GO:0005739 mitochondrion | EXP PMID:25944712 N-terminome analysis of the human mitochondrial proteome. | ACCEPT | Summary: Identified in the mitochondrial N-terminome. Reason: Identified in the mitochondrial N-terminome. SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:25944712 The present study describes the free N-terminome analysis of human mitochondria-enriched samples |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: Identified in phosphoproteomics of isolated human muscle mitochondria. Reason: Identified in phosphoproteomics of isolated human muscle mitochondria. SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:20833797 We performed a phosphoproteomics study of functional mitochondria isolated from human muscle biopsies |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: MitoCoP high-confidence mitochondrial proteome. Reason: MitoCoP high-confidence mitochondrial proteome. SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. 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: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Reason: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:15877282 Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas mitochondrial staining. Reason: Human Protein Atlas mitochondrial staining. SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:15877282 Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. |
| GO:0005739 mitochondrion | IDA PMID:10727444 Interaction between succinyl CoA synthetase and the heme-bio... | ACCEPT | Summary: Mitochondrially expressed SCS-betaA studied in transfected cells. Reason: Mitochondrially expressed SCS-betaA studied in transfected cells. SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:10727444 we verified that mitochodrially expressed SCS-betaA associates specifically with ALAS-E and not with ALAS-N |
| GO:0005739 mitochondrion | IDA PMID:15877282 Deficiency of the ADP-forming succinyl-CoA synthase activity... | ACCEPT | Summary: Succinyl-CoA synthetase deficiency measured in patient muscle mitochondria. Reason: Succinyl-CoA synthetase deficiency measured in patient muscle mitochondria. SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:15877282 Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Reason: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. |
| GO:0005739 mitochondrion | NAS PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Reason: SUCLA2 is the beta subunit of mitochondrial ATP-forming succinyl-CoA synthetase, a matrix TCA-cycle enzyme; mitochondrial localization is well established. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial matrix is where the TCA cycle and succinyl-CoA synthetase act. Reason: Mitochondrial matrix is where the TCA cycle and succinyl-CoA synthetase act. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70997 | ACCEPT | Summary: Reactome places the SUCLG1:SUCLA2 ADP-forming succinate-CoA ligase in the mitochondrial matrix. Reason: Reactome places the SUCLG1:SUCLA2 ADP-forming succinate-CoA ligase in the mitochondrial matrix. 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. |
| GO:0006099 tricarboxylic acid cycle | IBA GO_REF:0000033 | ACCEPT | Summary: Succinyl-CoA synthetase catalyses the substrate-level phosphorylation step of the TCA cycle; core BP. Reason: Succinyl-CoA synthetase catalyses the substrate-level phosphorylation step of the TCA cycle; core BP. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. |
| GO:0006099 tricarboxylic acid cycle | IEA GO_REF:0000120 | ACCEPT | Summary: TCA cycle; combined IEA consistent with experimental data. Reason: TCA cycle; combined IEA consistent with experimental data. Core BP. Supporting Evidence: PMID:17287286 The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. |
| GO:0006099 tricarboxylic acid cycle | NAS PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: TCA cycle, stated for succinyl-CoA synthetase. Reason: TCA cycle, stated for succinyl-CoA synthetase. Core BP. Supporting Evidence: PMID:32627745 Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation step in the tricarboxylic acid cycle. |
| GO:0006104 succinyl-CoA metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: SUCLA2 interconverts succinyl-CoA and succinate; succinyl-CoA metabolic process is directly carried out by its activity. Reason: SUCLA2 interconverts succinyl-CoA and succinate; succinyl-CoA metabolic process is directly carried out by its activity. Accumulation of succinyl-CoA in deficiency explains the methylmalonic aciduria. The term is kept beside its child GO:1901289 succinyl-CoA catabolic process because the reaction runs in both directions and the child names only the direction that consumes succinyl-CoA (the forward direction of the TCA cycle). Supporting Evidence: PMID:17287286 elevated methylmalonic acid, can be explained by an accumulation of the substrate of the enzyme, succinyl-CoA, which in turn leads to elevated methylmalonic acid |
| GO:0006104 succinyl-CoA metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Succinyl-CoA metabolic process; consistent with the core activity. Reason: Succinyl-CoA metabolic process; consistent with the core activity. The term is kept beside its child GO:1901289 succinyl-CoA catabolic process because the reaction runs in both directions and the child names only the direction that consumes succinyl-CoA (the forward direction of the TCA cycle). Supporting Evidence: PMID:17287286 elevated methylmalonic acid, can be explained by an accumulation of the substrate of the enzyme, succinyl-CoA, which in turn leads to elevated methylmalonic acid |
| GO:0006104 succinyl-CoA metabolic process | TAS PMID:9765291 Genetic evidence for the expression of ATP- and GTP-specific... | ACCEPT | Summary: Succinyl-CoA metabolic process; A-beta (SUCLA2) encodes the ATP-specific succinyl-CoA synthetase beta subunit. Reason: Succinyl-CoA metabolic process; A-beta (SUCLA2) encodes the ATP-specific succinyl-CoA synthetase beta subunit. The term is kept beside its child GO:1901289 succinyl-CoA catabolic process because the reaction runs in both directions and the child names only the direction that consumes succinyl-CoA (the forward direction of the TCA cycle). Supporting Evidence: PMID:9765291 The expression of A-beta is strong in numerous mouse and human tissues, which suggests that ATP-specific succinyl-CoA synthetase also plays an important role in species throughout the animal kingdom. |
| GO:0006105 succinate metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Involvement in succinate metabolic process, from an electronic inference. Reason: Succinate metabolic process is correct and as precise as this inference warrants, since SUCLA2 produces succinate from succinyl-CoA. It is kept as non-core rather than refined because it is neither an ancestor nor a descendant of GO:0006099 tricarboxylic acid cycle, the core step, as confirmed in both directions against the QuickGO is_a/part_of closure. The two are separate branches, not a general and a specific form of one claim. 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: Promiscuous TCA-cycle enzymes, including succinyl-CoA synthetase, form malyl-CoA as a side product from malate. Reason: Promiscuous TCA-cycle enzymes, including succinyl-CoA synthetase, form malyl-CoA as a side product from malate. This is a minor side activity, not a physiological pathway role. In the preprint of the study the catalytic efficiency of the ADP-forming enzyme with malate was 340-fold lower than with succinate. 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:0006781 succinyl-CoA pathway | NAS PMID:10727444 Interaction between succinyl CoA synthetase and the heme-bio... | MARK AS OVER ANNOTATED | Summary: Succinyl-CoA pathway (use of succinyl-CoA for protoporphyrin IX synthesis) is based on the SUCLA2-ALAS2 interaction and a proposal that it promotes succinyl-CoA use by ALAS2. Reason: Succinyl-CoA pathway (use of succinyl-CoA for protoporphyrin IX synthesis) is based on the SUCLA2-ALAS2 interaction and a proposal that it promotes succinyl-CoA use by ALAS2. SUCLA2 does not catalyse any step of heme synthesis, and the substrate-channelling role remains speculative. Supporting Evidence: PMID:10727444 our findings suggest that appropriate association of SCS-betaA and ALAS-E promotes efficient use of succinyl CoA by ALAS-E or helps translocate ALAS-E into mitochondria |
| GO:0009361 succinate-CoA ligase complex (ADP-forming) | IEA GO_REF:0000107 | ACCEPT | Summary: SUCLA2 is the beta subunit of the ADP-forming (ATP-specific) succinyl-CoA synthetase, an alpha-beta heterodimer with SUCLG1. Reason: SUCLA2 is the beta subunit of the ADP-forming (ATP-specific) succinyl-CoA synthetase, an alpha-beta heterodimer with SUCLG1. 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:9765291 Highly ATP- and GTP-specific isoforms of succinyl-CoA synthetase in pigeon incorporate the same alpha-subunit, but different beta-subunits |
| GO:0009361 succinate-CoA ligase complex (ADP-forming) | NAS PMID:32627745 Tartryl-CoA inhibits succinyl-CoA synthetase. | ACCEPT | Summary: Succinyl-CoA synthetase is an alpha-beta heterodimer; SUCLA2 is the ATP-specific beta subunit of the ADP-forming complex. Reason: Succinyl-CoA synthetase is an alpha-beta heterodimer; SUCLA2 is the ATP-specific beta subunit of the ADP-forming complex. 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. |
| 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 (it is proposed as a new term in the SUCLG1 and SUCLG2 reviews). 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/SUCLA2/SUCLA2-uniprot.txt Also able to act as an ATP-specific itaconyl- and malyl-CoA synthetase (PubMed:40108300). |
| GO:0042709 succinate-CoA ligase complex | IBA GO_REF:0000033 | TOO GENERAL | Summary: SUCLA2 is a subunit of the succinate-CoA ligase complex; IBA consistent with experimental data. Reason: Changed from ACCEPT. True, and the node placement is sound: the root of the beta-subunit family cannot carry a nucleotide-specific complex term because its descendants include ADP- and GDP-forming lineages. For SUCLA2 the specific child GO:0009361 succinate-CoA ligase complex (ADP-forming) is accepted on two rows of this review and is the core in_complex, so the parent adds nothing. This matches the action on the same row of the paralog SUCLG2 and of the orthologs LSC2 (S. cerevisiae) and SPCC1620.08 (S. pombe). 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. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MODIFY | Summary: Metal ion binding (Mg2+), from an electronic inference. Reason: Correct but more general than the evidence supports. The metal is Mg2+, and the specific child GO:0000287 magnesium ion binding is already carried by SUCLA2 from the family rule and kept as non-core in this review. The replacement is a cofactor detail of the core activity, not a core function. Proposed replacements: magnesium ion binding Supporting Evidence: file:human/SUCLA2/SUCLA2-uniprot.txt Binds 1 Mg(2+) ion per 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 is a promiscuous side activity of TCA-cycle succinyl-CoA synthetase that generates malyl-CoA, a damaged metabolite repaired by CLYBL. Reason: Malate-CoA ligase activity is a promiscuous side activity of TCA-cycle succinyl-CoA synthetase that generates malyl-CoA, a damaged metabolite repaired by CLYBL. Real, but not the physiological function. In the preprint of the study the catalytic efficiency of the ADP-forming enzyme with malate was 340-fold lower than with succinate. 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:0050074 malate-CoA ligase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Malate-CoA ligase activity, from an electronic inference. Reason: Malate-CoA ligase activity is a promiscuous side activity of succinyl-CoA synthetase. 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:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Localisation to extracellular exosome, from detection in a urinary exosome proteome. Reason: Detection in a urinary exosome proteome does not indicate a function in exosomes for this mitochondrial matrix enzyme; likely co-isolation of abundant mitochondrial protein. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| 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 SUCLG1. 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: Involvement in succinyl-CoA catabolic process: in the oxidative direction of the TCA cycle, succinyl-CoA synthetase converts succinyl-CoA to succinate. Reason: In the oxidative direction of the TCA cycle, succinyl-CoA synthetase converts succinyl-CoA to succinate, i.e. succinyl-CoA catabolism. 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, shown directly but without naming which complex. Reason: True of SUCLA2 but uninformative, because more specific complex terms accepted in this review already entail it - GO:0009361 succinate-CoA ligase complex (ADP-forming) on two rows and GO:0042709 succinate-CoA ligase complex, with GO:0009361 also the core in_complex. Both confirmed descendants of GO:1902494 in the QuickGO is_a/part_of closure. 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. |
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Download this section (compressed HTML)Q: By what mechanism does loss of ATP-specific succinyl-CoA synthetase lead to mtDNA depletion: impaired mitochondrial NDPK-dependent dNTP salvage, protein hypersuccinylation, or reduced TCA flux?
Q: Does the SUCLA2-ALAS2 interaction channel succinyl-CoA into heme biosynthesis in erythroid cells in vivo?
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 SUCLA2 and SUCLG1 stands.
Q: Are the reported kinase-regulated associations of SUCLA2 with glutaminase and OXCT1, which are proposed to control their succinylation, properties of the endogenous protein in normal tissues, and is the effect more than a change in local succinyl-CoA supply?
Experiment: Measure mitochondrial dNTP pools, mtDNA copy number and lysine succinylation in SUCLA2-null human iPSC-derived neurons, with rescue by wild-type SUCLA2 versus an NDPK-binding-deficient SUCLA2 mutant, to separate the dNTP-salvage and succinyl-CoA-accumulation hypotheses.
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