{"gene":"PF3D7_1320800","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2014,"finding":"The E2 subunit of α-ketoglutarate dehydrogenase (KDH), corresponding to PF3D7_1320800 (dihydrolipoyllysine-residue succinyltransferase / KDH-E2), localizes to the mitochondrion of P. falciparum, as demonstrated by direct localization experiments.","method":"Subcellular localization experiment (live imaging / fluorescence microscopy) of the KDH E2 subunit in P. falciparum","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment in a single lab study; mitochondrial localization established but functional consequence not independently replicated","pmids":["25116855"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"Lipoylation of the KDH E2 subunit (PF3D7_1320800) requires both LipL1 and LipL2 acting together through a novel two-enzyme mechanism; LipL1 alone cannot lipoylate KDH-E2, and this lipoylation occurs exclusively under strongly reducing conditions, distinguishing it from H-protein lipoylation.","method":"In vitro lipoylation assay under defined redox conditions; genetic/biochemical dissection of LipL1 and LipL2 contributions","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with defined redox conditions and two-enzyme dissection in a single rigorous study; novel mechanism with multiple orthogonal conditions tested","pmids":["25116855"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"The KDH complex (which includes PF3D7_1320800 as its E2 subunit) is one of two main mitochondrial ketoacid dehydrogenase enzymes whose activity depends on LipL2-mediated lipoate attachment; genetic deletion of KDH activity participates in a synthetic lethal relationship with the other ketoacid dehydrogenase (BCDH), and together they are required for mitochondrial acetyl-CoA biosynthesis essential for histone acetylation and parasite survival.","method":"Metabolite-labeling experiments with genetic deletion lines affecting mitochondrial dehydrogenase activity; synthetic lethality analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolite labeling combined with genetic deletion in a single lab study; KDH-E2 (PF3D7_1320800) implicated as component of the essential complex but findings attributed to the complex rather than the subunit in isolation","pmids":["37068227"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1320800 (KDH-E2, the dihydrolipoyllysine-residue succinyltransferase / E2 subunit of the α-ketoglutarate dehydrogenase complex) localizes to the P. falciparum mitochondrion, where it is lipoylated exclusively under strongly reducing conditions via a novel two-enzyme mechanism requiring both LipL1 and LipL2; as part of the KDH complex it is essential for mitochondrial acetyl-CoA production, which in turn supports histone and protein acetylation throughout the parasite."},"narrative":{"mechanistic_narrative":"PF3D7_1320800 encodes KDH-E2, the dihydrolipoyllysine-residue succinyltransferase (E2) subunit of the α-ketoglutarate dehydrogenase (KDH) complex, which localizes to the mitochondrion of P. falciparum [PMID:25116855]. Catalytic competence of KDH-E2 depends on post-translational lipoylation, which proceeds through a novel two-enzyme mechanism requiring both LipL1 and LipL2 acting together — LipL1 alone is insufficient — and occurs exclusively under strongly reducing conditions, distinguishing it from H-protein lipoylation [PMID:25116855]. As the E2 component of KDH, PF3D7_1320800 contributes to a mitochondrial ketoacid dehydrogenase system that, together with the branched-chain ketoacid dehydrogenase (BCDH), supports mitochondrial acetyl-CoA biosynthesis required for histone acetylation and parasite survival, with KDH and BCDH in a synthetic-lethal relationship [PMID:37068227]. Beyond its mitochondrial localization, its lipoylation requirements, and its role as a component of this essential complex, no further subunit-specific mechanistic detail for PF3D7_1320800 has been characterized in the available corpus.","teleology":[{"year":2014,"claim":"Establishing where the KDH E2 subunit acts was prerequisite to placing PF3D7_1320800 in parasite metabolism; localization pinned it to the mitochondrion.","evidence":"Subcellular localization/fluorescence imaging of the KDH E2 subunit in P. falciparum","pmids":["25116855"],"confidence":"Medium","gaps":["Functional consequence of localization not independently replicated","Does not resolve KDH-E2 activity or complex assembly in vivo"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"It was unknown how KDH-E2 acquires the lipoyl cofactor needed for catalysis; dissection showed lipoylation requires LipL1 and LipL2 together under strongly reducing conditions, defining a novel two-enzyme mechanism distinct from H-protein lipoylation.","evidence":"In vitro lipoylation assay under defined redox conditions with genetic/biochemical dissection of LipL1 and LipL2 contributions","pmids":["25116855"],"confidence":"High","gaps":["Physiological trigger for the strongly reducing requirement in vivo not defined","Structural basis for the LipL1/LipL2 cooperation not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"The downstream metabolic role of the KDH complex was clarified: KDH and BCDH form a synthetic-lethal pair whose LipL2-dependent activity feeds mitochondrial acetyl-CoA production required for histone acetylation and survival.","evidence":"Metabolite-labeling with genetic deletion lines and synthetic lethality analysis in P. falciparum","pmids":["37068227"],"confidence":"Medium","gaps":["Effects attributed to the complex rather than to PF3D7_1320800 in isolation","Individual contribution of KDH-E2 versus other KDH subunits to acetyl-CoA output not separated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether PF3D7_1320800 has subunit-specific functions or interaction properties beyond its role in the KDH complex remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No subunit-resolved genetic knockout phenotype for PF3D7_1320800 alone","No structural or reciprocal interaction data isolating KDH-E2 within the complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["alpha-ketoglutarate dehydrogenase (KDH) complex"],"partners":["LIPL1 (LIPOYLATION OF KDH-E2)","LIPL2 (LIPOYLATION OF KDH-E2)"],"other_free_text":["Lipoylation of KDH-E2 requires LipL1 and LipL2 together and occurs only under strongly reducing conditions, distinct from H-protein lipoylation [#1].","KDH and BCDH are in a synthetic-lethal relationship supporting mitochondrial acetyl-CoA production for histone acetylation and parasite survival [#2]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25116855","id":"PMC_25116855","title":"Redox-dependent lipoylation of mitochondrial proteins in Plasmodium falciparum.","date":"2014","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25116855","citation_count":19,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37068227","id":"PMC_37068227","title":"The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37068227","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3743,"output_tokens":1024,"usd":0.013295,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5781,"output_tokens":1931,"usd":0.03859,"stage2_stop_reason":"end_turn"},"total_usd":0.051885,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"The E2 subunit of α-ketoglutarate dehydrogenase (KDH), corresponding to PF3D7_1320800 (dihydrolipoyllysine-residue succinyltransferase / KDH-E2), localizes to the mitochondrion of P. falciparum, as demonstrated by direct localization experiments.\",\n      \"method\": \"Subcellular localization experiment (live imaging / fluorescence microscopy) of the KDH E2 subunit in P. falciparum\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment in a single lab study; mitochondrial localization established but functional consequence not independently replicated\",\n      \"pmids\": [\"25116855\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Lipoylation of the KDH E2 subunit (PF3D7_1320800) requires both LipL1 and LipL2 acting together through a novel two-enzyme mechanism; LipL1 alone cannot lipoylate KDH-E2, and this lipoylation occurs exclusively under strongly reducing conditions, distinguishing it from H-protein lipoylation.\",\n      \"method\": \"In vitro lipoylation assay under defined redox conditions; genetic/biochemical dissection of LipL1 and LipL2 contributions\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with defined redox conditions and two-enzyme dissection in a single rigorous study; novel mechanism with multiple orthogonal conditions tested\",\n      \"pmids\": [\"25116855\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The KDH complex (which includes PF3D7_1320800 as its E2 subunit) is one of two main mitochondrial ketoacid dehydrogenase enzymes whose activity depends on LipL2-mediated lipoate attachment; genetic deletion of KDH activity participates in a synthetic lethal relationship with the other ketoacid dehydrogenase (BCDH), and together they are required for mitochondrial acetyl-CoA biosynthesis essential for histone acetylation and parasite survival.\",\n      \"method\": \"Metabolite-labeling experiments with genetic deletion lines affecting mitochondrial dehydrogenase activity; synthetic lethality analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolite labeling combined with genetic deletion in a single lab study; KDH-E2 (PF3D7_1320800) implicated as component of the essential complex but findings attributed to the complex rather than the subunit in isolation\",\n      \"pmids\": [\"37068227\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1320800 (KDH-E2, the dihydrolipoyllysine-residue succinyltransferase / E2 subunit of the α-ketoglutarate dehydrogenase complex) localizes to the P. falciparum mitochondrion, where it is lipoylated exclusively under strongly reducing conditions via a novel two-enzyme mechanism requiring both LipL1 and LipL2; as part of the KDH complex it is essential for mitochondrial acetyl-CoA production, which in turn supports histone and protein acetylation throughout the parasite.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1320800 encodes KDH-E2, the dihydrolipoyllysine-residue succinyltransferase (E2) subunit of the α-ketoglutarate dehydrogenase (KDH) complex, which localizes to the mitochondrion of P. falciparum [#0]. Catalytic competence of KDH-E2 depends on post-translational lipoylation, which proceeds through a novel two-enzyme mechanism requiring both LipL1 and LipL2 acting together — LipL1 alone is insufficient — and occurs exclusively under strongly reducing conditions, distinguishing it from H-protein lipoylation [#1]. As the E2 component of KDH, PF3D7_1320800 contributes to a mitochondrial ketoacid dehydrogenase system that, together with the branched-chain ketoacid dehydrogenase (BCDH), supports mitochondrial acetyl-CoA biosynthesis required for histone acetylation and parasite survival, with KDH and BCDH in a synthetic-lethal relationship [#2]. Beyond its mitochondrial localization, its lipoylation requirements, and its role as a component of this essential complex, no further subunit-specific mechanistic detail for PF3D7_1320800 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing where the KDH E2 subunit acts was prerequisite to placing PF3D7_1320800 in parasite metabolism; localization pinned it to the mitochondrion.\",\n      \"evidence\": \"Subcellular localization/fluorescence imaging of the KDH E2 subunit in P. falciparum\",\n      \"pmids\": [\"25116855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of localization not independently replicated\",\n        \"Does not resolve KDH-E2 activity or complex assembly in vivo\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"It was unknown how KDH-E2 acquires the lipoyl cofactor needed for catalysis; dissection showed lipoylation requires LipL1 and LipL2 together under strongly reducing conditions, defining a novel two-enzyme mechanism distinct from H-protein lipoylation.\",\n      \"evidence\": \"In vitro lipoylation assay under defined redox conditions with genetic/biochemical dissection of LipL1 and LipL2 contributions\",\n      \"pmids\": [\"25116855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological trigger for the strongly reducing requirement in vivo not defined\",\n        \"Structural basis for the LipL1/LipL2 cooperation not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The downstream metabolic role of the KDH complex was clarified: KDH and BCDH form a synthetic-lethal pair whose LipL2-dependent activity feeds mitochondrial acetyl-CoA production required for histone acetylation and survival.\",\n      \"evidence\": \"Metabolite-labeling with genetic deletion lines and synthetic lethality analysis in P. falciparum\",\n      \"pmids\": [\"37068227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Effects attributed to the complex rather than to PF3D7_1320800 in isolation\",\n        \"Individual contribution of KDH-E2 versus other KDH subunits to acetyl-CoA output not separated\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PF3D7_1320800 has subunit-specific functions or interaction properties beyond its role in the KDH complex remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No subunit-resolved genetic knockout phenotype for PF3D7_1320800 alone\",\n        \"No structural or reciprocal interaction data isolating KDH-E2 within the complex\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004149\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006099\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0006085\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"alpha-ketoglutarate dehydrogenase (KDH) complex\"\n    ],\n    \"partners\": [\n      \"LipL1 (lipoylation of KDH-E2)\",\n      \"LipL2 (lipoylation of KDH-E2)\"\n    ],\n    \"other_free_text\": [\n      \"Lipoylation of KDH-E2 requires LipL1 and LipL2 together and occurs only under strongly reducing conditions, distinct from H-protein lipoylation [#1].\",\n      \"KDH and BCDH are in a synthetic-lethal relationship supporting mitochondrial acetyl-CoA production for histone acetylation and parasite survival [#2].\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1320800","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 2 of 2 cited papers name other catalogue genes (PF3D7_0923600, PF3D7_0820700, PF3D7_1314600). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1320800","name":null,"product":"dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1419100","name":null,"product":"dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1421400","name":null,"product":"dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}