{"gene":"PF3D7_1013700","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2013,"finding":"TRX2 (PF3D7_1013700) is a genuine member of the Plasmodium Translocon of Exported Proteins (PTEX) complex, validated by genetic tagging and co-immunoprecipitation approaches alongside PTEX150, HSP101, EXP2, and PTEX88.","method":"Genetic tagging, co-immunoprecipitation, validation as bona fide PTEX component","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP/genetic tagging in a single lab with multiple orthogonal methods confirming complex membership","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2013,"finding":"Genetic deletion of TRX2 in P. berghei yields viable but slow-growing knockout parasites with reduced growth rates in vitro and in vivo and reduced capacity to cause severe disease in a cerebral malaria model, indicating TRX2 is not essential for parasite survival but optimizes PTEX activity.","method":"Genetic knockout (gene deletion), in vitro and in vivo growth assays, cerebral malaria disease model","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with defined phenotypic readouts in a single lab, multiple assays (in vitro growth, in vivo growth, disease severity)","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2013,"finding":"TRX2 and other PTEX components are expressed in early gametocytes, mosquito stages, and liver stages, indicating that the PTEX export machinery (including TRX2) is not restricted to asexual blood stages.","method":"Expression analysis across life-cycle stages (stage-specific protein detection)","journal":"Molecular microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single detection method per stage; no functional loss-of-function in these stages","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2017,"finding":"TRX2 (thioredoxin 2, a poor substrate for thioredoxin reductase that also lacks access to thioredoxin reductase due to its subcellular localization) can be reduced by the glutathione system, demonstrating functional cross-talk between the glutathione and thioredoxin antioxidant systems in P. falciparum.","method":"In vitro biochemical assay measuring reduction of thioredoxins by the glutathione system","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay directly demonstrating glutathione-mediated reduction of TRX2, single lab, single method","pmids":["28479253"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1013700 (TRX2) is a thioredoxin-like protein and bona fide component of the PTEX export translocon at the parasitophorous vacuole membrane; it is non-essential for blood-stage survival but promotes optimal PTEX-mediated protein export and normal parasite growth, and its antioxidant activity is sustained by the glutathione system (which can reduce TRX2 in the absence of thioredoxin reductase access), providing functional redundancy across subcellular compartments."},"narrative":{"mechanistic_narrative":"PF3D7_1013700 (TRX2) is a thioredoxin-like protein that functions as a bona fide component of the Plasmodium Translocon of Exported Proteins (PTEX), the machinery that exports parasite proteins across the parasitophorous vacuole membrane, where it associates with PTEX150, HSP101, EXP2, and PTEX88 [PMID:23869529]. TRX2 is not essential for blood-stage survival: its genetic deletion in P. berghei yields viable but slow-growing parasites with reduced in vitro and in vivo growth and a diminished capacity to cause severe disease in a cerebral malaria model, establishing that it optimizes rather than enables PTEX-mediated export [PMID:23869529]. Biochemically, TRX2 is a poor substrate for thioredoxin reductase and can instead be reduced by the glutathione system, demonstrating cross-talk between the parasite's glutathione and thioredoxin antioxidant systems [PMID:28479253]. Beyond its membership in PTEX, its antioxidant role in export, and this redox connectivity, no further mechanistic detail for TRX2 has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Establishing that TRX2 is a genuine PTEX subunit answered where this thioredoxin-like protein acts, placing it at the protein-export translocon rather than as a free-standing redox enzyme.","evidence":"Genetic tagging and reciprocal co-immunoprecipitation with PTEX150, HSP101, EXP2, and PTEX88","pmids":["23869529"],"confidence":"Medium","gaps":["Does not define TRX2's structural position within PTEX or its stoichiometry","Does not establish whether TRX2's redox activity is required for its association with the complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2013,"claim":"Deleting TRX2 tested whether the subunit is essential and showed it is dispensable but growth-optimizing, distinguishing it from core translocon components.","evidence":"Gene knockout in P. berghei with in vitro/in vivo growth assays and a cerebral malaria disease model","pmids":["23869529"],"confidence":"Medium","gaps":["The molecular basis linking TRX2 loss to reduced growth (e.g. impaired export of specific substrates) is not defined","Knockout was done in P. berghei; the phenotype in P. falciparum is not directly tested"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2013,"claim":"Expression profiling addressed whether TRX2 acts only in blood stages, showing PTEX components including TRX2 are present in gametocytes, mosquito, and liver stages.","evidence":"Stage-specific protein detection across the life cycle","pmids":["23869529"],"confidence":"Low","gaps":["Single detection method per stage with no loss-of-function to establish function in these stages","Does not show TRX2 is functionally required for export outside asexual blood stages"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2017,"claim":"Determining how TRX2 stays reduced addressed a redox-source problem, showing the glutathione system can reduce it since it is a poor thioredoxin-reductase substrate with limited reductase access.","evidence":"In vitro biochemical assay measuring glutathione-mediated reduction of thioredoxins in P. falciparum","pmids":["28479253"],"confidence":"Medium","gaps":["In vitro assay only; glutathione-dependent reduction of TRX2 within the intact translocon in vivo is not shown","Does not connect TRX2's redox state to a specific export or growth outcome"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The specific molecular function of TRX2 within PTEX — the substrates it reduces, whether it unfolds or maintains cargo in an export-competent state, and how its redox activity translates into the growth-optimizing effect — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified redox substrate of TRX2 within the export pathway","No structural model of TRX2 in the PTEX complex","Mechanistic link between TRX2 redox state and PTEX export efficiency undefined"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PTEX (Plasmodium Translocon of Exported Proteins) — with PTEX150, HSP101, EXP2, PTEX88 [#0]"],"partners":["PTEX150 [#0]","HSP101 [#0]","EXP2 [#0]","PTEX88 [#0]"],"other_free_text":["Non-essential for blood-stage survival; deletion in P. berghei gives viable but slow-growing parasites with reduced virulence in a cerebral malaria model [#1]","Poor substrate for thioredoxin reductase; reducible by the glutathione system, indicating glutathione/thioredoxin antioxidant cross-talk [#3]","Expressed in gametocytes, mosquito, and liver stages, not restricted to asexual blood stages (Low confidence) [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"23869529","id":"PMC_23869529","title":"The Plasmodium translocon of exported proteins (PTEX) component thioredoxin-2 is important for maintaining normal blood-stage growth.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23869529","citation_count":72,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin-like protein"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30514877","id":"PMC_30514877","title":"The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30514877","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin-like protein"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28479253","id":"PMC_28479253","title":"Glutathione and thioredoxin systems of the malaria parasite Plasmodium falciparum: Partners in crime?","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28479253","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin-like protein"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4005,"output_tokens":1137,"usd":0.014535,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5892,"output_tokens":2326,"usd":0.043805,"stage2_stop_reason":"end_turn"},"total_usd":0.05834,"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\": 2013,\n      \"finding\": \"TRX2 (PF3D7_1013700) is a genuine member of the Plasmodium Translocon of Exported Proteins (PTEX) complex, validated by genetic tagging and co-immunoprecipitation approaches alongside PTEX150, HSP101, EXP2, and PTEX88.\",\n      \"method\": \"Genetic tagging, co-immunoprecipitation, validation as bona fide PTEX component\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP/genetic tagging in a single lab with multiple orthogonal methods confirming complex membership\",\n      \"pmids\": [\"23869529\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Genetic deletion of TRX2 in P. berghei yields viable but slow-growing knockout parasites with reduced growth rates in vitro and in vivo and reduced capacity to cause severe disease in a cerebral malaria model, indicating TRX2 is not essential for parasite survival but optimizes PTEX activity.\",\n      \"method\": \"Genetic knockout (gene deletion), in vitro and in vivo growth assays, cerebral malaria disease model\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with defined phenotypic readouts in a single lab, multiple assays (in vitro growth, in vivo growth, disease severity)\",\n      \"pmids\": [\"23869529\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRX2 and other PTEX components are expressed in early gametocytes, mosquito stages, and liver stages, indicating that the PTEX export machinery (including TRX2) is not restricted to asexual blood stages.\",\n      \"method\": \"Expression analysis across life-cycle stages (stage-specific protein detection)\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single detection method per stage; no functional loss-of-function in these stages\",\n      \"pmids\": [\"23869529\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRX2 (thioredoxin 2, a poor substrate for thioredoxin reductase that also lacks access to thioredoxin reductase due to its subcellular localization) can be reduced by the glutathione system, demonstrating functional cross-talk between the glutathione and thioredoxin antioxidant systems in P. falciparum.\",\n      \"method\": \"In vitro biochemical assay measuring reduction of thioredoxins by the glutathione system\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay directly demonstrating glutathione-mediated reduction of TRX2, single lab, single method\",\n      \"pmids\": [\"28479253\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1013700 (TRX2) is a thioredoxin-like protein and bona fide component of the PTEX export translocon at the parasitophorous vacuole membrane; it is non-essential for blood-stage survival but promotes optimal PTEX-mediated protein export and normal parasite growth, and its antioxidant activity is sustained by the glutathione system (which can reduce TRX2 in the absence of thioredoxin reductase access), providing functional redundancy across subcellular compartments.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1013700 (TRX2) is a thioredoxin-like protein that functions as a bona fide component of the Plasmodium Translocon of Exported Proteins (PTEX), the machinery that exports parasite proteins across the parasitophorous vacuole membrane, where it associates with PTEX150, HSP101, EXP2, and PTEX88 [#0]. TRX2 is not essential for blood-stage survival: its genetic deletion in P. berghei yields viable but slow-growing parasites with reduced in vitro and in vivo growth and a diminished capacity to cause severe disease in a cerebral malaria model, establishing that it optimizes rather than enables PTEX-mediated export [#1]. Biochemically, TRX2 is a poor substrate for thioredoxin reductase and can instead be reduced by the glutathione system, demonstrating cross-talk between the parasite's glutathione and thioredoxin antioxidant systems [#3]. Beyond its membership in PTEX, its antioxidant role in export, and this redox connectivity, no further mechanistic detail for TRX2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing that TRX2 is a genuine PTEX subunit answered where this thioredoxin-like protein acts, placing it at the protein-export translocon rather than as a free-standing redox enzyme.\",\n      \"evidence\": \"Genetic tagging and reciprocal co-immunoprecipitation with PTEX150, HSP101, EXP2, and PTEX88\",\n      \"pmids\": [\"23869529\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Does not define TRX2's structural position within PTEX or its stoichiometry\",\n        \"Does not establish whether TRX2's redox activity is required for its association with the complex\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Deleting TRX2 tested whether the subunit is essential and showed it is dispensable but growth-optimizing, distinguishing it from core translocon components.\",\n      \"evidence\": \"Gene knockout in P. berghei with in vitro/in vivo growth assays and a cerebral malaria disease model\",\n      \"pmids\": [\"23869529\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"The molecular basis linking TRX2 loss to reduced growth (e.g. impaired export of specific substrates) is not defined\",\n        \"Knockout was done in P. berghei; the phenotype in P. falciparum is not directly tested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expression profiling addressed whether TRX2 acts only in blood stages, showing PTEX components including TRX2 are present in gametocytes, mosquito, and liver stages.\",\n      \"evidence\": \"Stage-specific protein detection across the life cycle\",\n      \"pmids\": [\"23869529\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single detection method per stage with no loss-of-function to establish function in these stages\",\n        \"Does not show TRX2 is functionally required for export outside asexual blood stages\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Determining how TRX2 stays reduced addressed a redox-source problem, showing the glutathione system can reduce it since it is a poor thioredoxin-reductase substrate with limited reductase access.\",\n      \"evidence\": \"In vitro biochemical assay measuring glutathione-mediated reduction of thioredoxins in P. falciparum\",\n      \"pmids\": [\"28479253\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"In vitro assay only; glutathione-dependent reduction of TRX2 within the intact translocon in vivo is not shown\",\n        \"Does not connect TRX2's redox state to a specific export or growth outcome\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific molecular function of TRX2 within PTEX — the substrates it reduces, whether it unfolds or maintains cargo in an export-competent state, and how its redox activity translates into the growth-optimizing effect — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No identified redox substrate of TRX2 within the export pathway\",\n        \"No structural model of TRX2 in the PTEX complex\",\n        \"Mechanistic link between TRX2 redox state and PTEX export efficiency undefined\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0015035\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0045454\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020005\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0065002\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"PTEX (Plasmodium Translocon of Exported Proteins) — with PTEX150, HSP101, EXP2, PTEX88 [#0]\"\n    ],\n    \"partners\": [\n      \"PTEX150 [#0]\",\n      \"HSP101 [#0]\",\n      \"EXP2 [#0]\",\n      \"PTEX88 [#0]\"\n    ],\n    \"other_free_text\": [\n      \"Non-essential for blood-stage survival; deletion in P. berghei gives viable but slow-growing parasites with reduced virulence in a cerebral malaria model [#1]\",\n      \"Poor substrate for thioredoxin reductase; reducible by the glutathione system, indicating glutathione/thioredoxin antioxidant cross-talk [#3]\",\n      \"Expressed in gametocytes, mosquito, and liver stages, not restricted to asexual blood stages (Low confidence) [#2]\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1013700","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 1 of 2 cited papers name other catalogue genes (PF3D7_1105600, PF3D7_1116800, PF3D7_1345100). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1013700","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1212100","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0813500","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}