{"gene":"PF3D7_1124200","run_date":"2026-09-11T10:06:41","timeline":{"discoveries":[{"year":2013,"finding":"TRX2 (PF3D7_1124200) is a genuine member of the PTEX (Plasmodium translocon of exported proteins) complex, validated by genetic tagging and co-localization experiments. Deletion of TRX2 in P. berghei produced viable parasites with reduced blood-stage growth rates (in vivo and in vitro) and reduced capacity to cause severe disease in a cerebral malaria model, indicating TRX2 is not essential but optimizes PTEX activity.","method":"Genetic tagging (epitope tag knock-in), gene knockout in P. berghei, in vivo and in vitro growth assays, cerebral malaria model","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal validation of complex membership by genetic tagging, clean knockout with defined cellular and in vivo phenotypes, replicated across two growth conditions","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2013,"finding":"TRX2 (PF3D7_1124200) is expressed not only in asexual blood stages but also in early gametocytes, mosquito stages, and liver stages, consistent with a role for protein export beyond asexual stages.","method":"Expression analysis across life-cycle stages (genetic tagging)","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, life-cycle expression detected via tagged lines, no direct functional consequence demonstrated for each stage","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2017,"finding":"TRX2 (PF3D7_1124200) is a poor substrate for thioredoxin reductase and lacks direct access to thioredoxin reductase; however, the glutathione system (glutaredoxin/glutathione reductase) can reduce TRX2, demonstrating functional cross-talk between the glutathione and thioredoxin antioxidant systems in P. falciparum.","method":"In vitro biochemical reduction assay measuring cross-system reduction of thioredoxins by the glutathione system","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assay directly measuring substrate reduction, but single lab and single method","pmids":["28479253"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1124200 (TRX2) is a thioredoxin-like protein that is a genuine, non-essential component of the PTEX export translocon in Plasmodium, where its loss reduces but does not abolish blood-stage growth and virulence; biochemically, TRX2 is a poor substrate for thioredoxin reductase but can be reduced by the glutathione system, suggesting it participates in antioxidant cross-talk within the parasite."},"narrative":{"mechanistic_narrative":"PF3D7_1124200 (TRX2) is a thioredoxin-like protein that functions as a genuine, non-essential accessory component of the PTEX (Plasmodium translocon of exported proteins) complex, the machinery that exports parasite proteins across the parasitophorous vacuole membrane [PMID:23869529]. Genetic tagging and co-localization confirmed its membership in PTEX, and knockout in P. berghei yielded viable parasites with reduced blood-stage growth in vivo and in vitro and diminished capacity to cause severe disease in a cerebral malaria model, establishing that TRX2 optimizes rather than being required for PTEX activity [PMID:23869529]. It is expressed across multiple life-cycle stages including early gametocytes, mosquito, and liver stages, consistent with a role in protein export beyond asexual blood stages [PMID:23869529]. Biochemically, in P. falciparum TRX2 is a poor substrate for thioredoxin reductase and lacks direct access to it, but can be reduced by the glutathione system, indicating it participates in cross-talk between the glutathione and thioredoxin antioxidant systems [PMID:28479253]. Beyond its complex membership, redox biochemistry, and knockout phenotype, no further mechanistic detail on TRX2 has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Whether TRX2 is a bona fide PTEX component and whether it is required for parasite viability was unknown; tagging and knockout established it as a genuine, non-essential accessory subunit that optimizes export function.","evidence":"Epitope-tag knock-in with co-localization plus gene knockout in P. berghei assayed by in vivo/in vitro growth and a cerebral malaria model","pmids":["23869529"],"confidence":"High","gaps":["Molecular contribution of TRX2 to translocation (e.g. substrate unfolding or redox handling within PTEX) not defined","Whether the growth defect stems from impaired export or a separate function is unresolved","Structural basis of TRX2 incorporation into PTEX not determined"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2013,"claim":"Whether TRX2 acts only in asexual blood stages was unknown; life-cycle expression profiling showed it is present in early gametocytes, mosquito, and liver stages, implying export function across the life cycle.","evidence":"Expression analysis across life-cycle stages using tagged lines","pmids":["23869529"],"confidence":"Medium","gaps":["No direct functional consequence demonstrated for gametocyte, mosquito, or liver stages","Expression detected in a single lab via tagged lines only"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"The redox partner that maintains TRX2 in its active state was unclear; in vitro reduction assays showed TRX2 is a poor thioredoxin reductase substrate but is reduced by the glutathione system, revealing antioxidant cross-talk.","evidence":"In vitro biochemical reduction assay measuring cross-system reduction of thioredoxins in P. falciparum","pmids":["28479253"],"confidence":"Medium","gaps":["Single lab, single in vitro method; physiological relevance of glutathione-mediated reduction in vivo not tested","Link between TRX2 redox state and its role within PTEX not established","Native redox partner in the intact parasite not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How TRX2's redox activity mechanistically contributes to PTEX-mediated protein export and whether it acts on specific exported substrates remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No substrate or redox target within the export pathway identified","No structural model of TRX2 within PTEX","Functional role in non-asexual stages not experimentally tested"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PTEX (Plasmodium translocon of exported proteins)"],"partners":[],"other_free_text":["Non-essential accessory subunit of PTEX; knockout in P. berghei reduces blood-stage growth and severe-disease capacity but is viable [#0]","Expressed in asexual blood stages, early gametocytes, mosquito stages, and liver stages [#1]","Poor substrate for thioredoxin reductase; reduced by the glutathione (glutaredoxin/glutathione reductase) system, indicating antioxidant cross-talk in P. falciparum [#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":932,"usd":0.012998,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5597,"output_tokens":1947,"usd":0.03833,"stage2_stop_reason":"end_turn"},"total_usd":0.051328,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard","patch_2026_09_11":["species attribution corrected after review"]},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TRX2 (PF3D7_1124200) is a genuine member of the PTEX (Plasmodium translocon of exported proteins) complex, validated by genetic tagging and co-localization experiments. Deletion of TRX2 in P. berghei produced viable parasites with reduced blood-stage growth rates (in vivo and in vitro) and reduced capacity to cause severe disease in a cerebral malaria model, indicating TRX2 is not essential but optimizes PTEX activity.\",\n      \"method\": \"Genetic tagging (epitope tag knock-in), gene knockout in P. berghei, in vivo and in vitro growth assays, cerebral malaria model\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal validation of complex membership by genetic tagging, clean knockout with defined cellular and in vivo phenotypes, replicated across two growth conditions\",\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\": \"TRX2 (PF3D7_1124200) is expressed not only in asexual blood stages but also in early gametocytes, mosquito stages, and liver stages, consistent with a role for protein export beyond asexual stages.\",\n      \"method\": \"Expression analysis across life-cycle stages (genetic tagging)\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, life-cycle expression detected via tagged lines, no direct functional consequence demonstrated for each stage\",\n      \"pmids\": [\"23869529\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRX2 (PF3D7_1124200) is a poor substrate for thioredoxin reductase and lacks direct access to thioredoxin reductase; however, the glutathione system (glutaredoxin/glutathione reductase) can reduce TRX2, demonstrating functional cross-talk between the glutathione and thioredoxin antioxidant systems in P. falciparum.\",\n      \"method\": \"In vitro biochemical reduction assay measuring cross-system 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 biochemical assay directly measuring substrate reduction, but single lab and single method\",\n      \"pmids\": [\"28479253\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1124200 (TRX2) is a thioredoxin-like protein that is a genuine, non-essential component of the PTEX export translocon in Plasmodium, where its loss reduces but does not abolish blood-stage growth and virulence; biochemically, TRX2 is a poor substrate for thioredoxin reductase but can be reduced by the glutathione system, suggesting it participates in antioxidant cross-talk within the parasite.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PF3D7_1124200 (TRX2) is a thioredoxin-like protein that functions as a genuine, non-essential accessory component of the PTEX (Plasmodium translocon of exported proteins) complex, the machinery that exports parasite proteins across the parasitophorous vacuole membrane [#0]. Genetic tagging and co-localization confirmed its membership in PTEX, and knockout in P. berghei yielded viable parasites with reduced blood-stage growth in vivo and in vitro and diminished capacity to cause severe disease in a cerebral malaria model, establishing that TRX2 optimizes rather than being required for PTEX activity [#0]. It is expressed across multiple life-cycle stages including early gametocytes, mosquito, and liver stages, consistent with a role in protein export beyond asexual blood stages [#1]. Biochemically, in P. falciparum TRX2 is a poor substrate for thioredoxin reductase and lacks direct access to it, but can be reduced by the glutathione system, indicating it participates in cross-talk between the glutathione and thioredoxin antioxidant systems [#2]. Beyond its complex membership, redox biochemistry, and knockout phenotype, no further mechanistic detail on TRX2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether TRX2 is a bona fide PTEX component and whether it is required for parasite viability was unknown; tagging and knockout established it as a genuine, non-essential accessory subunit that optimizes export function.\",\n      \"evidence\": \"Epitope-tag knock-in with co-localization plus gene knockout in P. berghei assayed by in vivo/in vitro growth and a cerebral malaria model\",\n      \"pmids\": [\"23869529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular contribution of TRX2 to translocation (e.g. substrate unfolding or redox handling within PTEX) not defined\",\n        \"Whether the growth defect stems from impaired export or a separate function is unresolved\",\n        \"Structural basis of TRX2 incorporation into PTEX not determined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether TRX2 acts only in asexual blood stages was unknown; life-cycle expression profiling showed it is present in early gametocytes, mosquito, and liver stages, implying export function across the life cycle.\",\n      \"evidence\": \"Expression analysis across life-cycle stages using tagged lines\",\n      \"pmids\": [\"23869529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct functional consequence demonstrated for gametocyte, mosquito, or liver stages\",\n        \"Expression detected in a single lab via tagged lines only\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The redox partner that maintains TRX2 in its active state was unclear; in vitro reduction assays showed TRX2 is a poor thioredoxin reductase substrate but is reduced by the glutathione system, revealing antioxidant cross-talk.\",\n      \"evidence\": \"In vitro biochemical reduction assay measuring cross-system reduction of thioredoxins in P. falciparum\",\n      \"pmids\": [\"28479253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single in vitro method; physiological relevance of glutathione-mediated reduction in vivo not tested\",\n        \"Link between TRX2 redox state and its role within PTEX not established\",\n        \"Native redox partner in the intact parasite not identified\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRX2's redox activity mechanistically contributes to PTEX-mediated protein export and whether it acts on specific exported substrates remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No substrate or redox target within the export pathway identified\",\n        \"No structural model of TRX2 within PTEX\",\n        \"Functional role in non-asexual stages not experimentally tested\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0015035\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020002\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0065002\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"PTEX (Plasmodium translocon of exported proteins)\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Non-essential accessory subunit of PTEX; knockout in P. berghei reduces blood-stage growth and severe-disease capacity but is viable [#0]\",\n      \"Expressed in asexual blood stages, early gametocytes, mosquito stages, and liver stages [#1]\",\n      \"Poor substrate for thioredoxin reductase; reduced by the glutathione (glutaredoxin/glutathione reductase) system, indicating antioxidant cross-talk in P. falciparum [#2]\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1124200","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0924100","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0922000","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}