{"gene":"PF3D7_0923600","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2007,"finding":"LipL2 (PF3D7_0923600) restored lipoate scavenging in lipoylation-deficient bacteria, demonstrating that it is a functional lipoate-scavenging enzyme in P. falciparum.","method":"Complementation assay in lipoylation-deficient bacteria","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation in bacteria with two orthogonal lines of evidence (bacterial rescue and radiolabel incorporation in parasites), single lab","pmids":["17244193"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"LipL2 (PF3D7_0923600) is dually targeted to both the mitochondrion and the apicoplast in P. falciparum erythrocytic stages, and provides residual lipoylation of the apicoplast-located pyruvate dehydrogenase E2 subunit when the biosynthetic enzyme LipB is disrupted, indicating a functional lipoate protein ligase activity in the apicoplast.","method":"Localization studies (fluorescence microscopy) and genetic disruption of LipB combined with immunodetection of lipoylated PDH","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization and genetic epistasis in single lab with two orthogonal readouts","pmids":["18069893"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"LipL2 (PF3D7_0923600) is located in both the mitochondrion and the apicoplast, and cannot compensate for the loss of LipL1 function during blood-stage development, suggesting a specific function for LipL2 that is distinct from LipL1's role in lipoylating mitochondrial substrates.","method":"Localization studies and genetic knockdown/functional analysis","journal":"Current pharmaceutical design","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article summarizing prior experimental findings, single lab, no new primary data described","pmids":["22607141"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"LipL2 (PF3D7_0923600) does not show canonical lipoate ligase activity and cannot independently lipoylate any of the mitochondrial substrates (H-protein, BCDH E2, or KDH E2). Instead, BCDH and KDH are lipoylated through a novel redox-sensitive mechanism requiring both LipL1 and LipL2, where strong reducing conditions are required specifically for BCDH and KDH lipoylation.","method":"In vitro lipoylation assays, redox-condition manipulation, and biochemical analysis of parasite protein lipoylation","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assays with defined substrates, redox manipulation, and negative-activity result for LipL2 alone contrasted with positive result for LipL1+LipL2 together; single lab but multiple orthogonal methods","pmids":["25116855"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"LipL2 (PF3D7_0923600) functions as a lipoyltransferase (not a canonical ligase) and is a member of a novel clade of lipoate attachment enzymes. PfLipL1 acts as a redox switch: depending on the lipoate redox state, it either functions as a canonical lipoate ligase (lipoylating H-protein) or as a lipoate-activating enzyme that works in conjunction with PfLipL2 to lipoylate BCDH and KDH.","method":"Biochemical characterization of enzyme activity, phylogenetic analysis, and in vitro lipoylation assays with redox-state manipulation","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assays demonstrating lipoyltransferase activity, multiple orthogonal methods (biochemical assay, phylogenetic classification, cross-species conservation shown with Chlamydia LipL2 homolog), single lab","pmids":["28836704"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"In P. berghei, the ortholog of LipL2 (lplA2) shows significantly increased mRNA expression when LplA1 is conditionally knocked out in late-stage infection, indicating that LipL2 can be activated as an alternative/compensatory pathway to maintain lipoic acid metabolism in the absence of LplA1.","method":"Conditional knockdown of LplA1 using anhydrotetracycline-inducible system; RT-PCR/gene expression profiling of lplA2 mRNA","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via conditional knockdown with defined phenotypic and transcriptional readout; single lab, single method for the compensatory expression finding","pmids":["28655332"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2023,"finding":"LipL2 (PF3D7_0923600) is essential for parasite survival solely because of its role in supporting mitochondrial acetyl-CoA metabolism: it is required for the lipoylation-dependent activity of the ketoacid dehydrogenase enzymes (BCDH and KDH), whose acetyl-CoA output is in turn required for histone acetylation and protein acetylation outside the mitochondrion.","method":"Metabolite-labeling experiments in P. falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity; epistasis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — metabolite labeling combined with genetic deletion epistasis, measuring both enzyme activity and downstream acetylation consequences, establishing essential role in a specific cellular process","pmids":["37068227"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0923600 (LipL2) is a mitochondrion- and apicoplast-dual-targeted lipoyltransferase (not a canonical lipoate ligase) in P. falciparum that works in concert with LipL1 via a redox-gated mechanism: under strongly reducing conditions, LipL1 activates lipoate and LipL2 transfers it to the E2 subunits of BCDH and KDH, producing mitochondrial acetyl-CoA that is essential for cellular acetyl-CoA metabolism and protein acetylation; LipL2's essentiality for parasite survival is attributable entirely to this acetyl-CoA-supporting role."},"narrative":{"mechanistic_narrative":"LipL2 (PF3D7_0923600) is a lipoate-attachment enzyme of P. falciparum that operates in the lipoate-scavenging arm of the parasite's lipoylation machinery, dually targeted to both the mitochondrion and the apicoplast [PMID:17244193, PMID:18069893]. Rather than acting as a canonical lipoate ligase, LipL2 functions as a lipoyltransferase: it cannot independently lipoylate any mitochondrial substrate, and instead works together with LipL1 through a redox-gated mechanism in which, under strongly reducing conditions, LipL1 activates lipoate and LipL2 transfers it to the E2 subunits of the branched-chain ketoacid dehydrogenase (BCDH) and α-ketoglutarate dehydrogenase (KDH) [PMID:25116855, PMID:28836704]. In the apicoplast, LipL2 provides residual lipoylation of the pyruvate dehydrogenase E2 subunit when the biosynthetic enzyme LipB is disrupted [PMID:18069893]. LipL2 is essential for parasite survival solely because this lipoylation-dependent BCDH/KDH activity supplies mitochondrial acetyl-CoA required for histone and other protein acetylation outside the mitochondrion [PMID:37068227].","teleology":[{"year":2007,"claim":"Establishing whether PF3D7_0923600 is a functional lipoate-handling enzyme at all, its capacity to scavenge lipoate was tested by heterologous rescue.","evidence":"Complementation of lipoylation-deficient bacteria by LipL2, with radiolabel incorporation in parasites","pmids":["17244193"],"confidence":"Medium","gaps":["Bacterial complementation does not define the native parasite substrates","Does not distinguish ligase from transferase activity"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"claim":"To place LipL2 within the parasite's compartmentalized lipoate pathways, its subcellular targeting and functional role were probed genetically.","evidence":"Fluorescence localization plus LipB disruption with immunodetection of lipoylated PDH E2 in P. falciparum","pmids":["18069893"],"confidence":"Medium","gaps":["Dual targeting mechanism to two organelles not defined","Extent of apicoplast vs mitochondrial contribution unquantified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Whether LipL2 is functionally redundant with LipL1 was addressed, indicating a distinct, non-compensating role in blood-stage lipoylation.","evidence":"Review summarizing localization and genetic knockdown/functional analysis in P. falciparum","pmids":["22607141"],"confidence":"Low","gaps":["Review article with no new primary data","Mechanistic basis of the LipL1/LipL2 distinction not established here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"The key mechanistic question — how LipL2 lipoylates its targets — was answered by showing it acts not alone but through a redox-sensitive two-enzyme mechanism with LipL1.","evidence":"In vitro lipoylation assays with defined substrates under manipulated redox conditions in P. falciparum","pmids":["25116855"],"confidence":"High","gaps":["Molecular basis of the redox switch not resolved","Physiological redox state driving BCDH/KDH lipoylation in vivo unmeasured"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"The enzymatic identity of LipL2 was refined to a lipoyltransferase of a novel clade, with LipL1 acting as the redox switch that partners with LipL2 for BCDH/KDH lipoylation.","evidence":"Biochemical activity characterization, phylogenetic analysis, and redox-state in vitro lipoylation assays in P. falciparum","pmids":["28836704"],"confidence":"High","gaps":["Structural basis of transferase catalysis not determined","How lipoate is channeled between LipL1 and LipL2 unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Whether the LipL2 ortholog serves as a compensatory pathway was tested in a rodent model, showing transcriptional upregulation upon loss of the partner enzyme.","evidence":"Anhydrotetracycline-inducible conditional knockout of LplA1 with RT-PCR profiling of lplA2 in P. berghei","pmids":["28655332"],"confidence":"Medium","gaps":["mRNA upregulation not shown to restore lipoylation functionally","Rodent finding not directly extended to P. falciparum LipL2"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2023,"claim":"Why LipL2 is essential was resolved by tracing its function to acetyl-CoA supply, linking mitochondrial dehydrogenase lipoylation to downstream protein acetylation.","evidence":"Metabolite-labeling and genetic-deletion epistasis measuring dehydrogenase activity and acetylation output in P. falciparum","pmids":["37068227"],"confidence":"High","gaps":["Contribution of the apicoplast-targeted pool to essentiality not separated","Mechanism of acetyl-CoA export/use for cytosolic acetylation not detailed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The structural and molecular basis of the LipL1/LipL2 redox-gated lipoate transfer, and the physiological role of LipL2's apicoplast pool, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of LipL2 or the LipL1-LipL2 assembly","Redox sensor identity and in vivo trigger unknown","Distinct apicoplast function versus mitochondrial function not disentangled"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["LIPL1"],"other_free_text":["Functions as a lipoyltransferase, not a canonical lipoate ligase, and belongs to a novel clade of lipoate-attachment enzymes [#4].","Lipoylation of BCDH and KDH E2 subunits requires both LipL1 and LipL2 under strongly reducing conditions; LipL2 alone cannot lipoylate H-protein, BCDH E2, or KDH E2 [#3].","Provides residual lipoylation of apicoplast PDH E2 when the biosynthetic enzyme LipB is disrupted [#1].","Essential for parasite survival attributable to supporting mitochondrial acetyl-CoA metabolism feeding histone and protein acetylation [#6].","In P. berghei, the ortholog lplA2 is transcriptionally upregulated when LplA1 is knocked out, indicating a compensatory response [#5]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"17244193","id":"PMC_17244193","title":"Scavenging of the cofactor lipoate is essential for the survival of the malaria parasite Plasmodium falciparum.","date":"2007","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17244193","citation_count":66,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["LipL2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18069893","id":"PMC_18069893","title":"Apicoplast lipoic acid protein ligase B is not essential for Plasmodium falciparum.","date":"2007","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/18069893","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["LplA2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22607141","id":"PMC_22607141","title":"Lipoic acid metabolism of Plasmodium--a suitable drug target.","date":"2012","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/22607141","citation_count":31,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["LplA2"],"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":["LipL2"],"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":14,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["LipL2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28836704","id":"PMC_28836704","title":"A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species.","date":"2017","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28836704","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["LipL2","PfLipL2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28655332","id":"PMC_28655332","title":"Conditional knock-out of lipoic acid protein ligase 1 reveals redundancy pathway for lipoic acid metabolism in Plasmodium berghei malaria parasite.","date":"2017","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/28655332","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["LplA2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6335,"output_tokens":2080,"usd":0.025102,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7297,"output_tokens":3049,"usd":0.056355,"stage2_stop_reason":"end_turn"},"total_usd":0.081457,"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\": 2007,\n      \"finding\": \"LipL2 (PF3D7_0923600) restored lipoate scavenging in lipoylation-deficient bacteria, demonstrating that it is a functional lipoate-scavenging enzyme in P. falciparum.\",\n      \"method\": \"Complementation assay in lipoylation-deficient bacteria\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation in bacteria with two orthogonal lines of evidence (bacterial rescue and radiolabel incorporation in parasites), single lab\",\n      \"pmids\": [\"17244193\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LipL2 (PF3D7_0923600) is dually targeted to both the mitochondrion and the apicoplast in P. falciparum erythrocytic stages, and provides residual lipoylation of the apicoplast-located pyruvate dehydrogenase E2 subunit when the biosynthetic enzyme LipB is disrupted, indicating a functional lipoate protein ligase activity in the apicoplast.\",\n      \"method\": \"Localization studies (fluorescence microscopy) and genetic disruption of LipB combined with immunodetection of lipoylated PDH\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and genetic epistasis in single lab with two orthogonal readouts\",\n      \"pmids\": [\"18069893\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LipL2 (PF3D7_0923600) is located in both the mitochondrion and the apicoplast, and cannot compensate for the loss of LipL1 function during blood-stage development, suggesting a specific function for LipL2 that is distinct from LipL1's role in lipoylating mitochondrial substrates.\",\n      \"method\": \"Localization studies and genetic knockdown/functional analysis\",\n      \"journal\": \"Current pharmaceutical design\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article summarizing prior experimental findings, single lab, no new primary data described\",\n      \"pmids\": [\"22607141\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LipL2 (PF3D7_0923600) does not show canonical lipoate ligase activity and cannot independently lipoylate any of the mitochondrial substrates (H-protein, BCDH E2, or KDH E2). Instead, BCDH and KDH are lipoylated through a novel redox-sensitive mechanism requiring both LipL1 and LipL2, where strong reducing conditions are required specifically for BCDH and KDH lipoylation.\",\n      \"method\": \"In vitro lipoylation assays, redox-condition manipulation, and biochemical analysis of parasite protein lipoylation\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assays with defined substrates, redox manipulation, and negative-activity result for LipL2 alone contrasted with positive result for LipL1+LipL2 together; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25116855\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LipL2 (PF3D7_0923600) functions as a lipoyltransferase (not a canonical ligase) and is a member of a novel clade of lipoate attachment enzymes. PfLipL1 acts as a redox switch: depending on the lipoate redox state, it either functions as a canonical lipoate ligase (lipoylating H-protein) or as a lipoate-activating enzyme that works in conjunction with PfLipL2 to lipoylate BCDH and KDH.\",\n      \"method\": \"Biochemical characterization of enzyme activity, phylogenetic analysis, and in vitro lipoylation assays with redox-state manipulation\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assays demonstrating lipoyltransferase activity, multiple orthogonal methods (biochemical assay, phylogenetic classification, cross-species conservation shown with Chlamydia LipL2 homolog), single lab\",\n      \"pmids\": [\"28836704\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In P. berghei, the ortholog of LipL2 (lplA2) shows significantly increased mRNA expression when LplA1 is conditionally knocked out in late-stage infection, indicating that LipL2 can be activated as an alternative/compensatory pathway to maintain lipoic acid metabolism in the absence of LplA1.\",\n      \"method\": \"Conditional knockdown of LplA1 using anhydrotetracycline-inducible system; RT-PCR/gene expression profiling of lplA2 mRNA\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via conditional knockdown with defined phenotypic and transcriptional readout; single lab, single method for the compensatory expression finding\",\n      \"pmids\": [\"28655332\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LipL2 (PF3D7_0923600) is essential for parasite survival solely because of its role in supporting mitochondrial acetyl-CoA metabolism: it is required for the lipoylation-dependent activity of the ketoacid dehydrogenase enzymes (BCDH and KDH), whose acetyl-CoA output is in turn required for histone acetylation and protein acetylation outside the mitochondrion.\",\n      \"method\": \"Metabolite-labeling experiments in P. falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity; epistasis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — metabolite labeling combined with genetic deletion epistasis, measuring both enzyme activity and downstream acetylation consequences, establishing essential role in a specific cellular process\",\n      \"pmids\": [\"37068227\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0923600 (LipL2) is a mitochondrion- and apicoplast-dual-targeted lipoyltransferase (not a canonical lipoate ligase) in P. falciparum that works in concert with LipL1 via a redox-gated mechanism: under strongly reducing conditions, LipL1 activates lipoate and LipL2 transfers it to the E2 subunits of BCDH and KDH, producing mitochondrial acetyl-CoA that is essential for cellular acetyl-CoA metabolism and protein acetylation; LipL2's essentiality for parasite survival is attributable entirely to this acetyl-CoA-supporting role.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LipL2 (PF3D7_0923600) is a lipoate-attachment enzyme of P. falciparum that operates in the lipoate-scavenging arm of the parasite's lipoylation machinery, dually targeted to both the mitochondrion and the apicoplast [#0, #1]. Rather than acting as a canonical lipoate ligase, LipL2 functions as a lipoyltransferase: it cannot independently lipoylate any mitochondrial substrate, and instead works together with LipL1 through a redox-gated mechanism in which, under strongly reducing conditions, LipL1 activates lipoate and LipL2 transfers it to the E2 subunits of the branched-chain ketoacid dehydrogenase (BCDH) and α-ketoglutarate dehydrogenase (KDH) [#3, #4]. In the apicoplast, LipL2 provides residual lipoylation of the pyruvate dehydrogenase E2 subunit when the biosynthetic enzyme LipB is disrupted [#1]. LipL2 is essential for parasite survival solely because this lipoylation-dependent BCDH/KDH activity supplies mitochondrial acetyl-CoA required for histone and other protein acetylation outside the mitochondrion [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing whether PF3D7_0923600 is a functional lipoate-handling enzyme at all, its capacity to scavenge lipoate was tested by heterologous rescue.\",\n      \"evidence\": \"Complementation of lipoylation-deficient bacteria by LipL2, with radiolabel incorporation in parasites\",\n      \"pmids\": [\"17244193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bacterial complementation does not define the native parasite substrates\", \"Does not distinguish ligase from transferase activity\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"To place LipL2 within the parasite's compartmentalized lipoate pathways, its subcellular targeting and functional role were probed genetically.\",\n      \"evidence\": \"Fluorescence localization plus LipB disruption with immunodetection of lipoylated PDH E2 in P. falciparum\",\n      \"pmids\": [\"18069893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dual targeting mechanism to two organelles not defined\", \"Extent of apicoplast vs mitochondrial contribution unquantified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether LipL2 is functionally redundant with LipL1 was addressed, indicating a distinct, non-compensating role in blood-stage lipoylation.\",\n      \"evidence\": \"Review summarizing localization and genetic knockdown/functional analysis in P. falciparum\",\n      \"pmids\": [\"22607141\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review article with no new primary data\", \"Mechanistic basis of the LipL1/LipL2 distinction not established here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The key mechanistic question — how LipL2 lipoylates its targets — was answered by showing it acts not alone but through a redox-sensitive two-enzyme mechanism with LipL1.\",\n      \"evidence\": \"In vitro lipoylation assays with defined substrates under manipulated redox conditions in P. falciparum\",\n      \"pmids\": [\"25116855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the redox switch not resolved\", \"Physiological redox state driving BCDH/KDH lipoylation in vivo unmeasured\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The enzymatic identity of LipL2 was refined to a lipoyltransferase of a novel clade, with LipL1 acting as the redox switch that partners with LipL2 for BCDH/KDH lipoylation.\",\n      \"evidence\": \"Biochemical activity characterization, phylogenetic analysis, and redox-state in vitro lipoylation assays in P. falciparum\",\n      \"pmids\": [\"28836704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of transferase catalysis not determined\", \"How lipoate is channeled between LipL1 and LipL2 unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether the LipL2 ortholog serves as a compensatory pathway was tested in a rodent model, showing transcriptional upregulation upon loss of the partner enzyme.\",\n      \"evidence\": \"Anhydrotetracycline-inducible conditional knockout of LplA1 with RT-PCR profiling of lplA2 in P. berghei\",\n      \"pmids\": [\"28655332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA upregulation not shown to restore lipoylation functionally\", \"Rodent finding not directly extended to P. falciparum LipL2\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Why LipL2 is essential was resolved by tracing its function to acetyl-CoA supply, linking mitochondrial dehydrogenase lipoylation to downstream protein acetylation.\",\n      \"evidence\": \"Metabolite-labeling and genetic-deletion epistasis measuring dehydrogenase activity and acetylation output in P. falciparum\",\n      \"pmids\": [\"37068227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of the apicoplast-targeted pool to essentiality not separated\", \"Mechanism of acetyl-CoA export/use for cytosolic acetylation not detailed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and molecular basis of the LipL1/LipL2 redox-gated lipoate transfer, and the physiological role of LipL2's apicoplast pool, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of LipL2 or the LipL1-LipL2 assembly\", \"Redox sensor identity and in vivo trigger unknown\", \"Distinct apicoplast function versus mitochondrial function not disentangled\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0033819\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0017118\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0016415\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0020011\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009107\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0006085\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0006473\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LipL1\"],\n    \"other_free_text\": [\n      \"Functions as a lipoyltransferase, not a canonical lipoate ligase, and belongs to a novel clade of lipoate-attachment enzymes [#4].\",\n      \"Lipoylation of BCDH and KDH E2 subunits requires both LipL1 and LipL2 under strongly reducing conditions; LipL2 alone cannot lipoylate H-protein, BCDH E2, or KDH E2 [#3].\",\n      \"Provides residual lipoylation of apicoplast PDH E2 when the biosynthetic enzyme LipB is disrupted [#1].\",\n      \"Essential for parasite survival attributable to supporting mitochondrial acetyl-CoA metabolism feeding histone and protein acetylation [#6].\",\n      \"In P. berghei, the ortholog lplA2 is transcriptionally upregulated when LplA1 is knocked out, indicating a compensatory response [#5].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0923600","name":null,"product":"lipoate-protein ligase 2","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0824500","name":null,"product":"lipoate-protein ligase 2","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0721600","name":null,"product":"lipoate-protein ligase 2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"LipL2","evaluation":null}