{"gene":"PF3D7_1438900","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2001,"finding":"Trx-Px1 (PfTPx1) is a 2-Cys peroxiredoxin that catalyzes thioredoxin-dependent reduction of H2O2, t-butylhydroperoxide, and cumene hydroperoxide; it is reduced by P. falciparum thioredoxin (PfTrx) with kcat values of 67, 56, and 41 min−1 for the three substrates respectively; in oxidizing conditions it converts to a faster-migrating species with altered kinetic properties, suggesting in vivo regulation.","method":"In vitro enzymatic assay (glutamine synthetase protector assay, kinetic measurements with purified recombinant protein), SDS-PAGE under oxidizing conditions","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified components, kinetic parameters measured, multiple substrates tested, replicated across multiple labs","pmids":["11231293"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2001,"finding":"Trx-Px1 (PfPrx-1) forms disulfide-linked dimers under non-reducing conditions and dissociates into monomers in the presence of DTT; it acts as a terminal peroxidase of the parasite thioredoxin system, accepting electrons from E. coli Trx/thioredoxin reductase to reduce H2O2.","method":"Recombinant protein expression in E. coli, non-reducing SDS-PAGE, enzymatic assay with E. coli Trx system","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified components, multiple orthogonal methods (SDS-PAGE + enzymatic assay), single lab","pmids":["11463468"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"Trx-Px1 (PfTrx-Px1) exhibits ping-pong kinetics with Km values of 0.78 µM for H2O2 and 18.94 µM for thioredoxin; it forms decamers (pentamers of homodimers) with a doughnut-like shape by gel filtration, cross-linking, and electron microscopy, with no detectable dimeric forms after gel filtration.","method":"Stopped-flow rapid kinetics, gel filtration, chemical cross-linking, electron microscopy","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Strong — stopped-flow kinetics, multiple orthogonal structural methods (gel filtration + cross-linking + EM), rigorous mechanistic characterization","pmids":["12946843"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"Genetic disruption of Trx-Px1 (PfTPx-1) in P. falciparum renders parasites hypersensitive to paraquat (superoxide donor) and sodium nitroprusside (nitric oxide donor), establishing that Trx-Px1 protects the parasite from oxidative and nitrosative stress.","method":"Gene targeting (knockout) in P. falciparum, chemical stress assays with paraquat and sodium nitroprusside","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with specific phenotypic readout, replicated in subsequent studies","pmids":["12860402"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"Trx-Px1 (TPx1) reduces peroxynitrite (ONOO−) with a rate constant of ~1×10^6 M−1 s−1 (pH 7.4, 37°C); plasmoredoxin (a parasite-specific 22-kDa protein) was identified as a novel reducing substrate of TPx1 in addition to thioredoxin; the catalytic cycle proceeds via oxidation of peroxidatic Cys50 followed by intermolecular disulfide bond formation between Cys50 and Cys170′ of the partner subunit, which is then resolved by thioredoxin or plasmoredoxin; mutation C170A abolishes covalent dimer formation and reduces kcat/Km ~50-fold, while C74A mutation does not affect dimerization or activity.","method":"Stopped-flow measurements, site-directed mutagenesis (C74A, C170A), in vitro enzymatic assay, non-reducing SDS-PAGE","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — stopped-flow kinetics, active-site mutagenesis with defined mechanistic outcome, identification of new substrate (plasmoredoxin), single lab with multiple orthogonal methods","pmids":["16307478"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"Trx-Px1 (PfTPx-1) is expressed constitutively in the parasite cytoplasm throughout the erythrocytic stage (ring, trophozoite, schizont), consistent with a housekeeping role in controlling intracellular ROS.","method":"Real-time quantitative RT-PCR, Western blotting, confocal laser scanning microscopy","journal":"Parasitology international","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — multiple expression methods (RT-PCR, Western blot, confocal microscopy) in a single study, but localization without direct functional consequence shown","pmids":["15710548"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Disruption of TPx-1 in P. berghei does not impair asexual blood-stage growth but reduces gametocyte production by up to 60% and delays peak gametocytemia, establishing a role for TPx-1 in gametocyte development; male/female ratio and male exflagellation are unaffected.","method":"Gene disruption (knockout) in P. berghei, gametocyte counts, exflagellation assay","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with specific sexual-stage phenotypic readout, multiple assays in a single study","pmids":["16597467"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"finding":"Disruption of TPx-1 in P. berghei does not affect midgut oocyst numbers but reduces sporozoite formation in oocysts to 10–20% and salivary gland sporozoite accumulation to 3–10% of wild-type; TPx-1-KO sporozoites show increased DNA strand breaks in oocysts, and have reduced infectivity in mice, though liver invasion and EEF initiation are unaffected.","method":"Gene disruption (knockout) in P. berghei, mosquito infection experiment, sporozoite counts, comet/DNA strand-break assay, mouse infection","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with quantitative sporozoite phenotype, DNA damage assay, infectivity testing; multiple orthogonal readouts","pmids":["18417228"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"finding":"Transcriptional activity of the pftpx-1 gene correlates with increased histone acetylation in its 5′ region, and reporter assays reveal putative enhancer elements in the 5′ region; chromatin immunoprecipitation showed that PfGCN5 histone acetyltransferase recruitment to these regulatory regions correlates with transcriptional activity.","method":"Reporter assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), DNase I footprinting","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, EMSA, footprinting, and reporter assay in single lab; multiple orthogonal methods but no functional validation of specific residues","pmids":["18692528"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Trx-Px1 localizes to the parasite cytosol in P. falciparum erythrocytic stages; a second plasmodial peroxiredoxin (TPx2) is targeted to the apicoplast, and differential targeting of glutathione reductase and thioredoxin reductase is achieved by alternative translation initiation.","method":"Systematic subcellular localization study using fluorescent protein fusions and confocal microscopy, fractionation","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fluorescent tagging and confocal microscopy in living parasites; single lab but systematic approach","pmids":["21203490"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"Trx-Px1 (thioredoxin peroxidase 1) is a target of protein S-glutathionylation in P. falciparum, identified by affinity purification of biotinylated glutathionylated proteins followed by proteomics; its ability to form mixed disulfides with glutathione was confirmed by biochemical analysis.","method":"Affinity purification (biotin-maleimide tagging after enzymatic deglutathionylation), mass spectrometry proteomics, biochemical mixed-disulfide analysis","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification combined with MS identification and biochemical confirmation, single lab","pmids":["21595565"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Disruption of PfTPx-1 in P. falciparum renders parasites hypersensitive to heat stress (fever-range temperatures), demonstrating a hyperthermal protective function distinct from other cytoplasmic peroxiredoxins; Pf1-Cys-Prx knockout lines did not show heat stress hypersensitivity, indicating the two cytosolic peroxiredoxins have independent functions.","method":"Gene disruption (knockout) of PfTPx-1 and Pf1-Cys-Prx in P. falciparum, heat stress assay, comparison of phenotypes","journal":"Parasitology international","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with specific heat-stress phenotypic readout, comparative analysis with parallel knockout of related gene to distinguish function","pmids":["23201565"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"In P. berghei TPx-1 knockout ookinetes, 1-Cys Prx expression occurs significantly earlier and is detectable under culture conditions (where it is normally absent), indicating that 1-Cys Prx partially compensates for loss of TPx-1 in the ookinete stage; tpx-1 transcript is upregulated in a dose-dependent manner when cultured ookinetes are challenged with exogenous ROS.","method":"Transcriptional profiling (RT-PCR), confocal immunofluorescence imaging, TPx-1 KO parasite analysis, ROS challenge assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with compensatory expression analysis, multiple orthogonal methods (RT-PCR, IFA), single lab","pmids":["23382676"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2014,"finding":"Disruption of TPx-1 in P. berghei results in significantly smaller liver schizonts and fewer merozoites produced per mature schizont compared to wild-type, establishing a role for TPx-1 in merozoite formation during liver schizont development.","method":"Gene disruption (knockout) in P. berghei, indirect immunofluorescence microscopy with anti-CSP and anti-MSP-1 antibodies, in vitro liver infection system","journal":"Parasitology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with specific liver-stage phenotypic readout using multiple antibody markers, single lab","pmids":["25284813"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2014,"finding":"P. knowlesi TPx-1 (PkTPx-1) binds double-stranded DNA and RNA and has RNA chaperone activity demonstrated in a nucleic acid melting assay, indicating a function beyond antioxidant activity; it is expressed in the cytoplasm of the parasite.","method":"Recombinant protein expression, mixed-function oxidation assay, nucleic acid binding assay, RNA chaperone (nucleic acid melting) assay, indirect immunofluorescence microscopy","journal":"Parasitology research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — in vitro assays with recombinant protein demonstrating novel nucleic acid binding and chaperone activity, single lab; ortholog in P. knowlesi not P. falciparum","pmids":["25092384"],"is_preprint":false,"attribution":[{"species":"Plasmodium knowlesi","strain":""}]},{"year":2022,"finding":"Trx-Px1 (PfTPx-1) localizes to a nuclear subcompartment associated with active transcription on the nuclear periphery in ring-stage P. falciparum; it associates with the var antisense lncRNA interactome; it co-localizes with S-adenosylmethionine synthetase (PfSAMS) in the nucleus; overexpression of Trx-Px1 activates var2csa expression (similar to PfSAMS overexpression); and Trx-Px1 knockdown alters the var gene switch rate and affects activation of additional gene subsets, indicating a role as a redox-controlled nuclear factor in var gene transcription regulation.","method":"RNA immunoprecipitation (var lncRNA interactome), confocal co-localization microscopy, overexpression and knockdown experiments with var gene expression assays (RT-PCR/reporter), nuclear fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation identifying nuclear association, co-localization, gain- and loss-of-function experiments with var gene readout, single lab with multiple orthogonal methods","pmids":["35939693"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"Trx-Px1 (PF3D7_1438900) is a cytosolic 2-Cys peroxiredoxin in P. falciparum that catalyzes thioredoxin- and plasmoredoxin-dependent reduction of H2O2, organic hydroperoxides, and peroxynitrite via a ping-pong mechanism involving oxidation of peroxidatic Cys50 and intermolecular disulfide formation with Cys170′ of the partner subunit; it assembles into decameric (doughnut-shaped) oligomers, is subject to S-glutathionylation as a redox-regulatory modification, and its transcription is regulated by histone acetylation and 5′ cis-elements; beyond its antioxidant role, Trx-Px1 localizes to a nuclear peripheral subcompartment in ring-stage parasites, associates with the var antisense lncRNA, and modulates var gene switching and activation, functioning as a redox sensor that links cellular redox state to epigenetic transcriptional control of virulence genes; knockout studies across multiple Plasmodium species establish essential roles in protecting against oxidative/nitrosative and heat stress, gametocyte development, sporozoite formation in the mosquito, and liver-stage merozoite production."},"narrative":{"mechanistic_narrative":"Trx-Px1 (PF3D7_1438900) is a cytosolic 2-Cys peroxiredoxin that serves as a terminal peroxidase of the Plasmodium thioredoxin antioxidant system, catalyzing the reduction of hydrogen peroxide, organic hydroperoxides, and peroxynitrite [PMID:11231293, PMID:16307478]. It operates by a ping-pong mechanism in which the peroxidatic Cys50 is oxidized and forms an intermolecular disulfide with Cys170′ of the partner subunit, a covalent dimer that is resolved by electron donors: mutation of C170 abolishes dimer formation and reduces catalytic efficiency ~50-fold, whereas C74 is dispensable [PMID:16307478]. Reducing equivalents are supplied by P. falciparum thioredoxin and by the parasite-specific protein plasmoredoxin [PMID:11231293, PMID:16307478]. The enzyme assembles into decameric, doughnut-shaped oligomers of five homodimers [PMID:12946843], and is expressed constitutively in the cytosol across the erythrocytic stages [PMID:15710548, PMID:21203490]. Its activity is subject to redox-regulatory S-glutathionylation [PMID:21595565], and its transcription is controlled by histone acetylation and PfGCN5 recruitment at 5′ cis-regulatory elements [PMID:18692528]. Genetic disruption establishes a protective role against oxidative and nitrosative stress in P. falciparum [PMID:12860402] and against fever-range heat stress, a function not shared by the other cytosolic peroxiredoxin [PMID:23201565]. Across the life cycle in P. berghei, TPx-1 is dispensable for asexual blood-stage growth but required for efficient gametocyte production [PMID:16597467], sporozoite formation and genome integrity in mosquito oocysts [PMID:18417228], and merozoite production during liver schizogony [PMID:25284813]. Beyond antioxidant catalysis, Trx-Px1 localizes to a nuclear peripheral subcompartment in ring-stage parasites, associates with the var antisense lncRNA interactome and PfSAMS, and modulates var gene activation and switching, implicating it as a redox-sensing nuclear factor linking cellular redox state to epigenetic control of virulence-gene transcription [PMID:35939693].","teleology":[{"year":2001,"claim":"Establishing that PF3D7_1438900 is an enzymatically active 2-Cys peroxiredoxin defined its core biochemical identity as a thioredoxin-dependent peroxidase.","evidence":"In vitro kinetic assays with purified recombinant protein and P. falciparum thioredoxin, plus non-reducing SDS-PAGE showing disulfide-linked dimers","pmids":["11231293","11463468"],"confidence":"High","gaps":["Physiological electron donors in vivo not yet defined beyond thioredoxin","Oligomeric state not resolved at this stage"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Defining the catalytic kinetics and quaternary structure showed how the enzyme is organized, resolving that it functions as a decameric assembly rather than a simple dimer.","evidence":"Stopped-flow rapid kinetics giving ping-pong parameters, plus gel filtration, cross-linking, and electron microscopy showing doughnut-shaped decamers","pmids":["12946843"],"confidence":"High","gaps":["Functional significance of decamerization for catalysis or regulation not established","No high-resolution atomic structure"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Genetic knockout in P. falciparum answered whether the enzyme's antioxidant activity is physiologically protective, linking it to defense against oxidative and nitrosative stress.","evidence":"Gene targeting in P. falciparum with paraquat and sodium nitroprusside stress assays","pmids":["12860402"],"confidence":"High","gaps":["Whether protection is direct catalysis or indirect not distinguished","No effect on normal growth quantified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Active-site mutagenesis and substrate profiling defined the catalytic cycle at residue resolution and identified plasmoredoxin as a second reducing substrate, extending the enzyme's redox network.","evidence":"Stopped-flow measurements of peroxynitrite reduction plus site-directed mutagenesis (C50/C170/C74) and non-reducing SDS-PAGE","pmids":["16307478"],"confidence":"High","gaps":["Relative in vivo contributions of thioredoxin versus plasmoredoxin not quantified","Physiological relevance of peroxynitrite reduction in the parasite unmeasured"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Expression profiling established the enzyme as a constitutively expressed cytosolic housekeeping antioxidant across the erythrocytic cycle.","evidence":"Quantitative RT-PCR, Western blotting, and confocal microscopy across ring, trophozoite, and schizont stages","pmids":["15710548"],"confidence":"Medium","gaps":["Localization shown without direct functional consequence","Stage-specific quantitative levels not tied to activity"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"claim":"Chromatin and reporter analysis addressed how the gene is transcriptionally regulated, linking its expression to histone acetylation and PfGCN5 recruitment at defined 5′ elements.","evidence":"Reporter assays, ChIP, EMSA, and DNase I footprinting on the pftpx-1 5′ region","pmids":["18692528"],"confidence":"Medium","gaps":["Specific cis-element residues not functionally validated","Trans-acting factors binding the elements not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Knockout in P. berghei tested requirement beyond the asexual stage, revealing a role in sexual-stage gametocyte development.","evidence":"Gene disruption in P. berghei with gametocyte counts and exflagellation assays","pmids":["16597467"],"confidence":"High","gaps":["Mechanism linking peroxidase activity to gametocytogenesis unknown","Blood-stage growth unaffected, so context-dependence unexplained"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2008,"claim":"Mosquito-stage knockout analysis extended the enzyme's role to sporozoite formation and revealed a link between its loss and genome integrity.","evidence":"P. berghei knockout with mosquito infection, sporozoite counts, DNA strand-break (comet) assay, and mouse infectivity","pmids":["18417228"],"confidence":"High","gaps":["Source of DNA damage in KO oocysts not mechanistically defined","Liver invasion unaffected, limiting phenotype to sporozoite production"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2010,"claim":"Systematic localization confirmed the cytosolic targeting of PF3D7_1438900 and distinguished it from an apicoplast-targeted sibling peroxiredoxin.","evidence":"Fluorescent-fusion confocal microscopy and fractionation across the plasmodial redox network","pmids":["21203490"],"confidence":"Medium","gaps":["Nuclear localization not detected in this study","Fusion tagging may not capture minor subcompartment pools"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"claim":"Proteomic and biochemical identification of S-glutathionylation revealed a redox-regulatory post-translational modification on the enzyme.","evidence":"Affinity purification of glutathionylated proteins with MS and biochemical mixed-disulfide analysis","pmids":["21595565"],"confidence":"Medium","gaps":["Functional effect of glutathionylation on activity not quantified","Modified residue not definitively mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Comparative knockout demonstrated a heat-stress protective role unique to PF3D7_1438900 among cytosolic peroxiredoxins, showing functional non-redundancy.","evidence":"Parallel knockout of PfTPx-1 and Pf1-Cys-Prx with fever-range heat stress assays","pmids":["23201565"],"confidence":"High","gaps":["Molecular basis of heat protection versus oxidative protection not distinguished","Whether heat sensitivity reflects protein or substrate changes unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Analysis of ookinete-stage knockouts revealed compensatory upregulation of 1-Cys Prx and ROS-responsive transcription of the gene, illuminating its integration into stage-specific redox defense.","evidence":"RT-PCR, confocal immunofluorescence, and ROS challenge of cultured P. berghei ookinetes","pmids":["23382676"],"confidence":"Medium","gaps":["Direct interaction with 1-Cys Prx not shown","Signaling pathway driving ROS-responsive transcription undefined"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2014,"claim":"Liver-stage knockout analysis established a requirement for the enzyme in merozoite production during hepatic schizogony.","evidence":"P. berghei knockout with anti-CSP/anti-MSP-1 immunofluorescence in an in vitro liver infection system","pmids":["25284813"],"confidence":"Medium","gaps":["Cause of reduced schizont size not mechanistically defined","Single-lab observation without complementation"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2014,"claim":"In vitro assays with the P. knowlesi ortholog uncovered nucleic-acid binding and RNA chaperone activity, indicating a moonlighting function beyond peroxidase catalysis.","evidence":"Recombinant PkTPx-1 nucleic acid binding and melting (chaperone) assays plus immunofluorescence","pmids":["25092384"],"confidence":"Medium","gaps":["Shown for the P. knowlesi ortholog, not P. falciparum PF3D7_1438900","In vivo relevance of nucleic-acid binding not demonstrated"],"attribution":[{"species":"Plasmodium knowlesi","strain":""}]},{"year":2022,"claim":"Nuclear localization and var lncRNA association experiments recast PF3D7_1438900 as a redox-sensing nuclear regulator of virulence-gene transcription, connecting redox state to epigenetic control.","evidence":"RNA immunoprecipitation of the var antisense lncRNA interactome, confocal co-localization with PfSAMS, and overexpression/knockdown with var expression readouts in P. falciparum","pmids":["35939693"],"confidence":"Medium","gaps":["Whether nuclear function requires peroxidase catalysis or redox state unresolved","Mechanism of recruitment to nuclear periphery unknown","Direct versus indirect effect on var switching not fully distinguished"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How Trx-Px1 physically bridges its cytosolic antioxidant catalysis and its nuclear role in var gene regulation, and whether one function depends on the redox chemistry of the other, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism linking peroxidase catalytic cycle to nuclear transcriptional control","Structural basis of nucleic-acid/lncRNA binding by P. falciparum protein not defined","Whether the same molecular pool performs both roles unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Homodecamer (pentamer of homodimers) [#2]","Disulfide-linked homodimer via Cys50-Cys170' [#1, #4]"],"partners":["P. FALCIPARUM THIOREDOXIN (PFTRX) [#0, #4]","PLASMOREDOXIN [#4]","PFGCN5 HISTONE ACETYLTRANSFERASE (AT 5' REGULATORY REGION) [#8]","S-ADENOSYLMETHIONINE SYNTHETASE (PFSAMS) [#15]","VAR ANTISENSE LNCRNA INTERACTOME [#15]","GLUTATHIONE (MIXED DISULFIDE/S-GLUTATHIONYLATION) [#10]"],"other_free_text":["Peroxidatic Cys50 and resolving Cys170' define the catalytic cysteines; C170A abolishes covalent dimer and reduces kcat/Km ~50-fold, C74A is dispensable [#4].","Substrates include H2O2, t-butyl and cumene hydroperoxide, and peroxynitrite [#0, #4].","Dispensable for asexual blood-stage growth but required for gametocyte development, sporozoite formation, and liver-stage merozoite production in P. berghei [#6, #7, #13].","Functionally non-redundant with 1-Cys peroxiredoxin for heat-stress protection, though 1-Cys Prx partially compensates in KO ookinetes [#11, #12].","Nucleic-acid binding and RNA chaperone activity shown for the P. knowlesi ortholog [#14]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"21203490","id":"PMC_21203490","title":"Compartmentation of redox metabolism in malaria parasites.","date":"2010","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/21203490","citation_count":122,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21595565","id":"PMC_21595565","title":"Protein S-glutathionylation in malaria parasites.","date":"2011","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21595565","citation_count":87,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin peroxidase 1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11231293","id":"PMC_11231293","title":"Thioredoxin peroxidases of the malarial parasite Plasmodium 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research","url":"https://pubmed.ncbi.nlm.nih.gov/22392134","citation_count":20,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TPx1","thioredoxin peroxidase 1","PvTPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18417228","id":"PMC_18417228","title":"Disruption of the Plasmodium berghei 2-Cys peroxiredoxin TPx-1 gene hinders the sporozoite development in the vector mosquito.","date":"2008","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/18417228","citation_count":20,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TPx1","PbTPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23382676","id":"PMC_23382676","title":"Expression of cytosolic peroxiredoxins in Plasmodium berghei ookinetes is regulated by environmental factors in the mosquito bloodmeal.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23382676","citation_count":20,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23201565","id":"PMC_23201565","title":"2-Cys peroxiredoxin of Plasmodium falciparum is involved in resistance to heat stress of the parasite.","date":"2012","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/23201565","citation_count":17,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfTPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35939693","id":"PMC_35939693","title":"A nuclear redox sensor modulates gene activation and var switching in Plasmodium falciparum.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35939693","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfTPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25092384","id":"PMC_25092384","title":"Plasmodium knowlesi thioredoxin peroxidase 1 binds to nucleic acids and has RNA chaperone activity.","date":"2014","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/25092384","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin peroxidase 1","PkTPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18692528","id":"PMC_18692528","title":"5' sequence- and chromatin modification-dependent gene expression in Plasmodium falciparum erythrocytic stage.","date":"2008","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/18692528","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfTPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25284813","id":"PMC_25284813","title":"Effect of thioredoxin peroxidase-1 gene disruption on the liver stages of the rodent malaria parasite Plasmodium berghei.","date":"2014","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/25284813","citation_count":9,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TPx1","thioredoxin peroxidase 1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25913091","id":"PMC_25913091","title":"Development of monoclonal antibodies against Plasmodium falciparum thioredoxin peroxidase 1 and its possible application for malaria diagnosis.","date":"2015","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/25913091","citation_count":9,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin peroxidase 1","PfTPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22429898","id":"PMC_22429898","title":"Crystal structures from the Plasmodium peroxiredoxins: new insights into oligomerization and product binding.","date":"2012","source":"BMC structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/22429898","citation_count":8,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PvTrx-Px1","PyTrx-Px1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23237790","id":"PMC_23237790","title":"Expression profiles of peroxiredoxins in liver stage of the rodent malaria parasite Plasmodium berghei.","date":"2012","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/23237790","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TPx1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13005,"output_tokens":4772,"usd":0.055297,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11226,"output_tokens":5806,"usd":0.10064,"stage2_stop_reason":"end_turn"},"total_usd":0.155937,"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\": 2001,\n      \"finding\": \"Trx-Px1 (PfTPx1) is a 2-Cys peroxiredoxin that catalyzes thioredoxin-dependent reduction of H2O2, t-butylhydroperoxide, and cumene hydroperoxide; it is reduced by P. falciparum thioredoxin (PfTrx) with kcat values of 67, 56, and 41 min−1 for the three substrates respectively; in oxidizing conditions it converts to a faster-migrating species with altered kinetic properties, suggesting in vivo regulation.\",\n      \"method\": \"In vitro enzymatic assay (glutamine synthetase protector assay, kinetic measurements with purified recombinant protein), SDS-PAGE under oxidizing conditions\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified components, kinetic parameters measured, multiple substrates tested, replicated across multiple labs\",\n      \"pmids\": [\"11231293\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Trx-Px1 (PfPrx-1) forms disulfide-linked dimers under non-reducing conditions and dissociates into monomers in the presence of DTT; it acts as a terminal peroxidase of the parasite thioredoxin system, accepting electrons from E. coli Trx/thioredoxin reductase to reduce H2O2.\",\n      \"method\": \"Recombinant protein expression in E. coli, non-reducing SDS-PAGE, enzymatic assay with E. coli Trx system\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified components, multiple orthogonal methods (SDS-PAGE + enzymatic assay), single lab\",\n      \"pmids\": [\"11463468\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Trx-Px1 (PfTrx-Px1) exhibits ping-pong kinetics with Km values of 0.78 µM for H2O2 and 18.94 µM for thioredoxin; it forms decamers (pentamers of homodimers) with a doughnut-like shape by gel filtration, cross-linking, and electron microscopy, with no detectable dimeric forms after gel filtration.\",\n      \"method\": \"Stopped-flow rapid kinetics, gel filtration, chemical cross-linking, electron microscopy\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — stopped-flow kinetics, multiple orthogonal structural methods (gel filtration + cross-linking + EM), rigorous mechanistic characterization\",\n      \"pmids\": [\"12946843\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic disruption of Trx-Px1 (PfTPx-1) in P. falciparum renders parasites hypersensitive to paraquat (superoxide donor) and sodium nitroprusside (nitric oxide donor), establishing that Trx-Px1 protects the parasite from oxidative and nitrosative stress.\",\n      \"method\": \"Gene targeting (knockout) in P. falciparum, chemical stress assays with paraquat and sodium nitroprusside\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with specific phenotypic readout, replicated in subsequent studies\",\n      \"pmids\": [\"12860402\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Trx-Px1 (TPx1) reduces peroxynitrite (ONOO−) with a rate constant of ~1×10^6 M−1 s−1 (pH 7.4, 37°C); plasmoredoxin (a parasite-specific 22-kDa protein) was identified as a novel reducing substrate of TPx1 in addition to thioredoxin; the catalytic cycle proceeds via oxidation of peroxidatic Cys50 followed by intermolecular disulfide bond formation between Cys50 and Cys170′ of the partner subunit, which is then resolved by thioredoxin or plasmoredoxin; mutation C170A abolishes covalent dimer formation and reduces kcat/Km ~50-fold, while C74A mutation does not affect dimerization or activity.\",\n      \"method\": \"Stopped-flow measurements, site-directed mutagenesis (C74A, C170A), in vitro enzymatic assay, non-reducing SDS-PAGE\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — stopped-flow kinetics, active-site mutagenesis with defined mechanistic outcome, identification of new substrate (plasmoredoxin), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16307478\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Trx-Px1 (PfTPx-1) is expressed constitutively in the parasite cytoplasm throughout the erythrocytic stage (ring, trophozoite, schizont), consistent with a housekeeping role in controlling intracellular ROS.\",\n      \"method\": \"Real-time quantitative RT-PCR, Western blotting, confocal laser scanning microscopy\",\n      \"journal\": \"Parasitology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — multiple expression methods (RT-PCR, Western blot, confocal microscopy) in a single study, but localization without direct functional consequence shown\",\n      \"pmids\": [\"15710548\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Disruption of TPx-1 in P. berghei does not impair asexual blood-stage growth but reduces gametocyte production by up to 60% and delays peak gametocytemia, establishing a role for TPx-1 in gametocyte development; male/female ratio and male exflagellation are unaffected.\",\n      \"method\": \"Gene disruption (knockout) in P. berghei, gametocyte counts, exflagellation assay\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with specific sexual-stage phenotypic readout, multiple assays in a single study\",\n      \"pmids\": [\"16597467\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Disruption of TPx-1 in P. berghei does not affect midgut oocyst numbers but reduces sporozoite formation in oocysts to 10–20% and salivary gland sporozoite accumulation to 3–10% of wild-type; TPx-1-KO sporozoites show increased DNA strand breaks in oocysts, and have reduced infectivity in mice, though liver invasion and EEF initiation are unaffected.\",\n      \"method\": \"Gene disruption (knockout) in P. berghei, mosquito infection experiment, sporozoite counts, comet/DNA strand-break assay, mouse infection\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with quantitative sporozoite phenotype, DNA damage assay, infectivity testing; multiple orthogonal readouts\",\n      \"pmids\": [\"18417228\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Transcriptional activity of the pftpx-1 gene correlates with increased histone acetylation in its 5′ region, and reporter assays reveal putative enhancer elements in the 5′ region; chromatin immunoprecipitation showed that PfGCN5 histone acetyltransferase recruitment to these regulatory regions correlates with transcriptional activity.\",\n      \"method\": \"Reporter assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), DNase I footprinting\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, EMSA, footprinting, and reporter assay in single lab; multiple orthogonal methods but no functional validation of specific residues\",\n      \"pmids\": [\"18692528\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Trx-Px1 localizes to the parasite cytosol in P. falciparum erythrocytic stages; a second plasmodial peroxiredoxin (TPx2) is targeted to the apicoplast, and differential targeting of glutathione reductase and thioredoxin reductase is achieved by alternative translation initiation.\",\n      \"method\": \"Systematic subcellular localization study using fluorescent protein fusions and confocal microscopy, fractionation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fluorescent tagging and confocal microscopy in living parasites; single lab but systematic approach\",\n      \"pmids\": [\"21203490\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Trx-Px1 (thioredoxin peroxidase 1) is a target of protein S-glutathionylation in P. falciparum, identified by affinity purification of biotinylated glutathionylated proteins followed by proteomics; its ability to form mixed disulfides with glutathione was confirmed by biochemical analysis.\",\n      \"method\": \"Affinity purification (biotin-maleimide tagging after enzymatic deglutathionylation), mass spectrometry proteomics, biochemical mixed-disulfide analysis\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification combined with MS identification and biochemical confirmation, single lab\",\n      \"pmids\": [\"21595565\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Disruption of PfTPx-1 in P. falciparum renders parasites hypersensitive to heat stress (fever-range temperatures), demonstrating a hyperthermal protective function distinct from other cytoplasmic peroxiredoxins; Pf1-Cys-Prx knockout lines did not show heat stress hypersensitivity, indicating the two cytosolic peroxiredoxins have independent functions.\",\n      \"method\": \"Gene disruption (knockout) of PfTPx-1 and Pf1-Cys-Prx in P. falciparum, heat stress assay, comparison of phenotypes\",\n      \"journal\": \"Parasitology international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with specific heat-stress phenotypic readout, comparative analysis with parallel knockout of related gene to distinguish function\",\n      \"pmids\": [\"23201565\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In P. berghei TPx-1 knockout ookinetes, 1-Cys Prx expression occurs significantly earlier and is detectable under culture conditions (where it is normally absent), indicating that 1-Cys Prx partially compensates for loss of TPx-1 in the ookinete stage; tpx-1 transcript is upregulated in a dose-dependent manner when cultured ookinetes are challenged with exogenous ROS.\",\n      \"method\": \"Transcriptional profiling (RT-PCR), confocal immunofluorescence imaging, TPx-1 KO parasite analysis, ROS challenge assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with compensatory expression analysis, multiple orthogonal methods (RT-PCR, IFA), single lab\",\n      \"pmids\": [\"23382676\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Disruption of TPx-1 in P. berghei results in significantly smaller liver schizonts and fewer merozoites produced per mature schizont compared to wild-type, establishing a role for TPx-1 in merozoite formation during liver schizont development.\",\n      \"method\": \"Gene disruption (knockout) in P. berghei, indirect immunofluorescence microscopy with anti-CSP and anti-MSP-1 antibodies, in vitro liver infection system\",\n      \"journal\": \"Parasitology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with specific liver-stage phenotypic readout using multiple antibody markers, single lab\",\n      \"pmids\": [\"25284813\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"P. knowlesi TPx-1 (PkTPx-1) binds double-stranded DNA and RNA and has RNA chaperone activity demonstrated in a nucleic acid melting assay, indicating a function beyond antioxidant activity; it is expressed in the cytoplasm of the parasite.\",\n      \"method\": \"Recombinant protein expression, mixed-function oxidation assay, nucleic acid binding assay, RNA chaperone (nucleic acid melting) assay, indirect immunofluorescence microscopy\",\n      \"journal\": \"Parasitology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — in vitro assays with recombinant protein demonstrating novel nucleic acid binding and chaperone activity, single lab; ortholog in P. knowlesi not P. falciparum\",\n      \"pmids\": [\"25092384\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Trx-Px1 (PfTPx-1) localizes to a nuclear subcompartment associated with active transcription on the nuclear periphery in ring-stage P. falciparum; it associates with the var antisense lncRNA interactome; it co-localizes with S-adenosylmethionine synthetase (PfSAMS) in the nucleus; overexpression of Trx-Px1 activates var2csa expression (similar to PfSAMS overexpression); and Trx-Px1 knockdown alters the var gene switch rate and affects activation of additional gene subsets, indicating a role as a redox-controlled nuclear factor in var gene transcription regulation.\",\n      \"method\": \"RNA immunoprecipitation (var lncRNA interactome), confocal co-localization microscopy, overexpression and knockdown experiments with var gene expression assays (RT-PCR/reporter), nuclear fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation identifying nuclear association, co-localization, gain- and loss-of-function experiments with var gene readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35939693\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"Trx-Px1 (PF3D7_1438900) is a cytosolic 2-Cys peroxiredoxin in P. falciparum that catalyzes thioredoxin- and plasmoredoxin-dependent reduction of H2O2, organic hydroperoxides, and peroxynitrite via a ping-pong mechanism involving oxidation of peroxidatic Cys50 and intermolecular disulfide formation with Cys170′ of the partner subunit; it assembles into decameric (doughnut-shaped) oligomers, is subject to S-glutathionylation as a redox-regulatory modification, and its transcription is regulated by histone acetylation and 5′ cis-elements; beyond its antioxidant role, Trx-Px1 localizes to a nuclear peripheral subcompartment in ring-stage parasites, associates with the var antisense lncRNA, and modulates var gene switching and activation, functioning as a redox sensor that links cellular redox state to epigenetic transcriptional control of virulence genes; knockout studies across multiple Plasmodium species establish essential roles in protecting against oxidative/nitrosative and heat stress, gametocyte development, sporozoite formation in the mosquito, and liver-stage merozoite production.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Trx-Px1 (PF3D7_1438900) is a cytosolic 2-Cys peroxiredoxin that serves as a terminal peroxidase of the Plasmodium thioredoxin antioxidant system, catalyzing the reduction of hydrogen peroxide, organic hydroperoxides, and peroxynitrite [#0, #4]. It operates by a ping-pong mechanism in which the peroxidatic Cys50 is oxidized and forms an intermolecular disulfide with Cys170′ of the partner subunit, a covalent dimer that is resolved by electron donors: mutation of C170 abolishes dimer formation and reduces catalytic efficiency ~50-fold, whereas C74 is dispensable [#4]. Reducing equivalents are supplied by P. falciparum thioredoxin and by the parasite-specific protein plasmoredoxin [#0, #4]. The enzyme assembles into decameric, doughnut-shaped oligomers of five homodimers [#2], and is expressed constitutively in the cytosol across the erythrocytic stages [#5, #9]. Its activity is subject to redox-regulatory S-glutathionylation [#10], and its transcription is controlled by histone acetylation and PfGCN5 recruitment at 5′ cis-regulatory elements [#8]. Genetic disruption establishes a protective role against oxidative and nitrosative stress in P. falciparum [#3] and against fever-range heat stress, a function not shared by the other cytosolic peroxiredoxin [#11]. Across the life cycle in P. berghei, TPx-1 is dispensable for asexual blood-stage growth but required for efficient gametocyte production [#6], sporozoite formation and genome integrity in mosquito oocysts [#7], and merozoite production during liver schizogony [#13]. Beyond antioxidant catalysis, Trx-Px1 localizes to a nuclear peripheral subcompartment in ring-stage parasites, associates with the var antisense lncRNA interactome and PfSAMS, and modulates var gene activation and switching, implicating it as a redox-sensing nuclear factor linking cellular redox state to epigenetic control of virulence-gene transcription [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that PF3D7_1438900 is an enzymatically active 2-Cys peroxiredoxin defined its core biochemical identity as a thioredoxin-dependent peroxidase.\",\n      \"evidence\": \"In vitro kinetic assays with purified recombinant protein and P. falciparum thioredoxin, plus non-reducing SDS-PAGE showing disulfide-linked dimers\",\n      \"pmids\": [\"11231293\", \"11463468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological electron donors in vivo not yet defined beyond thioredoxin\", \"Oligomeric state not resolved at this stage\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining the catalytic kinetics and quaternary structure showed how the enzyme is organized, resolving that it functions as a decameric assembly rather than a simple dimer.\",\n      \"evidence\": \"Stopped-flow rapid kinetics giving ping-pong parameters, plus gel filtration, cross-linking, and electron microscopy showing doughnut-shaped decamers\",\n      \"pmids\": [\"12946843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of decamerization for catalysis or regulation not established\", \"No high-resolution atomic structure\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic knockout in P. falciparum answered whether the enzyme's antioxidant activity is physiologically protective, linking it to defense against oxidative and nitrosative stress.\",\n      \"evidence\": \"Gene targeting in P. falciparum with paraquat and sodium nitroprusside stress assays\",\n      \"pmids\": [\"12860402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether protection is direct catalysis or indirect not distinguished\", \"No effect on normal growth quantified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Active-site mutagenesis and substrate profiling defined the catalytic cycle at residue resolution and identified plasmoredoxin as a second reducing substrate, extending the enzyme's redox network.\",\n      \"evidence\": \"Stopped-flow measurements of peroxynitrite reduction plus site-directed mutagenesis (C50/C170/C74) and non-reducing SDS-PAGE\",\n      \"pmids\": [\"16307478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contributions of thioredoxin versus plasmoredoxin not quantified\", \"Physiological relevance of peroxynitrite reduction in the parasite unmeasured\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Expression profiling established the enzyme as a constitutively expressed cytosolic housekeeping antioxidant across the erythrocytic cycle.\",\n      \"evidence\": \"Quantitative RT-PCR, Western blotting, and confocal microscopy across ring, trophozoite, and schizont stages\",\n      \"pmids\": [\"15710548\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization shown without direct functional consequence\", \"Stage-specific quantitative levels not tied to activity\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Chromatin and reporter analysis addressed how the gene is transcriptionally regulated, linking its expression to histone acetylation and PfGCN5 recruitment at defined 5′ elements.\",\n      \"evidence\": \"Reporter assays, ChIP, EMSA, and DNase I footprinting on the pftpx-1 5′ region\",\n      \"pmids\": [\"18692528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cis-element residues not functionally validated\", \"Trans-acting factors binding the elements not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Knockout in P. berghei tested requirement beyond the asexual stage, revealing a role in sexual-stage gametocyte development.\",\n      \"evidence\": \"Gene disruption in P. berghei with gametocyte counts and exflagellation assays\",\n      \"pmids\": [\"16597467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking peroxidase activity to gametocytogenesis unknown\", \"Blood-stage growth unaffected, so context-dependence unexplained\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mosquito-stage knockout analysis extended the enzyme's role to sporozoite formation and revealed a link between its loss and genome integrity.\",\n      \"evidence\": \"P. berghei knockout with mosquito infection, sporozoite counts, DNA strand-break (comet) assay, and mouse infectivity\",\n      \"pmids\": [\"18417228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of DNA damage in KO oocysts not mechanistically defined\", \"Liver invasion unaffected, limiting phenotype to sporozoite production\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Systematic localization confirmed the cytosolic targeting of PF3D7_1438900 and distinguished it from an apicoplast-targeted sibling peroxiredoxin.\",\n      \"evidence\": \"Fluorescent-fusion confocal microscopy and fractionation across the plasmodial redox network\",\n      \"pmids\": [\"21203490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear localization not detected in this study\", \"Fusion tagging may not capture minor subcompartment pools\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Proteomic and biochemical identification of S-glutathionylation revealed a redox-regulatory post-translational modification on the enzyme.\",\n      \"evidence\": \"Affinity purification of glutathionylated proteins with MS and biochemical mixed-disulfide analysis\",\n      \"pmids\": [\"21595565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect of glutathionylation on activity not quantified\", \"Modified residue not definitively mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Comparative knockout demonstrated a heat-stress protective role unique to PF3D7_1438900 among cytosolic peroxiredoxins, showing functional non-redundancy.\",\n      \"evidence\": \"Parallel knockout of PfTPx-1 and Pf1-Cys-Prx with fever-range heat stress assays\",\n      \"pmids\": [\"23201565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of heat protection versus oxidative protection not distinguished\", \"Whether heat sensitivity reflects protein or substrate changes unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Analysis of ookinete-stage knockouts revealed compensatory upregulation of 1-Cys Prx and ROS-responsive transcription of the gene, illuminating its integration into stage-specific redox defense.\",\n      \"evidence\": \"RT-PCR, confocal immunofluorescence, and ROS challenge of cultured P. berghei ookinetes\",\n      \"pmids\": [\"23382676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with 1-Cys Prx not shown\", \"Signaling pathway driving ROS-responsive transcription undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Liver-stage knockout analysis established a requirement for the enzyme in merozoite production during hepatic schizogony.\",\n      \"evidence\": \"P. berghei knockout with anti-CSP/anti-MSP-1 immunofluorescence in an in vitro liver infection system\",\n      \"pmids\": [\"25284813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of reduced schizont size not mechanistically defined\", \"Single-lab observation without complementation\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In vitro assays with the P. knowlesi ortholog uncovered nucleic-acid binding and RNA chaperone activity, indicating a moonlighting function beyond peroxidase catalysis.\",\n      \"evidence\": \"Recombinant PkTPx-1 nucleic acid binding and melting (chaperone) assays plus immunofluorescence\",\n      \"pmids\": [\"25092384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shown for the P. knowlesi ortholog, not P. falciparum PF3D7_1438900\", \"In vivo relevance of nucleic-acid binding not demonstrated\"],\n      \"attribution\": [{\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Nuclear localization and var lncRNA association experiments recast PF3D7_1438900 as a redox-sensing nuclear regulator of virulence-gene transcription, connecting redox state to epigenetic control.\",\n      \"evidence\": \"RNA immunoprecipitation of the var antisense lncRNA interactome, confocal co-localization with PfSAMS, and overexpression/knockdown with var expression readouts in P. falciparum\",\n      \"pmids\": [\"35939693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether nuclear function requires peroxidase catalysis or redox state unresolved\", \"Mechanism of recruitment to nuclear periphery unknown\", \"Direct versus indirect effect on var switching not fully distinguished\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Trx-Px1 physically bridges its cytosolic antioxidant catalysis and its nuclear role in var gene regulation, and whether one function depends on the redox chemistry of the other, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism linking peroxidase catalytic cycle to nuclear transcriptional control\", \"Structural basis of nucleic-acid/lncRNA binding by P. falciparum protein not defined\", \"Whether the same molecular pool performs both roles unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008379\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0051920\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0004601\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"GO:0003690\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0003724\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 9, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0034399\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0034614\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0006979\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"GO:0009266\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0045893\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0060968\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"complexes\": [\n      \"Homodecamer (pentamer of homodimers) [#2]\",\n      \"Disulfide-linked homodimer via Cys50-Cys170' [#1, #4]\"\n    ],\n    \"partners\": [\n      \"P. falciparum thioredoxin (PfTrx) [#0, #4]\",\n      \"Plasmoredoxin [#4]\",\n      \"PfGCN5 histone acetyltransferase (at 5' regulatory region) [#8]\",\n      \"S-adenosylmethionine synthetase (PfSAMS) [#15]\",\n      \"var antisense lncRNA interactome [#15]\",\n      \"Glutathione (mixed disulfide/S-glutathionylation) [#10]\"\n    ],\n    \"other_free_text\": [\n      \"Peroxidatic Cys50 and resolving Cys170' define the catalytic cysteines; C170A abolishes covalent dimer and reduces kcat/Km ~50-fold, C74A is dispensable [#4].\",\n      \"Substrates include H2O2, t-butyl and cumene hydroperoxide, and peroxynitrite [#0, #4].\",\n      \"Dispensable for asexual blood-stage growth but required for gametocyte development, sporozoite formation, and liver-stage merozoite production in P. berghei [#6, #7, #13].\",\n      \"Functionally non-redundant with 1-Cys peroxiredoxin for heat-stress protection, though 1-Cys Prx partially compensates in KO ookinetes [#11, #12].\",\n      \"Nucleic-acid binding and RNA chaperone activity shown for the P. knowlesi ortholog [#14].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1438900","name":null,"product":"thioredoxin peroxidase 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1302800","name":null,"product":"thioredoxin peroxidase 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1243400","name":null,"product":"thioredoxin peroxidase 1","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"TPx1","evaluation":null}