{"gene":"PF3D7_0820700","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2014,"finding":"The E2 subunit of KDH (PF3D7_0820700 complex component) localizes to the mitochondrion of P. falciparum, and KDH is lipoylated through a novel two-component mechanism requiring both LipL1 and LipL2 together; LipL1 alone cannot lipoylate KDH, and this lipoylation occurs exclusively under strong reducing conditions.","method":"Mitochondrial localization by fluorescence microscopy; in vitro lipoylation assays with LipL1 and LipL2 under varying redox conditions; biochemical fractionation","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence, in vitro enzymatic assays with multiple conditions and controls, two orthogonal methods in a single focused study","pmids":["25116855"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Genetic knockout of α-ketoglutarate dehydrogenase (KDH) in P. falciparum does not impair asexual blood-stage growth but blocks oocyst development in mosquitoes, establishing that KDH function is essential for the mosquito-stage life cycle; (13)C isotope labeling of KO parasites revealed altered TCA pathway fluxes and changed exchange of substrates between cytosolic and mitochondrial pools.","method":"Genetic knockout (homologous recombination), life-cycle phenotyping across blood and mosquito stages, (13)C-isotope mass spectrometry metabolic flux analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined life-cycle phenotypic readout plus orthogonal metabolic flux analysis, single lab but multiple independent KO lines and rigorous controls","pmids":["25843709"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0820700 (KDH, the E1 component of α-ketoglutarate dehydrogenase) resides in the P. falciparum mitochondrion as part of the TCA cycle complex, is lipoylated exclusively under strongly reducing conditions via a novel two-protein mechanism requiring both LipL1 and LipL2, is dispensable for asexual blood-stage growth, and is essential for oocyst development in the mosquito host."},"narrative":{"mechanistic_narrative":"PF3D7_0820700 (KDH) is the E1 component of the mitochondrial α-ketoglutarate dehydrogenase complex of Plasmodium falciparum, functioning within the TCA cycle machinery localized to the parasite mitochondrion [PMID:25116855]. Activation of the complex depends on lipoylation of KDH through a novel two-component mechanism that requires both LipL1 and LipL2 acting together—LipL1 alone is insufficient—and this modification occurs exclusively under strongly reducing conditions [PMID:25116855]. Functionally, KDH is dispensable for asexual blood-stage growth but essential for oocyst development in the mosquito, and its loss reshapes TCA pathway fluxes and the exchange of substrates between cytosolic and mitochondrial pools [PMID:25843709]. Beyond these lipoylation, localization, and life-cycle findings, no further mechanistic detail about KDH has been characterized in the available corpus.","teleology":[{"year":2014,"claim":"It was unknown where the KDH complex resides and how it is post-translationally activated; this work localized the complex to the mitochondrion and defined a two-protein lipoylation mechanism, establishing how KDH is enzymatically licensed.","evidence":"Fluorescence microscopy localization, biochemical fractionation, and in vitro lipoylation assays with LipL1/LipL2 under varying redox conditions","pmids":["25116855"],"confidence":"High","gaps":["The catalytic activity of the E1 (PF3D7_0820700) subunit itself was not directly assayed","The physiological trigger producing the strongly reducing conditions required for lipoylation in vivo is undefined","Structural basis for why both LipL1 and LipL2 are jointly required is unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"The physiological requirement for KDH across the life cycle was unknown; genetic knockout showed it is dispensable in blood stages but essential for mosquito oocyst development, pinpointing a stage-specific metabolic dependency.","evidence":"Homologous-recombination knockout with life-cycle phenotyping and (13)C-isotope metabolic flux analysis","pmids":["25843709"],"confidence":"High","gaps":["The specific metabolic demand that makes KDH essential in the mosquito stage is not resolved","Whether the mosquito-stage requirement reflects E1 catalytic activity versus complex integrity was not dissected","Downstream consequences of altered cytosolic/mitochondrial substrate exchange for parasite viability are unquantified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How the two-component lipoylation mechanism and the strongly reducing requirement mechanistically connect to the stage-specific essentiality of KDH remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the KDH complex or its E1 subunit exists in the corpus","The regulatory link between redox state, lipoylation, and mosquito-stage metabolic demand is uncharacterized"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["α-ketoglutarate dehydrogenase (KDH) complex"],"partners":["LIPL1 (LIPOYLATION)","LIPL2 (LIPOYLATION)"],"other_free_text":["Lipoylation of KDH requires both LipL1 and LipL2 together and occurs exclusively under strongly reducing conditions [#0]","KDH is dispensable for asexual blood-stage growth but essential for mosquito oocyst development [#1]","Knockout alters TCA pathway fluxes and cytosolic/mitochondrial substrate exchange [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25843709","id":"PMC_25843709","title":"Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25843709","citation_count":135,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"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":["KDH"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34805091","id":"PMC_34805091","title":"Lipoic Acid Metabolism as a Potential Chemotherapeutic Target Against Plasmodium falciparum and Staphylococcus aureus.","date":"2021","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34805091","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KDH"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4064,"output_tokens":722,"usd":0.011511,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5371,"output_tokens":1634,"usd":0.033853,"stage2_stop_reason":"end_turn"},"total_usd":0.045364,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"The E2 subunit of KDH (PF3D7_0820700 complex component) localizes to the mitochondrion of P. falciparum, and KDH is lipoylated through a novel two-component mechanism requiring both LipL1 and LipL2 together; LipL1 alone cannot lipoylate KDH, and this lipoylation occurs exclusively under strong reducing conditions.\",\n      \"method\": \"Mitochondrial localization by fluorescence microscopy; in vitro lipoylation assays with LipL1 and LipL2 under varying redox conditions; biochemical fractionation\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence, in vitro enzymatic assays with multiple conditions and controls, two orthogonal methods in a single focused study\",\n      \"pmids\": [\"25116855\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Genetic knockout of α-ketoglutarate dehydrogenase (KDH) in P. falciparum does not impair asexual blood-stage growth but blocks oocyst development in mosquitoes, establishing that KDH function is essential for the mosquito-stage life cycle; (13)C isotope labeling of KO parasites revealed altered TCA pathway fluxes and changed exchange of substrates between cytosolic and mitochondrial pools.\",\n      \"method\": \"Genetic knockout (homologous recombination), life-cycle phenotyping across blood and mosquito stages, (13)C-isotope mass spectrometry metabolic flux analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined life-cycle phenotypic readout plus orthogonal metabolic flux analysis, single lab but multiple independent KO lines and rigorous controls\",\n      \"pmids\": [\"25843709\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_0820700 (KDH, the E1 component of α-ketoglutarate dehydrogenase) resides in the P. falciparum mitochondrion as part of the TCA cycle complex, is lipoylated exclusively under strongly reducing conditions via a novel two-protein mechanism requiring both LipL1 and LipL2, is dispensable for asexual blood-stage growth, and is essential for oocyst development in the mosquito host.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0820700 (KDH) is the E1 component of the mitochondrial α-ketoglutarate dehydrogenase complex of Plasmodium falciparum, functioning within the TCA cycle machinery localized to the parasite mitochondrion [#0]. Activation of the complex depends on lipoylation of KDH through a novel two-component mechanism that requires both LipL1 and LipL2 acting together—LipL1 alone is insufficient—and this modification occurs exclusively under strongly reducing conditions [#0]. Functionally, KDH is dispensable for asexual blood-stage growth but essential for oocyst development in the mosquito, and its loss reshapes TCA pathway fluxes and the exchange of substrates between cytosolic and mitochondrial pools [#1]. Beyond these lipoylation, localization, and life-cycle findings, no further mechanistic detail about KDH has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"It was unknown where the KDH complex resides and how it is post-translationally activated; this work localized the complex to the mitochondrion and defined a two-protein lipoylation mechanism, establishing how KDH is enzymatically licensed.\",\n      \"evidence\": \"Fluorescence microscopy localization, biochemical fractionation, and in vitro lipoylation assays with LipL1/LipL2 under varying redox conditions\",\n      \"pmids\": [\"25116855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The catalytic activity of the E1 (PF3D7_0820700) subunit itself was not directly assayed\",\n        \"The physiological trigger producing the strongly reducing conditions required for lipoylation in vivo is undefined\",\n        \"Structural basis for why both LipL1 and LipL2 are jointly required is unresolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The physiological requirement for KDH across the life cycle was unknown; genetic knockout showed it is dispensable in blood stages but essential for mosquito oocyst development, pinpointing a stage-specific metabolic dependency.\",\n      \"evidence\": \"Homologous-recombination knockout with life-cycle phenotyping and (13)C-isotope metabolic flux analysis\",\n      \"pmids\": [\"25843709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific metabolic demand that makes KDH essential in the mosquito stage is not resolved\",\n        \"Whether the mosquito-stage requirement reflects E1 catalytic activity versus complex integrity was not dissected\",\n        \"Downstream consequences of altered cytosolic/mitochondrial substrate exchange for parasite viability are unquantified\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two-component lipoylation mechanism and the strongly reducing requirement mechanistically connect to the stage-specific essentiality of KDH remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the KDH complex or its E1 subunit exists in the corpus\",\n        \"The regulatory link between redox state, lipoylation, and mosquito-stage metabolic demand is uncharacterized\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004591\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006099\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"α-ketoglutarate dehydrogenase (KDH) complex\"\n    ],\n    \"partners\": [\n      \"LipL1 (lipoylation)\",\n      \"LipL2 (lipoylation)\"\n    ],\n    \"other_free_text\": [\n      \"Lipoylation of KDH requires both LipL1 and LipL2 together and occurs exclusively under strongly reducing conditions [#0]\",\n      \"KDH is dispensable for asexual blood-stage growth but essential for mosquito oocyst development [#1]\",\n      \"Knockout alters TCA pathway fluxes and cytosolic/mitochondrial substrate exchange [#1]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0820700","name":null,"product":"2-oxoglutarate dehydrogenase E1 component","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0710100","name":null,"product":"2-oxoglutarate dehydrogenase E1 component, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1314700","name":null,"product":"2-oxoglutarate dehydrogenase E1 component, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"KDH","evaluation":null}