{"gene":"TG_239490","gene_symbol":"BCKDH-E1a","run_date":"2026-09-10T21:09:19","timeline":{"discoveries":[{"year":2014,"finding":"The mitochondrial branched-chain ketoacid dehydrogenase (BCKDH) complex, including the E1a subunit, functionally replaces mitochondrial pyruvate dehydrogenase (PDH) in Toxoplasma gondii, catalysing the conversion of pyruvate to acetyl-CoA in the mitochondrion. Deletion of the E1a subunit of T. gondii BCKDH significantly impaired intracellular growth and virulence.","method":"Genetic deletion of BCKDH-E1a in T. gondii combined with metabolic profiling to assess TCA cycle function and intracellular growth assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular phenotype (growth, virulence) combined with metabolic evidence, replicated across two apicomplexan species (T. gondii and P. berghei)","pmids":["25032958"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2020,"finding":"The BCKDH complex, which includes BCKDH-E1a, is the mitochondrial source of acetyl-CoA in T. gondii; loss of BCKDH results in an altered TCA cycle and hypo-acetylation of mitochondrial proteins. Parasites lacking BCKDH survive through compensatory metabolic adaptations implemented at the transcriptional, translational, and post-translational levels.","method":"Multi-omics analysis (acetylome, transcriptome, proteome, metabolome) of BCKDH-knockout T. gondii parasites","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal omics methods (acetylome, metabolome, proteome, transcriptome) in a single rigorous study on BCKDH-knockout parasites","pmids":["32546260"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"BCKDH-E1a is the alpha subunit of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex in Toxoplasma gondii, which functionally substitutes for the absent mitochondrial pyruvate dehydrogenase by converting pyruvate to acetyl-CoA, thereby fuelling the TCA cycle and supporting mitochondrial protein acetylation; its deletion impairs intracellular growth and virulence, but parasites can survive through compensatory transcriptional, translational, and post-translational adaptations."},"narrative":{"mechanistic_narrative":"BCKDH-E1a is the alpha subunit of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex in Toxoplasma gondii, which functionally substitutes for the absent mitochondrial pyruvate dehydrogenase by catalysing the conversion of pyruvate to acetyl-CoA in the mitochondrion, thereby fuelling the TCA cycle [PMID:25032958]. Genetic deletion of BCKDH-E1a significantly impairs intracellular growth and virulence [PMID:25032958]. As the mitochondrial source of acetyl-CoA, the BCKDH complex also supports mitochondrial protein acetylation, and its loss produces an altered TCA cycle and hypo-acetylation of mitochondrial proteins, with parasites surviving through compensatory adaptations at the transcriptional, translational, and post-translational levels [PMID:32546260]. Beyond its role in this complex, nothing further is known about BCKDH-E1a in the available corpus.","teleology":[{"year":2014,"claim":"It was unknown how apicomplexan parasites generate mitochondrial acetyl-CoA lacking a conventional mitochondrial PDH; this showed that the BCKDH complex, including the E1a subunit, catalyses pyruvate-to-acetyl-CoA conversion, establishing BCKDH-E1a as essential for TCA cycle function, growth, and virulence.","evidence":"Genetic deletion of BCKDH-E1a with metabolic profiling and intracellular growth assays in T. gondii (and P. berghei)","pmids":["25032958"],"confidence":"High","gaps":["No structural or enzymatic characterization of the E1a subunit itself","Contribution of E1a versus other complex subunits to catalysis not resolved","Mechanism of virulence attenuation not defined at the molecular level"],"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2020,"claim":"It was unknown how parasites tolerate loss of the BCKDH-derived acetyl-CoA pool; multi-omics showed BCKDH is the mitochondrial acetyl-CoA source and that its loss causes an altered TCA cycle and mitochondrial protein hypo-acetylation, with survival enabled by compensatory transcriptional, translational, and post-translational adaptation.","evidence":"Acetylome, transcriptome, proteome, and metabolome analysis of BCKDH-knockout T. gondii","pmids":["32546260"],"confidence":"High","gaps":["The specific compensatory pathways restoring acetyl-CoA are not identified","Direct contribution of E1a distinct from the intact complex not isolated","Which mitochondrial proteins are functionally affected by hypo-acetylation not established"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex"],"partners":[],"other_free_text":["BCKDH functionally substitutes for the absent mitochondrial pyruvate dehydrogenase in Toxoplasma gondii, converting pyruvate to acetyl-CoA [#0]","Loss of BCKDH causes mitochondrial protein hypo-acetylation and an altered TCA cycle, with survival via transcriptional, translational, and post-translational compensation [#1]"]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"25032958","id":"PMC_25032958","title":"BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25032958","citation_count":102,"is_preprint":false},{"pmid":"32546260","id":"PMC_32546260","title":"Multi-omics analysis delineates the distinct functions of sub-cellular acetyl-CoA pools in Toxoplasma gondii.","date":"2020","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/32546260","citation_count":39,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3461,"output_tokens":1114,"usd":0.013546,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6047,"output_tokens":2304,"usd":0.043917,"stage2_stop_reason":"end_turn"},"total_usd":0.107294,"stage1_batch_id":"msgbatch_01TEPNZ4MCzJ7xtsNwosiDRk","stage2_batch_id":"msgbatch_01FQShM7n1sfCr4pWTDShmki","note":"batch pricing = 50% of standard","corrective_rerun":"2026-09-10 wrong-gene rerun (round-4 rules)","corrective_reason":"re-read with subject anchor"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"The mitochondrial branched-chain ketoacid dehydrogenase (BCKDH) complex, including the E1a subunit, functionally replaces mitochondrial pyruvate dehydrogenase (PDH) in Toxoplasma gondii, catalysing the conversion of pyruvate to acetyl-CoA in the mitochondrion. Deletion of the E1a subunit of T. gondii BCKDH significantly impaired intracellular growth and virulence.\",\n      \"method\": \"Genetic deletion of BCKDH-E1a in T. gondii combined with metabolic profiling to assess TCA cycle function and intracellular growth assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular phenotype (growth, virulence) combined with metabolic evidence, replicated across two apicomplexan species (T. gondii and P. berghei)\",\n      \"pmids\": [\"25032958\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The BCKDH complex, which includes BCKDH-E1a, is the mitochondrial source of acetyl-CoA in T. gondii; loss of BCKDH results in an altered TCA cycle and hypo-acetylation of mitochondrial proteins. Parasites lacking BCKDH survive through compensatory metabolic adaptations implemented at the transcriptional, translational, and post-translational levels.\",\n      \"method\": \"Multi-omics analysis (acetylome, transcriptome, proteome, metabolome) of BCKDH-knockout T. gondii parasites\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal omics methods (acetylome, metabolome, proteome, transcriptome) in a single rigorous study on BCKDH-knockout parasites\",\n      \"pmids\": [\"32546260\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"BCKDH-E1a is the alpha subunit of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex in Toxoplasma gondii, which functionally substitutes for the absent mitochondrial pyruvate dehydrogenase by converting pyruvate to acetyl-CoA, thereby fuelling the TCA cycle and supporting mitochondrial protein acetylation; its deletion impairs intracellular growth and virulence, but parasites can survive through compensatory transcriptional, translational, and post-translational adaptations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BCKDH-E1a is the alpha subunit of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex in Toxoplasma gondii, which functionally substitutes for the absent mitochondrial pyruvate dehydrogenase by catalysing the conversion of pyruvate to acetyl-CoA in the mitochondrion, thereby fuelling the TCA cycle [#0]. Genetic deletion of BCKDH-E1a significantly impairs intracellular growth and virulence [#0]. As the mitochondrial source of acetyl-CoA, the BCKDH complex also supports mitochondrial protein acetylation, and its loss produces an altered TCA cycle and hypo-acetylation of mitochondrial proteins, with parasites surviving through compensatory adaptations at the transcriptional, translational, and post-translational levels [#1]. Beyond its role in this complex, nothing further is known about BCKDH-E1a in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"It was unknown how apicomplexan parasites generate mitochondrial acetyl-CoA lacking a conventional mitochondrial PDH; this showed that the BCKDH complex, including the E1a subunit, catalyses pyruvate-to-acetyl-CoA conversion, establishing BCKDH-E1a as essential for TCA cycle function, growth, and virulence.\",\n      \"evidence\": \"Genetic deletion of BCKDH-E1a with metabolic profiling and intracellular growth assays in T. gondii (and P. berghei)\",\n      \"pmids\": [\"25032958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural or enzymatic characterization of the E1a subunit itself\",\n        \"Contribution of E1a versus other complex subunits to catalysis not resolved\",\n        \"Mechanism of virulence attenuation not defined at the molecular level\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"It was unknown how parasites tolerate loss of the BCKDH-derived acetyl-CoA pool; multi-omics showed BCKDH is the mitochondrial acetyl-CoA source and that its loss causes an altered TCA cycle and mitochondrial protein hypo-acetylation, with survival enabled by compensatory transcriptional, translational, and post-translational adaptation.\",\n      \"evidence\": \"Acetylome, transcriptome, proteome, and metabolome analysis of BCKDH-knockout T. gondii\",\n      \"pmids\": [\"32546260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific compensatory pathways restoring acetyl-CoA are not identified\",\n        \"Direct contribution of E1a distinct from the intact complex not isolated\",\n        \"Which mitochondrial proteins are functionally affected by hypo-acetylation not established\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The enzymatic mechanism, subunit stoichiometry, and structural basis of substrate handling by BCKDH-E1a within the complex remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the E1a subunit or the assembled BCKDH complex\",\n        \"No direct kinetic measurement of E1a-catalysed steps\",\n        \"Regulation of BCKDH-E1a expression or activity not defined\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003863\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006099\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0006085\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\n      \"Mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"BCKDH functionally substitutes for the absent mitochondrial pyruvate dehydrogenase in Toxoplasma gondii, converting pyruvate to acetyl-CoA [#0]\",\n      \"Loss of BCKDH causes mitochondrial protein hypo-acetylation and an altered TCA cycle, with survival via transcriptional, translational, and post-translational compensation [#1]\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_239490","name":"BCKDH-E1a","product":"2-oxoisovalerate dehydrogenase subunit alpha","uniprot_acc":"S8GG59","chromosome":"TGME49_chrVI","start_pos":711139},{"strain":"GT1","gene_id":"TGGT1_239490","name":null,"product":"dehydrogenase E1 component family protein","uniprot_acc":null,"chromosome":"TGGT1_chrVI","start_pos":705091},{"strain":"RH88","gene_id":"TGRH88_031490","name":null,"product":"dehydrogenase E1 component family protein","uniprot_acc":null,"chromosome":"CM023087","start_pos":2985912},{"strain":"VEG","gene_id":"TGVEG_239490","name":null,"product":"dehydrogenase E1 component family protein","uniprot_acc":"A0A125YLZ8","chromosome":"TGVEG_chrVI","start_pos":725272}]}