{"gene":"PF3D7_1217100","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2016,"finding":"PF3D7_1217100 (PfTopoVIA) forms a heteromeric complex with PfTopoVIB as shown by yeast two-hybrid analysis. The PfTopoVIB-VIA complex (requiring both subunits) can rescue the lethal phenotype of yeast ΔtopoII mutants, whereas PfTopoVIB alone cannot, establishing that TOP6A (PfTopoVIA) is essential for functional complementation. Cell-free extracts containing the PfTopoVIB-VIA complex exhibit ATP- and Mg2+-dependent decatenation activity, and this activity is specifically abrogated by anti-PfTopoVIB antibody. Radicicol and etoposide inhibit this decatenation activity, whereas the gyrase inhibitor novobiocin does not.","method":"Yeast two-hybrid (protein-protein interaction); heterologous expression in Saccharomyces cerevisiae; genetic complementation of yeast ΔtopoII mutants; cell-free decatenation assay; antibody inhibition; pharmacological inhibitor panel","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, genetic complementation, biochemical decatenation assay, antibody abrogation) in a single lab using a heterologous system; no in vitro reconstitution with purified Plasmodium protein","pmids":["27303712"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1217100 (TOP6A/PfTopoVIA) is the A subunit of the P. falciparum type II topoisomerase VI complex: it heterodimerizes with PfTopoVIB, and the combined PfTopoVIB-VIA complex performs ATP- and Mg2+-dependent DNA decatenation activity that is inhibited by radicicol and etoposide but not novobiocin; TOP6A alone is insufficient for type II topoisomerase function in a heterologous yeast complementation assay."},"narrative":{"mechanistic_narrative":"PF3D7_1217100 (TOP6A/PfTopoVIA) is the A subunit of the P. falciparum type II topoisomerase VI complex, functioning in ATP-dependent DNA topology management [PMID:27303712]. It heterodimerizes with PfTopoVIB, and only the combined PfTopoVIB-VIA complex — not PfTopoVIB alone — rescues the lethal phenotype of yeast Δtopo II mutants, establishing TOP6A as essential for functional type II topoisomerase complementation [PMID:27303712]. Cell-free extracts containing the PfTopoVIB-VIA complex exhibit ATP- and Mg2+-dependent DNA decatenation activity that is abrogated by anti-PfTopoVIB antibody and inhibited by radicicol and etoposide but not by the gyrase inhibitor novobiocin [PMID:27303712]. Beyond its membership in this heteromeric complex and the associated decatenation activity, no further mechanistic detail about PF3D7_1217100 has been characterized in the available corpus.","teleology":[{"year":2016,"claim":"It was unknown whether P. falciparum encodes a functional type II topoisomerase VI and what role the A subunit plays; this work established that PfTopoVIA (PF3D7_1217100) partners with PfTopoVIB to form a complex that is essential and sufficient for type II topoisomerase activity.","evidence":"Yeast two-hybrid interaction, genetic complementation of yeast Δtopo II mutants, cell-free ATP/Mg2+-dependent decatenation assay with antibody and inhibitor panels, in a heterologous S. cerevisiae system","pmids":["27303712"],"confidence":"Medium","gaps":["No in vitro reconstitution with purified Plasmodium TOP6A protein; activity shown only in cell-free extracts","Catalytic contribution of TOP6A itself versus PfTopoVIB not separately dissected","Native localization, expression timing, and essentiality within P. falciparum blood-stage biology not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The intrinsic catalytic role of TOP6A, its structure, and its function within intact P. falciparum parasites remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TOP6A or the PfTopoVIB-VIA complex","No reconstitution with purified recombinant TOP6A","No characterization of TOP6A localization or requirement in the native parasite"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfTopoVIB-VIA type II topoisomerase VI complex"],"partners":["PFTOPOVIB"],"other_free_text":["ATP- and Mg2+-dependent DNA decatenation activity of the PfTopoVIB-VIA complex is inhibited by radicicol and etoposide but not by novobiocin [#0]","TOP6A alone is insufficient for type II topoisomerase function in yeast Δtopo II complementation; both subunits are required [#0]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"3011062","id":"PMC_3011062","title":"Purification and characterization of Plasmodium berghei DNA topoisomerases I and II: drug action, inhibition of decatenation and relaxation, and stimulation of DNA cleavage.","date":"1986","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3011062","citation_count":77,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"3088783","id":"PMC_3088783","title":"Rapid repeated DNA replication during microgametogenesis and DNA synthesis in young zygotes of Plasmodium berghei.","date":"1986","source":"Transactions of the Royal Society of Tropical Medicine and Hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/3088783","citation_count":61,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"4971014","id":"PMC_4971014","title":"DNA, RNA , and protein synthesis in erythrocytic forms of Plasmodium knowlesi.","date":"1968","source":"The American journal of tropical medicine and hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/4971014","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15948708","id":"PMC_15948708","title":"DNA-[adenine] methylation in lower eukaryotes.","date":"2005","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/15948708","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2892060","id":"PMC_2892060","title":"From Laveran's discovery to DNA probes: new trends in diagnosis of malaria.","date":"1987","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/2892060","citation_count":31,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27303712","id":"PMC_27303712","title":"Radicicol-Mediated Inhibition of Topoisomerase VIB-VIA Activity of the Human Malaria Parasite Plasmodium falciparum.","date":"2016","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/27303712","citation_count":20,"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":4743,"output_tokens":587,"usd":0.011517,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5168,"output_tokens":1390,"usd":0.030295,"stage2_stop_reason":"end_turn"},"total_usd":0.041812,"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\": 2016,\n      \"finding\": \"PF3D7_1217100 (PfTopoVIA) forms a heteromeric complex with PfTopoVIB as shown by yeast two-hybrid analysis. The PfTopoVIB-VIA complex (requiring both subunits) can rescue the lethal phenotype of yeast ΔtopoII mutants, whereas PfTopoVIB alone cannot, establishing that TOP6A (PfTopoVIA) is essential for functional complementation. Cell-free extracts containing the PfTopoVIB-VIA complex exhibit ATP- and Mg2+-dependent decatenation activity, and this activity is specifically abrogated by anti-PfTopoVIB antibody. Radicicol and etoposide inhibit this decatenation activity, whereas the gyrase inhibitor novobiocin does not.\",\n      \"method\": \"Yeast two-hybrid (protein-protein interaction); heterologous expression in Saccharomyces cerevisiae; genetic complementation of yeast ΔtopoII mutants; cell-free decatenation assay; antibody inhibition; pharmacological inhibitor panel\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, genetic complementation, biochemical decatenation assay, antibody abrogation) in a single lab using a heterologous system; no in vitro reconstitution with purified Plasmodium protein\",\n      \"pmids\": [\"27303712\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1217100 (TOP6A/PfTopoVIA) is the A subunit of the P. falciparum type II topoisomerase VI complex: it heterodimerizes with PfTopoVIB, and the combined PfTopoVIB-VIA complex performs ATP- and Mg2+-dependent DNA decatenation activity that is inhibited by radicicol and etoposide but not novobiocin; TOP6A alone is insufficient for type II topoisomerase function in a heterologous yeast complementation assay.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1217100 (TOP6A/PfTopoVIA) is the A subunit of the P. falciparum type II topoisomerase VI complex, functioning in ATP-dependent DNA topology management [#0]. It heterodimerizes with PfTopoVIB, and only the combined PfTopoVIB-VIA complex — not PfTopoVIB alone — rescues the lethal phenotype of yeast Δtopo II mutants, establishing TOP6A as essential for functional type II topoisomerase complementation [#0]. Cell-free extracts containing the PfTopoVIB-VIA complex exhibit ATP- and Mg2+-dependent DNA decatenation activity that is abrogated by anti-PfTopoVIB antibody and inhibited by radicicol and etoposide but not by the gyrase inhibitor novobiocin [#0]. Beyond its membership in this heteromeric complex and the associated decatenation activity, no further mechanistic detail about PF3D7_1217100 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"It was unknown whether P. falciparum encodes a functional type II topoisomerase VI and what role the A subunit plays; this work established that PfTopoVIA (PF3D7_1217100) partners with PfTopoVIB to form a complex that is essential and sufficient for type II topoisomerase activity.\",\n      \"evidence\": \"Yeast two-hybrid interaction, genetic complementation of yeast Δtopo II mutants, cell-free ATP/Mg2+-dependent decatenation assay with antibody and inhibitor panels, in a heterologous S. cerevisiae system\",\n      \"pmids\": [\n        \"27303712\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution with purified Plasmodium TOP6A protein; activity shown only in cell-free extracts\",\n        \"Catalytic contribution of TOP6A itself versus PfTopoVIB not separately dissected\",\n        \"Native localization, expression timing, and essentiality within P. falciparum blood-stage biology not addressed\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic catalytic role of TOP6A, its structure, and its function within intact P. falciparum parasites remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of TOP6A or the PfTopoVIB-VIA complex\",\n        \"No reconstitution with purified recombinant TOP6A\",\n        \"No characterization of TOP6A localization or requirement in the native parasite\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0003918\",\n        \"supporting_discovery_ids\": [0]\n      },\n      {\n        \"term_id\": \"GO:0042802\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0006265\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"complexes\": [\n      \"PfTopoVIB-VIA type II topoisomerase VI complex\"\n    ],\n    \"partners\": [\n      \"PfTopoVIB\"\n    ],\n    \"other_free_text\": [\n      \"ATP- and Mg2+-dependent DNA decatenation activity of the PfTopoVIB-VIA complex is inhibited by radicicol and etoposide but not by novobiocin [#0]\",\n      \"TOP6A alone is insufficient for type II topoisomerase function in yeast Δtopo II complementation; both subunits are required [#0]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1217100","name":null,"product":"DNA topoisomerase 6 subunit A","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1432700","name":null,"product":"meiotic recombination protein SPO11, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1436700","name":null,"product":"DNA topoisomerase 6 subunit A, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"TOP6A","evaluation":null}