Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Tpx1 is predominantly cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription-factor signaling. A minor mitochondrial intermembrane-space pool is also reported under oxidative conditions, but the cytosol is the principal site of function. Reason: Supported by phylogenetic inference and corroborated by falcon deep research and experimental localization data. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
GO:0006979 response to oxidative stress	IBA GO_REF:0000033	ACCEPT	Summary: Response to oxidative stress is a central biological process for Tpx1, which is the major peroxide-detoxifying enzyme during aerobic growth; tpx1 deletion causes extreme peroxide sensitivity. This is a true core function rather than a peripheral context, though the more specific term hydrogen peroxide catabolic process is preferred for the MF/process pairing. Reason: Falcon deep research and primary literature establish oxidative stress defense as a central, not peripheral, role for Tpx1. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is central to peroxide defense during aerobic growth: loss of Tpx1 yields strong peroxide sensitivity and evidence of increased oxidative damage, consistent with a major antioxidant role.
GO:0008379 thioredoxin peroxidase activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function. Tpx1 is a thioredoxin-dependent peroxidase that detoxifies hydrogen peroxide and organic peroxides, recycled primarily by the cytosolic thioredoxin system (Trx1 main donor), consistent with its classification as the single typical 2-Cys peroxiredoxin of S. pombe. Reason: Supported by phylogenetic inference and corroborated by experimental literature and falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 functions as a thioredoxin-dependent peroxidase that detoxifies hydrogen peroxide and can also reduce organic peroxides, consistent with its classification as a typical 2‑Cys peroxiredoxin. file:SCHPO/tpx1/tpx1-deep-research-falcon.md Trx1 is described as the main electron donor for Tpx1, with Trx3 reported as partially compensatory when Trx1 is absent; thioredoxin reductase (Trr1) maintains the thioredoxin pool using NADPH.
GO:0042744 hydrogen peroxide catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process. As the major 2-Cys peroxiredoxin, Tpx1 reduces hydrogen peroxide to water; tpx1 deletion causes extreme peroxide sensitivity and increased oxidative damage markers, directly supporting this catabolic role in vivo. Reason: Supported by phylogenetic inference and corroborated by falcon deep research and primary literature. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Experimentally, tpx1 deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo.
GO:0045454 cell redox homeostasis	IBA GO_REF:0000033	ACCEPT	Summary: Core process. Tpx1 maintains cellular redox balance via the thioredoxin-coupled peroxidatic cycle (Cys48 peroxidatic / Cys169 resolving), the reducing equivalents being supplied by the thioredoxin system (Trx1/Trr1/NADPH). Reason: Supported by phylogenetic inference and corroborated by falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Trx1 is described as the main electron donor for Tpx1, with Trx3 reported as partially compensatory when Trx1 is absent; thioredoxin reductase (Trr1) maintains the thioredoxin pool using NADPH.
GO:0000165 MAPK cascade	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Tpx1 acts as a redox transducer in the Sty1 (p38/SAPK) MAPK pathway, promoting Sty1 activation in response to H2O2. This is a genuine signaling role of the gene, though this generic IEA term is less specific than the experimentally supported positive regulation of p38MAPK cascade (GO:1900745) annotation retained elsewhere. Reason: Genuine but generic; the experimentally supported p38MAPK regulation term is preferred for the core signaling role. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Underwood (2019) describes Tpx1 as a direct redox transducer promoting Sty1 activation, and other mechanistic discussion links Tpx1 to Sty1 regulation and oxidation events, including interactions/disulfide formation with Sty1.
GO:0004601 peroxidase activity	IEA GO_REF:0000043	ACCEPT	Summary: Correct but generic. Peroxidase activity is the parent of the specific thioredoxin-dependent peroxiredoxin activity (GO:0140824) that captures the actual mechanism; retained as a true but less informative grouping term. Reason: Accurate parent term; the more specific thioredoxin-dependent peroxiredoxin activity is the core MF. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 functions as a thioredoxin-dependent peroxidase that detoxifies hydrogen peroxide and can also reduce organic peroxides, consistent with its classification as a typical 2‑Cys peroxiredoxin.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Nuclear localization is reported from large-scale localization analysis (also annotated HDA from PMID:16823372). Plausible given Tpx1 influence on transcription-factor (Pap1) activation, but Tpx1 is predominantly cytosolic and the bulk of its function is executed in the cytosol. Retained as non-core. Reason: Supported by localization screens but secondary to the predominant cytosolic site of function per falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Consistent with the predominant cytosolic localization of Tpx1. Cytosol (GO:0005829) is the more precise term and is also annotated; cytoplasm is the accurate parent. Reason: Supported by experimental localization and falcon deep research; cytosol is the more specific term. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
GO:0016209 antioxidant activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: High-level grouping term that is correct (Tpx1 is a major antioxidant enzyme) but uninformative relative to the specific thioredoxin-dependent peroxiredoxin activity. Retained as non-core. Reason: Correct but generic grouping term superseded by the specific peroxiredoxin MF.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Very high-level grouping term. Correct (Tpx1 is a thiol-based oxidoreductase, EC 1.11.1.24) but far less informative than the specific peroxiredoxin activity term. Retained as non-core. Reason: Accurate but uninformative root-level term superseded by the specific peroxiredoxin MF.
GO:0034599 cellular response to oxidative stress	IEA GO_REF:0000117	ACCEPT	Summary: Consistent with Tpx1 acting as both the major peroxide scavenger and a H2O2 sensor/transducer that routes oxidative-stress information to the Pap1 and Sty1 response pathways. Reason: Supported by falcon deep research and primary literature on Tpx1-mediated oxidative stress signaling. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md A defining feature of S. pombe Tpx1 is that it is not only an antioxidant enzyme but also a central peroxide sensor/transducer that routes H2O2 information to at least two major oxidative stress response branches: Pap1 (AP‑1-like) and the Sty1/Atf1 stress-activated MAPK pathway.
GO:0051920 peroxiredoxin activity	IEA GO_REF:0000002	ACCEPT	Summary: Accurate. Tpx1 is the single typical 2-Cys peroxiredoxin of S. pombe, using a peroxidatic Cys48 and resolving Cys169. The more specific thioredoxin-dependent peroxiredoxin activity (GO:0140824) is preferred as core MF. Reason: Supported by InterPro/family inference and corroborated by falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md catalytic cycle in S. pombe involves a peroxidatic cysteine (Cys48) and resolving cysteine (Cys169), consistent with typical 2‑Cys Prx chemistry.
GO:0140824 thioredoxin-dependent peroxiredoxin activity	IEA GO_REF:0000120	ACCEPT	Summary: Core molecular function. Tpx1 reduces peroxides using the thioredoxin system as electron donor (Trx1 main donor, Trr1/NADPH recycling), matching the EC 1.11.1.24 catalytic activity in UniProt. This is the most specific MF term and is duplicated by an IDA-supported annotation below. Reason: Supported by IEA and corroborated by experimental IDA evidence and falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Trx1 is described as the main electron donor for Tpx1, with Trx3 reported as partially compensatory when Trx1 is absent; thioredoxin reductase (Trr1) maintains the thioredoxin pool using NADPH.
GO:0005078 MAP kinase scaffold activity	EXP PMID:37572670 A peroxiredoxin-P38 MAPK scaffold increases MAPK activity by...	MARK AS OVER ANNOTATED	Summary: The scaffold-activity annotation rests on an artificial, genetically encoded peroxiredoxin-P38 fusion protein that substitutes for the Mcs4 scaffold and MAP3K activity in driving cells into mitosis "by a mechanism that does not require the H2O2-sensing cysteine of the Prdx." This demonstrates what a covalent Prdx-MAPK fusion can do, but assigning native Tpx1 a dedicated MAP kinase scaffold molecular function on this basis is an over-extension: the native redox-transducer role for the Sty1/p38 pathway is more accurately captured by the positive regulation of p38MAPK cascade (GO:1900745) process term retained elsewhere. Reason: Evidence is from an engineered Prdx-P38 fusion construct (cysteine-independent), not native Tpx1; the genuine signaling role is captured by the p38MAPK regulation process term, so a dedicated scaffold MF over-annotates the native protein. Supporting Evidence: PMID:37572670 We demonstrate that a P38-Prdx fusion protein compensates for loss of the yeast scaffold protein Mcs4 and MAP3K activity, driving yeast into mitosis file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 contributes to activation and signaling context for the S. pombe stress-activated MAPK Sty1 and downstream transcription factor Atf1, functioning as a redox transducer/scaffold in peroxide signaling.
GO:0015035 protein-disulfide reductase activity	EXP PMID:37572670 A peroxiredoxin-P38 MAPK scaffold increases MAPK activity by...	KEEP AS NON CORE	Summary: Reflects Tpx1 redox-relay chemistry: as a 2-Cys peroxiredoxin it forms transient mixed disulfides with partner proteins (e.g., Pap1, Pka1, Csn5, thioredoxins), exchanging thiol-disulfide redox equivalents. Captures the relay/disulfide-exchange aspect of Tpx1 function rather than its primary peroxidase activity; retained as non-core. Reason: Captures the disulfide-relay aspect of Tpx1; secondary to the core peroxidase function and reinforced by falcon redox-relay evidence. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Pka1 and Csn5 form protein–protein disulfide complexes with Tpx1 in response to 0.2 mM H2O2, consistent with Tpx1 functioning as a redox relay to regulatory proteins.
GO:1900745 positive regulation of p38MAPK cascade	IMP PMID:37572670 A peroxiredoxin-P38 MAPK scaffold increases MAPK activity by...	KEEP AS NON CORE	Summary: Experimentally supported (IMP). Tpx1 positively regulates the Sty1/p38 MAPK cascade, acting as a direct redox transducer promoting Sty1 activation. This signaling role can be genetically separated from the peroxidase activity (e.g., tpx1C169S retains Sty1 regulation), establishing it as a bona fide second function of the gene. Reason: Bona fide signaling function supported by IMP evidence and falcon deep research; non-core relative to the primary detoxification role. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md role in Sty1 pathway signaling can be genetically separated from its thioredoxin peroxidase activity using alleles such as tpx1C169S, described as disrupting thioredoxin peroxidase activity while leaving Sty1 regulation intact.
GO:0061692 cellular detoxification of hydrogen peroxide	IMP PMID:24521463 A genetic approach to study H2O2 scavenging in fission yeast...	ACCEPT	Summary: Core process, experimentally supported (IMP). Genetic dissection establishes Tpx1 (with catalase) as a principal H2O2-scavenging enzyme; tpx1 deletion causes extreme peroxide sensitivity, directly demonstrating its role in cellular H2O2 detoxification. Reason: Strong IMP evidence corroborated by falcon deep research; a core function of the gene. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Experimentally, tpx1 deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo.
GO:0005737 cytoplasm	IDA PMID:22344694 The transcription factors Pap1 and Prr1 collaborate to activ...	ACCEPT	Summary: Cytoplasmic localization, consistent with Tpx1 acting in the cytosol as the upstream redox transmitter for the cytosolic Pap1 transcription factor. The more specific cytosol term is also annotated. Reason: Direct localization evidence corroborated by falcon deep research; cytosol is the more specific term. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
GO:0051082 unfolded protein binding	IDA PMID:20356456 Distinct functional roles of peroxiredoxin isozymes and glut...	MODIFY	Summary: Recombinant TPx (Tpx1) inhibited thermal aggregation of citrate synthase, demonstrating molecular chaperone (holdase) activity in vitro, a known moonlighting property of typical 2-Cys peroxiredoxins. The activity is better captured by the MF term protein folding chaperone (GO:0044183) than by the binding-only term unfolded protein binding. Both terms are molecular function, so this is a within-aspect refinement. Reason: In-vitro chaperone (anti-aggregation) activity is more precisely a protein folding chaperone MF than a binding term; supported by the original IDA reference. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:20356456 to inhibit the aggregation. The chaperone activities of PMP20 and GPx were
GO:0140824 thioredoxin-dependent peroxiredoxin activity	IDA PMID:20356456 Distinct functional roles of peroxiredoxin isozymes and glut...	ACCEPT	Summary: Core molecular function, directly demonstrated (IDA): recombinant TPx reduces peroxides using the thioredoxin system, matching EC 1.11.1.24. This is the most specific and best-supported MF term for Tpx1. Reason: Direct in-vitro demonstration corroborated by falcon deep research; the primary core MF of the gene. Supporting Evidence: PMID:20356456 TPx (thioredoxin peroxidase) exhibited a capacity for peroxide reduction with the thioredoxin system. file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 functions as a thioredoxin-dependent peroxidase that detoxifies hydrogen peroxide and can also reduce organic peroxides, consistent with its classification as a typical 2‑Cys peroxiredoxin.
GO:0008379 thioredoxin peroxidase activity	IMP PMID:24268782 A peroxiredoxin promotes H2O2 signaling and oxidative stress...	ACCEPT	Summary: Core molecular function supported by mutational/genetic evidence. Tpx1 reduces peroxides via its thioredoxin-coupled cycle; the catalytic mechanism uses peroxidatic Cys48 and resolving Cys169. Notably, Brown et al. show the only essential function of this thioredoxin peroxidase activity in H2O2 resistance is to inhibit the thioredoxin family protein Txl1 by oxidizing it, i.e. the peroxidase activity also drives an oxidative redox relay rather than acting purely as a reductive detoxifier. Reason: Supported by IMP evidence and falcon deep research; a core function of the gene. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md catalytic cycle in S. pombe involves a peroxidatic cysteine (Cys48) and resolving cysteine (Cys169), consistent with typical 2‑Cys Prx chemistry.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:24268782 A peroxiredoxin promotes H2O2 signaling and oxidative stress...	KEEP AS NON CORE	Summary: Reflects the Tpx1->Pap1 redox relay: under mild H2O2, Tpx1 is required for Pap1 oxidation/activation, driving Pap1-dependent antioxidant gene transcription. Mechanistically this relay operates by Tpx1 transferring oxidizing equivalents to partner proteins (Brown et al. show the essential relay in H2O2 resistance is oxidation/inhibition of the thioredoxin family protein Txl1), amplifying the H2O2 signal. This is an indirect, signaling-mediated effect on transcription (Tpx1 is not itself a transcription factor), so it is kept as a non-core consequence of the H2O2-sensor role. Reason: Genuine but indirect/signaling-mediated effect on transcription via Pap1; non-core relative to the primary peroxidase function. Reinforced by falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is reported to be required for Pap1 oxidation/activation under mild peroxide stress, acting as the primary peroxide sensor/transducer for this pathway; Pap1 nuclear accumulation and downstream gene induction depend on Tpx1-mediated redox control.
GO:0042744 hydrogen peroxide catabolic process	IMP PMID:24521463 A genetic approach to study H2O2 scavenging in fission yeast...	ACCEPT	Summary: Core process, IMP-supported. Genetic dissection of H2O2 scavenging shows Tpx1 is a principal peroxide-catabolizing enzyme during aerobic growth alongside catalase. Reason: Strong IMP evidence corroborated by falcon deep research; a core function of the gene. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is central to peroxide defense during aerobic growth: loss of Tpx1 yields strong peroxide sensitivity and evidence of increased oxidative damage, consistent with a major antioxidant role.
GO:0045454 cell redox homeostasis	IMP PMID:24521463 A genetic approach to study H2O2 scavenging in fission yeast...	ACCEPT	Summary: Core process, IMP-supported. By scavenging peroxides through the thioredoxin-coupled cycle, Tpx1 maintains intracellular redox balance during aerobic growth and peroxide stress. Reason: Supported by IMP evidence and falcon deep research; a core function of the gene. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Trx1 is described as the main electron donor for Tpx1, with Trx3 reported as partially compensatory when Trx1 is absent; thioredoxin reductase (Trr1) maintains the thioredoxin pool using NADPH.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:22245228 Inactivation of a peroxiredoxin by hydrogen peroxide is crit...	KEEP AS NON CORE	Summary: Reflects signal gating by Tpx1 hyperoxidation: at high H2O2, Tpx1 is hyperoxidized (Cys-sulfinic acid) and inactivated, which redirects thioredoxin reducing capacity to repair oxidized proteins and reset the transcriptional response. The effect on transcription is indirect and signaling-mediated, so it is kept as non-core. Reason: Indirect, signaling-mediated transcriptional effect via the hyperoxidation switch; non-core relative to the primary peroxidase function. Reinforced by falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md which inactivates thioredoxin-dependent peroxidase activity because thioredoxin cannot directly reduce the sulfinic form. Hyperoxidized typical 2‑Cys Prxs can be repaired by sulfiredoxin (Srx) via an ATP-dependent reaction, restoring catalytic competence and changing signaling capacity over time.
GO:0042744 hydrogen peroxide catabolic process	IMP PMID:22245228 Inactivation of a peroxiredoxin by hydrogen peroxide is crit...	ACCEPT	Summary: Core process. Confirms Tpx1 as a major H2O2-catabolizing enzyme whose peroxidase activity (and its reversible inactivation by hyperoxidation) governs cellular peroxide levels. Reason: Supported by IMP evidence and falcon deep research; a core function of the gene. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Experimentally, tpx1 deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo.
GO:0005737 cytoplasm	IDA PMID:22245228 Inactivation of a peroxiredoxin by hydrogen peroxide is crit...	ACCEPT	Summary: Directly observed cytoplasmic localization, consistent with the predominantly cytosolic site where Tpx1 detoxifies peroxides and controls cytosolic thioredoxin/Pap1 signaling. Reason: Direct localization evidence corroborated by falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
GO:0004601 peroxidase activity	IDA PMID:17409354 The peroxiredoxin Tpx1 is essential as a H2O2 scavenger duri...	ACCEPT	Summary: Directly demonstrated peroxidase activity. Tpx1 is essential as the H2O2 scavenger during aerobic growth. The specific thioredoxin-dependent peroxiredoxin activity term is the preferred core MF; this is the accurate parent. Reason: Direct experimental evidence; accurate parent of the specific peroxiredoxin MF. Corroborated by falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 functions as a thioredoxin-dependent peroxidase that detoxifies hydrogen peroxide and can also reduce organic peroxides, consistent with its classification as a typical 2‑Cys peroxiredoxin.
GO:0005515 protein binding	IPI PMID:17409354 The peroxiredoxin Tpx1 is essential as a H2O2 scavenger duri...	MARK AS OVER ANNOTATED	Summary: Uninformative per curation guidelines. Tpx1 does form functionally meaningful interactions (homodimer, transient mixed disulfides with thioredoxins, Pap1, Pka1, Csn5, and Srx1), but these are captured by more specific MF terms such as thioredoxin-dependent peroxiredoxin activity and protein-disulfide reductase activity. The bare protein binding term adds no information. Reason: Generic protein binding is uninformative; specific MF terms (peroxiredoxin/disulfide-relay activities) capture the actual interactions.
GO:0045454 cell redox homeostasis	IMP PMID:17409354 The peroxiredoxin Tpx1 is essential as a H2O2 scavenger duri...	ACCEPT	Summary: Core process. As the essential H2O2 scavenger during aerobic growth, Tpx1 is central to maintaining cellular redox balance. Reason: Supported by IMP evidence and falcon deep research; a core function of the gene. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is central to peroxide defense during aerobic growth: loss of Tpx1 yields strong peroxide sensitivity and evidence of increased oxidative damage, consistent with a major antioxidant role.
GO:0051920 peroxiredoxin activity	IDA PMID:17409354 The peroxiredoxin Tpx1 is essential as a H2O2 scavenger duri...	ACCEPT	Summary: Directly demonstrated peroxiredoxin activity. The more specific thioredoxin-dependent peroxiredoxin activity (GO:0140824) term is the preferred core MF. Reason: Direct experimental evidence corroborated by falcon deep research; specific peroxiredoxin MF is preferred. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md catalytic cycle in S. pombe involves a peroxidatic cysteine (Cys48) and resolving cysteine (Cys169), consistent with typical 2‑Cys Prx chemistry.
GO:0005634 nucleus	HDA PMID:16823372 ORFeome cloning and global analysis of protein localization ...	KEEP AS NON CORE	Summary: Nuclear signal from a genome-wide GFP localization screen. Plausible given Tpx1 influence on Pap1 activation, but Tpx1 is predominantly cytosolic and executes its core function in the cytosol; retained as non-core. Reason: High-throughput localization signal; secondary to the predominant cytosolic site of function per falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
GO:0005829 cytosol	HDA PMID:16823372 ORFeome cloning and global analysis of protein localization ...	ACCEPT	Summary: Cytosolic localization from a genome-wide GFP localization screen, concordant with the predominant cytosolic site where Tpx1 detoxifies peroxides and controls thioredoxin/Pap1 signaling. This is the principal site of function. Reason: High-throughput localization consistent with the predominant cytosolic site of function per falcon deep research. Supporting Evidence: file:SCHPO/tpx1/tpx1-deep-research-falcon.md Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
GO:0005515 protein binding	IPI PMID:15824112 Oxidation of a eukaryotic 2-Cys peroxiredoxin is a molecular...	MARK AS OVER ANNOTATED	Summary: Uninformative per curation guidelines. This IPI derives from the Tpx1-Srx1 interaction (sulfiredoxin-mediated repair of hyperoxidized Tpx1) and the Tpx1-Pap1 redox switch, but the bare protein binding term conveys none of this. The specific redox-relay/peroxidase MF terms and the regulatory process terms capture the biology. Reason: Generic protein binding is uninformative; the Srx1/Pap1 interactions are better captured by specific MF/process terms.

Core Functions

Thioredoxin-dependent peroxiredoxin activity that detoxifies H2O2 and maintains cellular redox balance during aerobic growth and peroxide stress.

Molecular Function:

thioredoxin-dependent peroxiredoxin activity

Directly Involved In:

hydrogen peroxide catabolic process cell redox homeostasis

Cellular Locations:

cytosol

Supporting Evidence:

PMID:17409354
The peroxiredoxin Tpx1 is essential as a H2O2 scavenger during aerobic growth in fission yeast.
PMID:20356456
TPx (thioredoxin peroxidase) exhibited a capacity for peroxide reduction with the thioredoxin system.

H2O2 sensor and redox relay driven by the same thioredoxin-dependent peroxiredoxin chemistry: the peroxidatic cysteine, once oxidized by H2O2, transfers oxidizing equivalents to partner proteins via transient mixed disulfides, thereby transducing peroxide signals to the Pap1 (AP-1-like) transcription factor and the Sty1/Atf1 (p38/SAPK) MAPK pathway. In H2O2 resistance this relay works by oxidizing (and thus inhibiting) the thioredoxin family protein Txl1, amplifying the H2O2 signal. This signaling role is genetically separable from bulk detoxification (e.g., via the tpx1C169S allele).

Molecular Function:

thioredoxin-dependent peroxiredoxin activity

Directly Involved In:

positive regulation of p38MAPK cascade cellular response to oxidative stress

Cellular Locations:

cytosol

Supporting Evidence:

file:SCHPO/tpx1/tpx1-deep-research-falcon.md
A defining feature of *S. pombe* Tpx1 is that it is not only an antioxidant enzyme but also a **central peroxide sensor/transducer** that routes H2O2 information to at least two major oxidative stress response branches: **Pap1** (AP‑1-like) and the **Sty1/Atf1** stress-activated MAPK pathway.
PMID:24268782
a Prx amplifies an H2O2 signal by driving the oxidation of a thioredoxin-like protein

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:15824112

Oxidation of a eukaryotic 2-Cys peroxiredoxin is a molecular switch controlling the transcriptional response to increasing levels of hydrogen peroxide.

PMID:16823372

ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe.

PMID:17409354

The peroxiredoxin Tpx1 is essential as a H2O2 scavenger during aerobic growth in fission yeast.

PMID:20356456

Distinct functional roles of peroxiredoxin isozymes and glutathione peroxidase from fission yeast, Schizosaccharomyces pombe.

PMID:22245228

Inactivation of a peroxiredoxin by hydrogen peroxide is critical for thioredoxin-mediated repair of oxidized proteins and cell survival.

PMID:22344694

The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2.

PMID:24268782

A peroxiredoxin promotes H2O2 signaling and oxidative stress resistance by oxidizing a thioredoxin family protein.

PMID:24521463

A genetic approach to study H2O2 scavenging in fission yeast--distinct roles of peroxiredoxin and catalase.

PMID:37572670

A peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms.

file:SCHPO/tpx1/tpx1-deep-research-falcon.md

Falcon deep research report on tpx1 (Edison Scientific Literature)

Tpx1 (UniProt O74887) is the single typical 2-Cys peroxiredoxin (thioredoxin peroxidase, EC 1.11.1.24) of S. pombe, reducing hydrogen peroxide and organic peroxides via a peroxidatic Cys48 and resolving Cys169, recycled by the thioredoxin system.

"Tpx1 functions as a **thioredoxin-dependent peroxidase** that detoxifies **hydrogen peroxide** and can also reduce **organic peroxides**, consistent with its classification as a typical 2‑Cys peroxiredoxin. Experimentally, *tpx1* deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo."
Tpx1 is recycled primarily by the cytosolic thioredoxin system, with Trx1 the main electron donor (Trx3 partially compensatory) and Trr1/NADPH maintaining the reduced thioredoxin pool.

"Trx1 is described as the main electron donor for Tpx1, with **Trx3** reported as partially compensatory when Trx1 is absent; thioredoxin reductase (**Trr1**) maintains the thioredoxin pool using NADPH."
Beyond detoxification, Tpx1 is a central H2O2 sensor/redox relay that routes peroxide information to two major stress branches: the Pap1 (AP-1-like) transcription factor and the Sty1/Atf1 stress-activated MAPK pathway.

"A defining feature of *S. pombe* Tpx1 is that it is not only an antioxidant enzyme but also a **central peroxide sensor/transducer** that routes H2O2 information to at least two major oxidative stress response branches: **Pap1** (AP‑1-like) and the **Sty1/Atf1** stress-activated MAPK pathway."
Under mild H2O2 (~0.2 mM), Tpx1 is required for Pap1 oxidation/activation, nuclear accumulation and downstream antioxidant gene induction, acting as the primary peroxide sensor/transducer for the Pap1 pathway.

"Tpx1 is reported to be required for **Pap1 oxidation/activation** under mild peroxide stress, acting as the primary peroxide sensor/transducer for this pathway; Pap1 nuclear accumulation and downstream gene induction depend on Tpx1-mediated redox control."
The Tpx1 signaling (Sty1) role can be genetically uncoupled from its peroxidase activity using separation-of-function alleles such as tpx1C169S, which disrupts thioredoxin peroxidase activity while leaving Sty1 regulation intact.

"role in Sty1 pathway signaling can be genetically separated from its thioredoxin peroxidase activity using alleles such as **tpx1C169S**, described as disrupting thioredoxin peroxidase activity while leaving Sty1 regulation intact."
At high peroxide flux Tpx1 is hyperoxidized to a sulfinic acid, which inactivates its thioredoxin-dependent peroxidase activity; sulfiredoxin (Srx1) repairs the hyperoxidized form in an ATP-dependent reaction, gating signaling over time.

"which **inactivates thioredoxin-dependent peroxidase activity** because thioredoxin cannot directly reduce the sulfinic form. Hyperoxidized typical 2‑Cys Prxs can be repaired by **sulfiredoxin (Srx)** via an **ATP-dependent** reaction, restoring catalytic competence and changing signaling capacity over time."
Tpx1 directly relays peroxide signals to regulatory proteins, forming protein-protein disulfide complexes with partners such as Pka1 and Csn5 in response to 0.2 mM H2O2.

"Pka1 and Csn5 form **protein–protein disulfide complexes with Tpx1** in response to **0.2 mM H2O2**, consistent with Tpx1 functioning as a redox relay to regulatory proteins."
Tpx1 is predominantly cytosolic before and after H2O2 exposure, with a minor mitochondrial intermembrane-space (IMS) pool detected under oxidative conditions.

"Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling."

Deep Research

Falcon

(tpx1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 15 citations 2 artifacts 2026-05-31T18:47:04.863737

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000028 The requested information regarding the Tpx1/Pap1 redox relay (and its mammalian equivalent, the PRDX/SRXN1 system) is primarily il (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Functional Annotation of Schizosaccharomyces pombe tpx1 (UniProt O74887)

Scope and identity verification

This report concerns Schizosaccharomyces pombe (strain 972) tpx1 (synonym tsa1; ORF SPCC576.03c), encoding the species’ major/sole typical 2-Cys peroxiredoxin (thioredoxin peroxidase), also referred to as Tpx1. The retrieved S. pombe literature consistently describes Tpx1 as a typical 2‑Cys peroxiredoxin operating with the thioredoxin system and mediating both peroxide detoxification and peroxide-triggered signaling, aligning with the UniProt-provided identity (O74887) and domain/family assignment (AhpC/Prx1 subfamily). (underwood2019ageneticapproaches pages 1-11, dantas2011theroleof pages 74-77, middleton2018therolesand pages 36-41)

1) Key concepts, definitions, and current understanding

1.1 Typical 2-Cys peroxiredoxins (Prx) / thioredoxin peroxidases (Tpx)

Typical 2‑Cys peroxiredoxins are abundant, conserved thiol peroxidases that reduce H2O2 and other hydroperoxides using a peroxidatic cysteine (CP) that reacts rapidly with peroxides to form a sulfenic acid (CP–SOH). In typical 2‑Cys Prxs, the sulfenic acid is resolved by forming an intermolecular disulfide with a resolving cysteine (CR) on the partner subunit (homodimer). The disulfide is then reduced by thioredoxin (Trx), which is regenerated by thioredoxin reductase (Trr) using NADPH, completing the catalytic cycle. (latimer2017mechanismsofh₂o₂induced pages 29-33, latimer2017mechanismsofh₂o₂induced pages 33-37, middleton2018therolesand pages 36-41)

In S. pombe, Tpx1 is described as the single typical 2‑Cys peroxiredoxin and is explicitly characterized as a thioredoxin-dependent peroxidase, consistent with the above mechanism. (underwood2019ageneticapproaches pages 1-11, dantas2011theroleof pages 74-77, middleton2018therolesand pages 36-41)

1.2 Hyperoxidation and sulfiredoxin repair (signal gating)

At high peroxide flux, CP–SOH can be further oxidized to a sulfinic acid (CP–SO2H) (“hyperoxidation/sulfinylation”), which inactivates thioredoxin-dependent peroxidase activity because thioredoxin cannot directly reduce the sulfinic form. Hyperoxidized typical 2‑Cys Prxs can be repaired by sulfiredoxin (Srx) via an ATP-dependent reaction, restoring catalytic competence and changing signaling capacity over time. (underwood2019ageneticapproaches pages 268-273, latimer2017mechanismsofh₂o₂induced pages 29-33, latimer2017mechanismsofh₂o₂induced pages 33-37)

1.3 Peroxiredoxins as H2O2 sensors and redox relays

Beyond antioxidant detoxification, typical 2‑Cys Prxs can act as H2O2 sensors and redox relays, transferring oxidative equivalents to downstream proteins via transient disulfide exchange or by controlling the redox state/availability of thioredoxins. This property enables peroxiredoxins to shape dose-dependent and time-dependent signaling outcomes. (latimer2017mechanismsofh₂o₂induced pages 33-37, latimer2017mechanismsofh₂o₂induced pages 43-48, jose2024temporalcoordinationof pages 1-2)

2) Molecular function of Tpx1 (enzyme reaction and substrate specificity)

2.1 Primary enzymatic function

Tpx1 functions as a thioredoxin-dependent peroxidase that detoxifies hydrogen peroxide and can also reduce organic peroxides, consistent with its classification as a typical 2‑Cys peroxiredoxin. Experimentally, tpx1 deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo. (dantas2011theroleof pages 74-77, middleton2018therolesand pages 36-41)

Tpx1’s catalytic cycle in S. pombe involves a peroxidatic cysteine (Cys48) and resolving cysteine (Cys169), consistent with typical 2‑Cys Prx chemistry. (dantas2011theroleof pages 74-77, arnedo2012studyofthe pages 130-136)

2.2 Electron donor specificity: thioredoxin system

Multiple lines of evidence support that Tpx1 is primarily recycled by the cytosolic thioredoxin system, with Trx1 as the main electron donor and additional thioredoxins contributing under specific contexts. In mechanistic experiments, Trx1 is described as the main electron donor for Tpx1, with Trx3 reported as partially compensatory when Trx1 is absent; thioredoxin reductase (Trr1) maintains the thioredoxin pool using NADPH. (arnedo2012studyofthe pages 130-136, middleton2018therolesand pages 36-41)

A comparative/evolutionary analysis also supports the mechanistic logic for thioredoxin preference: the presence of paired conserved cysteines (peroxidatic/resolving) is highlighted as characteristic of fungal GPx/TPx enzymes that prefer thioredoxin as the electron donor. (Ahmad et al., 2022; publication date Apr 2022; URL https://doi.org/10.1186/s13568-022-01381-2) (ahmad2022basisforusing pages 1-2)

3) Biological processes and pathways involving Tpx1

3.1 Oxidative stress defense (detoxification and homeostasis)

Tpx1 is central to peroxide defense during aerobic growth: loss of Tpx1 yields strong peroxide sensitivity and evidence of increased oxidative damage, consistent with a major antioxidant role. (dantas2011theroleof pages 74-77)

3.2 H2O2 signaling: Pap1 transcription factor pathway

Pap1 is an AP‑1-like transcription factor central to oxidative stress transcriptional programs in S. pombe. Tpx1 is reported to be required for Pap1 oxidation/activation under mild peroxide stress, acting as the primary peroxide sensor/transducer for this pathway; Pap1 nuclear accumulation and downstream gene induction depend on Tpx1-mediated redox control. (latimer2017mechanismsofh₂o₂induced pages 51-55, arnedo2012studyofthe pages 126-130)

Mechanistically, under mild H2O2 (explicitly reported as 0.2 mM H2O2 in mechanistic studies), loss of Tpx1 abolishes Pap1 oxidation and Pap1-dependent gene induction. (arnedo2012studyofthe pages 130-136)

A key model is that Tpx1 promotes Pap1 activation both by enabling oxidative transfer and by oxidizing/engaging the thioredoxin system such that thioredoxins are less available to reduce oxidized Pap1, thereby permitting Pap1 activation and nuclear accumulation. (latimer2017mechanismsofh₂o₂induced pages 43-48, latimer2017mechanismsofh₂o₂induced pages 51-55)

3.3 H2O2 signaling: Sty1 MAPK / Atf1 pathway

Tpx1 contributes to activation and signaling context for the S. pombe stress-activated MAPK Sty1 and downstream transcription factor Atf1, functioning as a redox transducer/scaffold in peroxide signaling. Underwood (2019) describes Tpx1 as a direct redox transducer promoting Sty1 activation, and other mechanistic discussion links Tpx1 to Sty1 regulation and oxidation events, including interactions/disulfide formation with Sty1. (underwood2019ageneticapproaches pages 1-11, latimer2017mechanismsofh₂o₂induced pages 43-48)

Tpx1’s role in Sty1 pathway signaling can be genetically separated from its thioredoxin peroxidase activity using alleles such as tpx1C169S, described as disrupting thioredoxin peroxidase activity while leaving Sty1 regulation intact. (underwood2019ageneticapproaches pages 1-11)

4) Subcellular localization and cellular context

4.1 Cytosolic localization

Tpx1 is primarily described as cytosolic before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling. (latimer2017mechanismsofh₂o₂induced pages 257-261)

4.2 Mitochondrial/IMS-associated pool

Evidence also supports a mitochondrial-associated pool: a “pool of Tpx1” was detected in the mitochondrial intermembrane space (IMS), and a small mitochondrial fraction is reported after H2O2 treatment. This is proposed to contribute to peroxide resistance and Pap1 activation and may intersect with mitochondrial physiology/protein import (e.g., suggested Tim40–Tpx1 disulfide-dependent associations). (underwood2019ageneticapproaches pages 1-11, latimer2017mechanismsofh₂o₂induced pages 257-261, latimer2017mechanismsofh₂o₂induced pages 265-269)

5) Key experimental evidence, mutants, and interaction partners

5.1 Catalytic cysteine mutants and mechanistic trapping

Tpx1 uses Cys48 (peroxidatic) and Cys169 (resolving). Mechanistic studies employed Tpx1C48S and Tpx1C169S to dissect mixed-disulfide intermediates and signaling competence, consistent with the typical 2‑Cys Prx catalytic model. (arnedo2012studyofthe pages 130-136, latimer2017mechanismsofh₂o₂induced pages 257-261)

5.2 Thioredoxin partners and redox-network wiring

Tpx1’s oxidized dimeric forms are described as prominent substrates for Trx1, effectively tying up thioredoxin reducing capacity during certain signaling states and thereby influencing Pap1 reduction/activation dynamics. (latimer2017mechanismsofh₂o₂induced pages 43-48)

5.3 Expanded redox interaction landscape (proteomics/genetics)

Genetic interaction mapping distinguished signaling-specific phenotypes (tpx1C169S) from deletion phenotypes (tpx1Δ), identifying 31 candidate interacting genes with tpx1C169S and 21 with tpx1Δ, with partial suppressors including pka1 and csn5. (underwood2019ageneticapproaches pages 1-11)

Moreover, direct peroxide-induced redox interactions were supported by the observation that Pka1 and Csn5 form protein–protein disulfide complexes with Tpx1 in response to 0.2 mM H2O2, consistent with Tpx1 functioning as a redox relay to regulatory proteins. (underwood2019ageneticapproaches pages 1-11)

Proteomic pulldown experiments (FlagTpx1C169S at 0.2 mM H2O2) recovered 34 proteins that co-purified specifically with the resolving-cysteine mutant, consistent with trapping mixed disulfide interactions. (latimer2017mechanismsofh₂o₂induced pages 257-261)

6) Recent developments and latest research (prioritizing 2023–2024)

6.1 2024 high-impact evidence for peroxiredoxin-gated TF programs

Jose et al. (Nature Communications; published Apr 2024; URL https://doi.org/10.1038/s41467-024-47837-w) provide recent high-authority evidence that 2‑Cys peroxiredoxins can control which transcription-factor programs are activated, depending on H2O2 dose and time. The paper explicitly references yeast evidence where Tpx1 activates Pap1 via redox relay, and emphasizes hyperoxidation as a mechanism that blocks relays until sulfiredoxin repair restores function, creating a time delay in signaling. (jose2024temporalcoordinationof pages 1-2)

Figure-based schematic and biochemical dose-response evidence in this work visually summarize the coupled cycles of peroxiredoxin oxidation, hyperoxidation, and sulfiredoxin-dependent repair (supporting the “gating” concept). (jose2024temporalcoordinationof media acdbd9d2, jose2024temporalcoordinationof media 3c448691)

6.2 Limitations in 2023–2024 Tpx1-specific retrieval

Within the current tool-retrieved corpus, no additional 2023–2024 primary studies directly focused on S. pombe Tpx1 (beyond the 2024 general H2O2/TF coordination paper referencing yeast mechanisms) were available for extraction in this run. Therefore, the “latest research” component is anchored primarily in Jose et al. (2024) and interpreted in the context of established S. pombe Tpx1/Pap1/Sty1 mechanistic literature. (jose2024temporalcoordinationof pages 1-2, underwood2019ageneticapproaches pages 1-11, arnedo2012studyofthe pages 130-136)

7) Current applications and real-world implementations

Tpx1 is primarily a model-system enzyme used to study thiol-based redox biochemistry and peroxide-triggered signaling, rather than a direct translational target in S. pombe. The S. pombe Tpx1/Pap1 and Tpx1/Sty1 modules serve as experimentally tractable paradigms for: (i) redox relay signaling, (ii) peroxide dose gating by hyperoxidation and sulfiredoxin repair, and (iii) redox control of MAPK and transcription factor outputs. (underwood2019ageneticapproaches pages 1-11, jose2024temporalcoordinationof pages 1-2, latimer2017mechanismsofh₂o₂induced pages 51-55)

8) Relevant statistics and data (selected)

A structured summary of quantitative findings (H2O2 doses, interaction counts, and phenotype statistics) is provided below.

Observation/assay	Condition	Key result	Interpretation	Source
Tpx1 oxidation state and oligomerization	Low H2O2, 0.2 mM	Tpx1 accumulates mainly as a disulfide-linked dimer associated with active peroxidase function	Detoxification-competent catalytic cycle under mild peroxide stress; also compatible with signaling at low dose	da Silva Dantas 2011 (Tpx1 review/thesis context); https://doi.org/10.?? unavailable in retrieved metadata (dantas2011theroleof pages 74-77)
Tpx1 hyperoxidation state	High H2O2, 5 mM	Tpx1 accumulates as a hyperoxidized, inactive monomer; monomer formation appears to follow dimer hyperoxidation	High-dose peroxide switches Tpx1 away from peroxidase activity, altering signaling output	da Silva Dantas 2011; URL unavailable in retrieved metadata (dantas2011theroleof pages 74-77)
FlagTpx1 mutant pulldown / co-purifying proteins	FlagTpx1C169S, 0.2 mM H2O2	34 proteins co-purified with FlagTpx1C169S; these were not seen with C48S or C48S/C169S controls	Resolving-cysteine mutant traps mixed-disulfide interactors, supporting direct redox-signaling contacts	Latimer 2017; URL unavailable in retrieved metadata (latimer2017mechanismsofh₂o₂induced pages 257-261)
Genetic interaction screens	SGA/QFA with tpx1C169S versus tpx1Δ backgrounds	31 candidate interacting genes with tpx1C169S; 21 with tpx1Δ; partial suppressors included pka1 and csn5	Distinguishes signaling-specific versus deletion phenotypes and identifies pathway modifiers of Tpx1 function	Underwood 2019; URL unavailable in retrieved metadata (underwood2019ageneticapproaches pages 1-11)
Direct redox partner trapping	0.2 mM H2O2	Pka1 and Csn5 formed direct protein-protein disulfide complexes with Tpx1	Experimental support that Tpx1 directly relays peroxide-dependent redox signals to signaling/regulatory proteins	Underwood 2019; URL unavailable in retrieved metadata (underwood2019ageneticapproaches pages 1-11)
Srk1 overexpression / cell length phenotype	Δtpx1 versus control; 84 cells measured	Reduced elongation response in Δtpx1; division-length difference significant (T test p = 7.8 × 10^-8; n = 84)	Tpx1 contributes to oxidation-dependent signaling affecting mitotic control, not just detoxification	Latimer 2017; URL unavailable in retrieved metadata (latimer2017mechanismsofh₂o₂induced pages 257-261)
Pap1 pathway requirement	Mild H2O2, 0.2 mM	Loss of Tpx1 abolishes Pap1 oxidation and Pap1-dependent gene induction; Trx1 is the main electron donor for Tpx1, with partial compensation by Trx3	Tpx1 is a peroxide sensor/transducer in addition to being a scavenger; links thioredoxin oxidation to transcriptional signaling	Calvo Arnedo 2012; URL unavailable in retrieved metadata (arnedo2012studyofthe pages 130-136)
Localization / mitochondrial pool	After H2O2 treatment	Tpx1 is mostly cytosolic, but a small mitochondrial/IMS-associated pool is detected after oxidative stress	Supports compartment-specific roles in peroxide handling and redox signaling beyond bulk cytosolic detoxification	Underwood 2019; Latimer 2017; URLs unavailable in retrieved metadata (underwood2019ageneticapproaches pages 1-11, latimer2017mechanismsofh₂o₂induced pages 257-261)

Table: This table compiles the main quantitative and structured findings retrieved for Schizosaccharomyces pombe Tpx1, emphasizing peroxide-dose effects, genetic interaction counts, trapped redox partners, and signaling phenotypes. It is useful for separating Tpx1’s detoxification role from its experimentally supported signaling functions.

9) Expert analysis / synthesis (functional annotation summary)

Tpx1 (UniProt O74887) is best functionally annotated as a typical 2‑Cys peroxiredoxin (EC 1.11.1.24) that reduces hydrogen peroxide and other hydroperoxides using Cys48 (peroxidatic) and Cys169 (resolving), with thioredoxin (primarily Trx1) as the physiological reductant. (arnedo2012studyofthe pages 130-136, dantas2011theroleof pages 74-77, middleton2018therolesand pages 36-41)

A defining feature of S. pombe Tpx1 is that it is not only an antioxidant enzyme but also a central peroxide sensor/transducer that routes H2O2 information to at least two major oxidative stress response branches: Pap1 (AP‑1-like) and the Sty1/Atf1 stress-activated MAPK pathway. Genetic separation-of-function alleles (e.g., tpx1C169S) support that detoxification and certain signaling outputs can be partially uncoupled, consistent with distinct redox-relay vs peroxidase-cycle roles. (underwood2019ageneticapproaches pages 1-11, arnedo2012studyofthe pages 126-130)

Subcellularly, Tpx1 is predominantly cytosolic, but evidence supports a mitochondrial IMS-associated pool emerging/observable under oxidative conditions, suggesting that compartmentalization contributes to its signaling and protective roles. (latimer2017mechanismsofh₂o₂induced pages 257-261, underwood2019ageneticapproaches pages 1-11)

Key sources (URLs and publication dates where available)

Jose E. et al. Temporal coordination of the transcription factor response to H2O2 stress. Nature Communications (Apr 2024). https://doi.org/10.1038/s41467-024-47837-w (jose2024temporalcoordinationof pages 1-2)
Ahmad F. et al. Basis for using thioredoxin as an electron donor by S. pombe Gpx1 and Tpx1. AMB Express (Apr 2022). https://doi.org/10.1186/s13568-022-01381-2 (ahmad2022basisforusing pages 1-2)
Quinn J. et al. Distinct regulatory proteins control the graded transcriptional response to increasing H2O2 levels in fission yeast. Molecular Biology of the Cell (Mar 2002). https://doi.org/10.1091/mbc.01-06-0288 (supports pathway framing; tpx1 induction context) (dantas2011theroleof pages 160-163)

Notes on evidence limitations

Some highly relevant classic S. pombe Tpx1 primary papers (e.g., Veal et al., 2004; Bozonet et al., 2005; Vivancos et al., 2006; Biochem Soc Trans 2014 review) were flagged as “unobtainable” by the tool in this run, so they could not be directly quoted/cited here. As a result, certain well-known mechanistic details may be under-represented compared with a full manual literature review. (tool output context; not citeable)

References

(underwood2019ageneticapproaches pages 1-11): ZE Underwood. A genetic approaches to understand peroxiredoxin-mediated h2o2 signalling mechanisms. Unknown journal, 2019.
(dantas2011theroleof pages 74-77): A da Silva Dantas. The role of redox-sensitive antioxidants in oxidative stress signalling in candida albicans. Unknown journal, 2011.
(middleton2018therolesand pages 36-41): FE Middleton. The roles and regulation of heat shock proteins in yeast. Unknown journal, 2018.
(latimer2017mechanismsofh₂o₂induced pages 29-33): HR Latimer. Mechanisms of h₂o₂-induced signal transduction. Unknown journal, 2017.
(latimer2017mechanismsofh₂o₂induced pages 33-37): HR Latimer. Mechanisms of h₂o₂-induced signal transduction. Unknown journal, 2017.
(underwood2019ageneticapproaches pages 268-273): ZE Underwood. A genetic approaches to understand peroxiredoxin-mediated h2o2 signalling mechanisms. Unknown journal, 2019.
(latimer2017mechanismsofh₂o₂induced pages 43-48): HR Latimer. Mechanisms of h₂o₂-induced signal transduction. Unknown journal, 2017.
(jose2024temporalcoordinationof pages 1-2): Elizabeth Jose, Woody March-Steinman, Bryce A. Wilson, Lisa Shanks, Chance Parkinson, Isabel Alvarado-Cruz, Joann B. Sweasy, and Andrew L. Paek. Temporal coordination of the transcription factor response to h2o2 stress. Nature Communications, Apr 2024. URL: https://doi.org/10.1038/s41467-024-47837-w, doi:10.1038/s41467-024-47837-w. This article has 45 citations and is from a highest quality peer-reviewed journal.
(arnedo2012studyofthe pages 130-136): MI Calvo Arnedo. Study of the role of pap1 as a sensor of h2o2 and as a transcriptional activator of stress responses in schizosaccharimyces pombe. Unknown journal, 2012.
(ahmad2022basisforusing pages 1-2): Fawad Ahmad, Muhammad Faizan Latif, Ying Luo, and Ying Huang. Basis for using thioredoxin as an electron donor by schizosaccharomyces pombe gpx1 and tpx1. AMB Express, Apr 2022. URL: https://doi.org/10.1186/s13568-022-01381-2, doi:10.1186/s13568-022-01381-2. This article has 3 citations and is from a peer-reviewed journal.
(latimer2017mechanismsofh₂o₂induced pages 51-55): HR Latimer. Mechanisms of h₂o₂-induced signal transduction. Unknown journal, 2017.
(arnedo2012studyofthe pages 126-130): MI Calvo Arnedo. Study of the role of pap1 as a sensor of h2o2 and as a transcriptional activator of stress responses in schizosaccharimyces pombe. Unknown journal, 2012.
(latimer2017mechanismsofh₂o₂induced pages 257-261): HR Latimer. Mechanisms of h₂o₂-induced signal transduction. Unknown journal, 2017.
(latimer2017mechanismsofh₂o₂induced pages 265-269): HR Latimer. Mechanisms of h₂o₂-induced signal transduction. Unknown journal, 2017.
(jose2024temporalcoordinationof media acdbd9d2): Elizabeth Jose, Woody March-Steinman, Bryce A. Wilson, Lisa Shanks, Chance Parkinson, Isabel Alvarado-Cruz, Joann B. Sweasy, and Andrew L. Paek. Temporal coordination of the transcription factor response to h2o2 stress. Nature Communications, Apr 2024. URL: https://doi.org/10.1038/s41467-024-47837-w, doi:10.1038/s41467-024-47837-w. This article has 45 citations and is from a highest quality peer-reviewed journal.
(jose2024temporalcoordinationof media 3c448691): Elizabeth Jose, Woody March-Steinman, Bryce A. Wilson, Lisa Shanks, Chance Parkinson, Isabel Alvarado-Cruz, Joann B. Sweasy, and Andrew L. Paek. Temporal coordination of the transcription factor response to h2o2 stress. Nature Communications, Apr 2024. URL: https://doi.org/10.1038/s41467-024-47837-w, doi:10.1038/s41467-024-47837-w. This article has 45 citations and is from a highest quality peer-reviewed journal.
(dantas2011theroleof pages 160-163): A da Silva Dantas. The role of redox-sensitive antioxidants in oxidative stress signalling in candida albicans. Unknown journal, 2011.

Artifacts

Edison artifact artifact-00

Citations

ahmad2022basisforusing pages 1-2
dantas2011theroleof pages 74-77
arnedo2012studyofthe pages 130-136
underwood2019ageneticapproaches pages 1-11
jose2024temporalcoordinationof pages 1-2
dantas2011theroleof pages 160-163
middleton2018therolesand pages 36-41
underwood2019ageneticapproaches pages 268-273
arnedo2012studyofthe pages 126-130
https://doi.org/10.1186/s13568-022-01381-2
https://doi.org/10.1038/s41467-024-47837-w
https://doi.org/10.??
https://doi.org/10.1091/mbc.01-06-0288
https://doi.org/10.1038/s41467-024-47837-w,
https://doi.org/10.1186/s13568-022-01381-2,

📚 Additional Documentation

Bioreason Rl Predictions

(tpx1-bioreason-rl-predictions.md)

BioReason Chat Export

Exported on March 22, 2026 at 12:50 AM

Organism: Schizosaccharomyces pombe

Sequence:

MSLQIGKPAPDFKGTAVVNGAFEEIKLADYKGKWVFLGFYPLDFTFVCPTEIVAFSEAASKFAERNAQVILTSTDSEYSHLAFINTPRKEGGLGGINIPLLADPSHKVSRDYGVLIEDAGVAFRGLFLIDPKGVLRQITINDLPVGRSVDEALRLLDAFQFVEEHGEVCPANWHKGSDTIDTKNPEKYFSKH

Thinking Trace

I begin with the InterPro architecture. The polypeptide is built on a thioredoxin-like scaffold: IPR036249 (Thioredoxin-like superfamily, residues 1–181) encompasses the entire core and is reinforced by IPR013766 (Thioredoxin domain, residues 3–161), which defines the canonical β-sheet flanked by α-helices that houses a reversible cysteine redox center. This thioredoxin fold is specialized here by multiple peroxiredoxin signatures: IPR050217 (Thiol-specific antioxidant peroxiredoxin family, residues 3–191) and IPR024706 (Peroxiredoxin, AhpC-type family, residues 3–183) collectively specify a peroxidatic enzyme that reduces hydroperoxides. IPR000866 (Alkyl hydroperoxide reductase subunit C/Thiol-specific antioxidant domain, residues 5–137) anchors the N-terminal catalytic core that bears the peroxidatic cysteine, while IPR019479 (Peroxiredoxin, C-terminal domain, residues 158–180) supplies the flexible C-terminal tail that tunes oligomerization and catalytic cycling. The ordered layout—an N-terminal thioredoxin fold carrying the peroxidatic motif followed by a regulatory C-terminus—creates a high-efficiency peroxidase module.

This domain architecture dictates molecular function. The thioredoxin-like catalytic center, together with the peroxiredoxin/AhpC-type family assignments, causes peroxiredoxin chemistry: nucleophilic attack of a conserved cysteine on hydrogen and organic hydroperoxides to form a cysteine-sulfenic intermediate that is subsequently resolved via thiol-disulfide exchange. This establishes peroxiredoxin activity (a thiol-dependent peroxidase), matching GO:0004601 as the operative molecular function. The peroxiredoxin C-terminal region stabilizes active-state oligomers and modulates turnover, ensuring robust peroxide detoxification.

From this chemistry, the biological process follows. By reducing hydrogen peroxide and alkyl hydroperoxides, the enzyme enforces cellular redox balance and eliminates reactive oxygen species. This places the protein squarely in hydrogen peroxide catabolic pathways and oxidative stress defense. Thus, it drives hydrogen peroxide breakdown and broader ROS handling, consistent with a role in maintaining the intracellular redox environment.

Cellular location is implied by the soluble thioredoxin-like fold and absence of transmembrane or secretion signals. Peroxiredoxins of this architecture function as soluble dimers/decamers in the cytosol, where they intercept diffusible peroxides and interface with cytosolic thioredoxin systems. Therefore, the most parsimonious localization is the cytoplasm.

Mechanistically, the protein likely cycles between reduced and sulfenylated states, with electrons supplied by thioredoxin/thioredoxin reductase. The thioredoxin-like core forms the catalytic platform; the AhpC-type family identity and peroxiredoxin C-terminus promote reversible oligomerization that tunes peroxidase versus chaperone-like states under stress. I hypothesize that thioredoxin and thioredoxin reductase dock transiently to re-reduce the enzyme, while interactions with cytosolic Hsp70/Hsp90 systems and redox-sensitive client proteins facilitate recovery from oxidative insults. Together, these features define a cytoplasmic thiol-dependent peroxidase that sustains redox homeostasis in fission yeast.

Functional Summary

A soluble antioxidant enzyme in fission yeast that uses a thioredoxin-like catalytic core to reduce hydrogen and organic hydroperoxides, thereby protecting the cell from oxidative damage and stabilizing redox balance. It likely operates as a cytoplasmic dimer/decamer whose C-terminal tail regulates catalytic cycling and oligomerization. By coupling peroxide detoxification to the thioredoxin/thioredoxin-reductase system, it sustains intracellular redox homeostasis during oxidative stress.

UniProt Summary

Thiol-specific antioxidant peroxidase which catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides (By similarity).

InterPro Domains

Thioredoxin-like superfamily (IPR036249, homologous_superfamily) — residues 1-181
Thioredoxin domain (IPR013766, domain) — residues 3-161
Thiol-specific antioxidant peroxiredoxin (IPR050217, family) — residues 3-191
Peroxiredoxin, AhpC-type (IPR024706, family) — residues 3-183
Alkyl hydroperoxide reductase subunit C/ Thiol specific antioxidant (IPR000866, domain) — residues 5-137
Peroxiredoxin, C-terminal (IPR019479, domain) — residues 158-180

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), catalytic activity (GO:0003824), antioxidant activity (GO:0016209), peroxidase activity (GO:0004601), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), unfolded protein binding (GO:0051082), oxidoreductase activity, acting on peroxide as acceptor (GO:0016684), peroxiredoxin activity (GO:0051920), thioredoxin-dependent peroxiredoxin activity (GO:0140824), thioredoxin peroxidase activity (GO:0008379)

Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), positive regulation of biological process (GO:0048518), detoxification (GO:0098754), regulation of biological process (GO:0050789), homeostatic process (GO:0042592), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), negative regulation of biological process (GO:0048519), response to chemical (GO:0042221), regulation of metabolic process (GO:0019222), organic substance metabolic process (GO:0071704), cellular detoxification (GO:1990748), detoxification of inorganic compound (GO:0061687), catabolic process (GO:0009056), negative regulation of metabolic process (GO:0009892), cellular homeostasis (GO:0019725), cellular metabolic process (GO:0044237), positive regulation of cellular process (GO:0048522), regulation of cellular process (GO:0050794), positive regulation of metabolic process (GO:0009893), cellular response to stimulus (GO:0051716), response to stress (GO:0006950), negative regulation of cellular process (GO:0048523), negative regulation of nitrogen compound metabolic process (GO:0051172), positive regulation of macromolecule metabolic process (GO:0010604), cell redox homeostasis (GO:0045454), response to oxidative stress (GO:0006979), reactive oxygen species metabolic process (GO:0072593), cellular catabolic process (GO:0044248), response to toxic substance (GO:0009636), regulation of macromolecule metabolic process (GO:0060255), hydrogen peroxide metabolic process (GO:0042743), response to oxygen-containing compound (GO:1901700), negative regulation of cellular metabolic process (GO:0031324), response to organic substance (GO:0010033), positive regulation of biosynthetic process (GO:0009891), response to inorganic substance (GO:0010035), positive regulation of cellular metabolic process (GO:0031325), cellular oxidant detoxification (GO:0098869), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), negative regulation of macromolecule metabolic process (GO:0010605), regulation of biosynthetic process (GO:0009889), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cellular metabolic process (GO:0031323), negative regulation of biosynthetic process (GO:0009890), regulation of primary metabolic process (GO:0080090), organic substance catabolic process (GO:1901575), positive regulation of nitrogen compound metabolic process (GO:0051173), cellular response to oxidative stress (GO:0034599), regulation of macromolecule biosynthetic process (GO:0010556), hydrogen peroxide catabolic process (GO:0042744), cellular response to chemical stress (GO:0062197), regulation of gene expression (GO:0010468), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), cellular response to toxic substance (GO:0097237), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), negative regulation of macromolecule biosynthetic process (GO:0010558), negative regulation of cellular biosynthetic process (GO:0031327), regulation of RNA metabolic process (GO:0051252), response to hydrogen peroxide (GO:0042542), negative regulation of RNA metabolic process (GO:0051253), cellular response to oxygen-containing compound (GO:1901701), response to reactive oxygen species (GO:0000302), negative regulation of nucleobase-containing compound metabolic process (GO:0045934), positive regulation of cellular biosynthetic process (GO:0031328), regulation of RNA biosynthetic process (GO:2001141), regulation of DNA-templated transcription (GO:0006355), positive regulation of RNA biosynthetic process (GO:1902680), negative regulation of RNA biosynthetic process (GO:1902679), cellular response to reactive oxygen species (GO:0034614), cellular response to hydrogen peroxide (GO:0070301), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of nucleic acid-templated transcription (GO:1903507), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of nucleic acid-templated transcription (GO:1903506), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of transcription by RNA polymerase II (GO:0000122)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), cytosol (GO:0005829), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), cytoplasm (GO:0005737), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), intracellular membrane-bounded organelle (GO:0043231), nucleus (GO:0005634)

Generated by BioReason

Bioreason Rl Review

(tpx1-bioreason-rl-review.md)

BioReason-Pro RL Review: tpx1 (S. pombe)

Source: tpx1-bioreason-rl-predictions.md

Correctness: 5/5
Completeness: 3/5

Functional Summary Review

BioReason's functional summary is accurate:

A soluble antioxidant enzyme in fission yeast that uses a thioredoxin-like catalytic core to reduce hydrogen and organic hydroperoxides, thereby protecting the cell from oxidative damage and stabilizing redox balance. It likely operates as a cytoplasmic dimer/decamer whose C-terminal tail regulates catalytic cycling and oligomerization. By coupling peroxide detoxification to the thioredoxin/thioredoxin-reductase system, it sustains intracellular redox homeostasis during oxidative stress.

This correctly identifies tpx1 as a thioredoxin-dependent peroxiredoxin with peroxidase activity. The curated review confirms:
- Thioredoxin-dependent peroxiredoxin activity (GO:0140824, IDA from PMID:20356456)
- Peroxidase activity (GO:0004601, IDA from PMID:17409354)
- Hydrogen peroxide catabolic process (GO:0042744, IMP)
- Cell redox homeostasis (GO:0045454, IMP)
- Cytosol/cytoplasm localization (IDA from PMID:22344694, HDA from PMID:16823372)

The domain architecture is correctly described -- tpx1 has the full complement of peroxiredoxin domains including the AhpC-type family (IPR024706) and the C-terminal domain (IPR019479).

The mention of oligomerization states (dimer/decamer) is consistent with typical 2-Cys peroxiredoxin biology, and the thioredoxin/thioredoxin-reductase regeneration system is correct.

What BioReason misses:
- The signaling role of tpx1 -- it acts as a MAP kinase scaffold (GO:0005078, EXP from PMID:37572670), which is a notable non-core function
- The role in transcriptional regulation (positive and negative regulation of transcription by RNA polymerase II)
- The protein-disulfide reductase activity (GO:0015035)
- The chaperone activity (GO:0051082/GO:0044183) -- tpx1 also has holdase-type chaperone function (PMID:20356456), similar to but stronger than pmp20
- The fact that tpx1 is described as "essential as a H2O2 scavenger during aerobic growth" (PMID:17409354), not just during oxidative stress

Comparison with interpro2go:

The interpro2go annotation (GO_REF:0000002) assigns peroxiredoxin activity (GO:0051920), which is correct and accepted in the curated review. BioReason correctly recapitulates and elaborates on this interpro2go annotation, providing a well-grounded functional narrative. Unlike the pmp20 case where BioReason incorrectly assumed peroxidase activity from the domain, here tpx1 actually does have the full catalytic apparatus (including resolving cysteine), making the domain-to-function inference valid. BioReason and interpro2go are aligned and both correct for the core peroxidase function.

Notes on thinking trace

The trace provides a thorough and accurate analysis of the domain architecture. The reasoning from thioredoxin-like fold through peroxiredoxin/AhpC-type identity to peroxidase function is sound and well-calibrated for this protein. The C-terminal domain discussion about oligomerization regulation is a nice mechanistic detail.

📄 View Raw YAML

id: O74887
gene_symbol: tpx1
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:284812
  label: Schizosaccharomyces pombe (strain 972 / ATCC 24843)
description: >-
  Tpx1 is the single typical 2-Cys peroxiredoxin (thioredoxin peroxidase, EC
  1.11.1.24) of Schizosaccharomyces pombe. Using a peroxidatic Cys48 and resolving
  Cys169 and the thioredoxin system (Trx1 main donor, Trr1/NADPH recycling) as
  reductant, it reduces hydrogen peroxide and organic peroxides to maintain low
  intracellular H2O2. Beyond bulk detoxification, Tpx1 is a central H2O2 sensor and
  redox relay: it transduces peroxide signals to the AP-1-like transcription factor
  Pap1 and to the Sty1/Atf1 (p38/SAPK) MAPK pathway via transient mixed disulfides.
  At high peroxide flux Tpx1 is hyperoxidized (Cys-sulfinic acid) and inactivated,
  and is repaired by sulfiredoxin (Srx1) in an ATP-dependent reaction, gating the
  dose- and time-dependent stress response. Tpx1 is predominantly cytosolic with a
  minor mitochondrial intermembrane-space pool under oxidative conditions.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Tpx1 is predominantly cytosolic before and after H2O2 exposure, consistent with its
      roles in controlling cytosolic thioredoxins and transcription-factor signaling. A
      minor mitochondrial intermembrane-space pool is also reported under oxidative
      conditions, but the cytosol is the principal site of function.
    action: ACCEPT
    reason: Supported by phylogenetic inference and corroborated by falcon deep research and experimental localization data.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
      reference_section_type: OTHER
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Response to oxidative stress is a central biological process for Tpx1, which is the
      major peroxide-detoxifying enzyme during aerobic growth; tpx1 deletion causes extreme
      peroxide sensitivity. This is a true core function rather than a peripheral context,
      though the more specific term hydrogen peroxide catabolic process is preferred for the
      MF/process pairing.
    action: ACCEPT
    reason: Falcon deep research and primary literature establish oxidative stress defense as a central, not peripheral, role for Tpx1.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is central to peroxide defense during aerobic growth: loss of Tpx1 yields strong peroxide sensitivity and evidence of increased oxidative damage, consistent with a major antioxidant role.
      reference_section_type: OTHER
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Core molecular function. Tpx1 is a thioredoxin-dependent peroxidase that detoxifies
      hydrogen peroxide and organic peroxides, recycled primarily by the cytosolic
      thioredoxin system (Trx1 main donor), consistent with its classification as the
      single typical 2-Cys peroxiredoxin of S. pombe.
    action: ACCEPT
    reason: Supported by phylogenetic inference and corroborated by experimental literature and falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 functions as a **thioredoxin-dependent peroxidase** that detoxifies **hydrogen peroxide** and can also reduce **organic peroxides**, consistent with its classification as a typical 2‑Cys peroxiredoxin.
      reference_section_type: OTHER
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Trx1 is described as the main electron donor for Tpx1, with **Trx3** reported as partially compensatory when Trx1 is absent; thioredoxin reductase (**Trr1**) maintains the thioredoxin pool using NADPH.
      reference_section_type: OTHER
- term:
    id: GO:0042744
    label: hydrogen peroxide catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Core biological process. As the major 2-Cys peroxiredoxin, Tpx1 reduces hydrogen
      peroxide to water; tpx1 deletion causes extreme peroxide sensitivity and increased
      oxidative damage markers, directly supporting this catabolic role in vivo.
    action: ACCEPT
    reason: Supported by phylogenetic inference and corroborated by falcon deep research and primary literature.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Experimentally, *tpx1* deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo.
      reference_section_type: OTHER
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Core process. Tpx1 maintains cellular redox balance via the thioredoxin-coupled
      peroxidatic cycle (Cys48 peroxidatic / Cys169 resolving), the reducing equivalents
      being supplied by the thioredoxin system (Trx1/Trr1/NADPH).
    action: ACCEPT
    reason: Supported by phylogenetic inference and corroborated by falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Trx1 is described as the main electron donor for Tpx1, with **Trx3** reported as partially compensatory when Trx1 is absent; thioredoxin reductase (**Trr1**) maintains the thioredoxin pool using NADPH.
      reference_section_type: OTHER
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: |-
      Tpx1 acts as a redox transducer in the Sty1 (p38/SAPK) MAPK pathway, promoting Sty1
      activation in response to H2O2. This is a genuine signaling role of the gene, though
      this generic IEA term is less specific than the experimentally supported
      positive regulation of p38MAPK cascade (GO:1900745) annotation retained elsewhere.
    action: KEEP_AS_NON_CORE
    reason: Genuine but generic; the experimentally supported p38MAPK regulation term is preferred for the core signaling role.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Underwood (2019) describes Tpx1 as a direct redox transducer promoting Sty1 activation, and other mechanistic discussion links Tpx1 to Sty1 regulation and oxidation events, including interactions/disulfide formation with Sty1.
      reference_section_type: OTHER
- term:
    id: GO:0004601
    label: peroxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: |-
      Correct but generic. Peroxidase activity is the parent of the specific
      thioredoxin-dependent peroxiredoxin activity (GO:0140824) that captures the actual
      mechanism; retained as a true but less informative grouping term.
    action: ACCEPT
    reason: Accurate parent term; the more specific thioredoxin-dependent peroxiredoxin activity is the core MF.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 functions as a **thioredoxin-dependent peroxidase** that detoxifies **hydrogen peroxide** and can also reduce **organic peroxides**, consistent with its classification as a typical 2‑Cys peroxiredoxin.
      reference_section_type: OTHER
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: |-
      Nuclear localization is reported from large-scale localization analysis (also annotated
      HDA from PMID:16823372). Plausible given Tpx1 influence on transcription-factor (Pap1)
      activation, but Tpx1 is predominantly cytosolic and the bulk of its function is
      executed in the cytosol. Retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Supported by localization screens but secondary to the predominant cytosolic site of function per falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
      reference_section_type: OTHER
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: |-
      Consistent with the predominant cytosolic localization of Tpx1. Cytosol (GO:0005829)
      is the more precise term and is also annotated; cytoplasm is the accurate parent.
    action: ACCEPT
    reason: Supported by experimental localization and falcon deep research; cytosol is the more specific term.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
      reference_section_type: OTHER
- term:
    id: GO:0016209
    label: antioxidant activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: |-
      High-level grouping term that is correct (Tpx1 is a major antioxidant enzyme) but
      uninformative relative to the specific thioredoxin-dependent peroxiredoxin activity.
      Retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic grouping term superseded by the specific peroxiredoxin MF.
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: |-
      Very high-level grouping term. Correct (Tpx1 is a thiol-based oxidoreductase, EC
      1.11.1.24) but far less informative than the specific peroxiredoxin activity term.
      Retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Accurate but uninformative root-level term superseded by the specific peroxiredoxin MF.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: |-
      Consistent with Tpx1 acting as both the major peroxide scavenger and a H2O2
      sensor/transducer that routes oxidative-stress information to the Pap1 and Sty1
      response pathways.
    action: ACCEPT
    reason: Supported by falcon deep research and primary literature on Tpx1-mediated oxidative stress signaling.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        A defining feature of *S. pombe* Tpx1 is that it is not only an antioxidant enzyme but also a **central peroxide sensor/transducer** that routes H2O2 information to at least two major oxidative stress response branches: **Pap1** (AP‑1-like) and the **Sty1/Atf1** stress-activated MAPK pathway.
      reference_section_type: OTHER
- term:
    id: GO:0051920
    label: peroxiredoxin activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: |-
      Accurate. Tpx1 is the single typical 2-Cys peroxiredoxin of S. pombe, using a
      peroxidatic Cys48 and resolving Cys169. The more specific
      thioredoxin-dependent peroxiredoxin activity (GO:0140824) is preferred as core MF.
    action: ACCEPT
    reason: Supported by InterPro/family inference and corroborated by falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        catalytic cycle in *S. pombe* involves a **peroxidatic cysteine (Cys48)** and **resolving cysteine (Cys169)**, consistent with typical 2‑Cys Prx chemistry.
      reference_section_type: OTHER
- term:
    id: GO:0140824
    label: thioredoxin-dependent peroxiredoxin activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: |-
      Core molecular function. Tpx1 reduces peroxides using the thioredoxin system as
      electron donor (Trx1 main donor, Trr1/NADPH recycling), matching the
      EC 1.11.1.24 catalytic activity in UniProt. This is the most specific MF term and is
      duplicated by an IDA-supported annotation below.
    action: ACCEPT
    reason: Supported by IEA and corroborated by experimental IDA evidence and falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Trx1 is described as the main electron donor for Tpx1, with **Trx3** reported as partially compensatory when Trx1 is absent; thioredoxin reductase (**Trr1**) maintains the thioredoxin pool using NADPH.
      reference_section_type: OTHER
- term:
    id: GO:0005078
    label: MAP kinase scaffold activity
  evidence_type: EXP
  original_reference_id: PMID:37572670
  review:
    summary: |-
      The scaffold-activity annotation rests on an artificial, genetically encoded
      peroxiredoxin-P38 fusion protein that substitutes for the Mcs4 scaffold and MAP3K
      activity in driving cells into mitosis "by a mechanism that does not require the
      H2O2-sensing cysteine of the Prdx." This demonstrates what a covalent Prdx-MAPK fusion
      can do, but assigning native Tpx1 a dedicated MAP kinase scaffold molecular function on
      this basis is an over-extension: the native redox-transducer role for the Sty1/p38
      pathway is more accurately captured by the positive regulation of p38MAPK cascade
      (GO:1900745) process term retained elsewhere.
    action: MARK_AS_OVER_ANNOTATED
    reason: Evidence is from an engineered Prdx-P38 fusion construct (cysteine-independent), not native Tpx1; the genuine signaling role is captured by the p38MAPK regulation process term, so a dedicated scaffold MF over-annotates the native protein.
    supported_by:
    - reference_id: PMID:37572670
      supporting_text: >-
        We demonstrate that a P38-Prdx fusion protein compensates for loss of the
        yeast scaffold protein Mcs4 and MAP3K activity, driving yeast into mitosis
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 contributes to activation and signaling context for the *S. pombe* stress-activated MAPK **Sty1** and downstream transcription factor **Atf1**, functioning as a redox transducer/scaffold in peroxide signaling.
      reference_section_type: OTHER
- term:
    id: GO:0015035
    label: protein-disulfide reductase activity
  evidence_type: EXP
  original_reference_id: PMID:37572670
  review:
    summary: |-
      Reflects Tpx1 redox-relay chemistry: as a 2-Cys peroxiredoxin it forms transient mixed
      disulfides with partner proteins (e.g., Pap1, Pka1, Csn5, thioredoxins), exchanging
      thiol-disulfide redox equivalents. Captures the relay/disulfide-exchange aspect of
      Tpx1 function rather than its primary peroxidase activity; retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Captures the disulfide-relay aspect of Tpx1; secondary to the core peroxidase function and reinforced by falcon redox-relay evidence.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Pka1 and Csn5 form **protein–protein disulfide complexes with Tpx1** in response to **0.2 mM H2O2**, consistent with Tpx1 functioning as a redox relay to regulatory proteins.
      reference_section_type: OTHER
- term:
    id: GO:1900745
    label: positive regulation of p38MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:37572670
  review:
    summary: |-
      Experimentally supported (IMP). Tpx1 positively regulates the Sty1/p38 MAPK cascade,
      acting as a direct redox transducer promoting Sty1 activation. This signaling role can
      be genetically separated from the peroxidase activity (e.g., tpx1C169S retains Sty1
      regulation), establishing it as a bona fide second function of the gene.
    action: KEEP_AS_NON_CORE
    reason: Bona fide signaling function supported by IMP evidence and falcon deep research; non-core relative to the primary detoxification role.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        role in Sty1 pathway signaling can be genetically separated from its thioredoxin peroxidase activity using alleles such as **tpx1C169S**, described as disrupting thioredoxin peroxidase activity while leaving Sty1 regulation intact.
      reference_section_type: OTHER
- term:
    id: GO:0061692
    label: cellular detoxification of hydrogen peroxide
  evidence_type: IMP
  original_reference_id: PMID:24521463
  review:
    summary: |-
      Core process, experimentally supported (IMP). Genetic dissection establishes Tpx1 (with
      catalase) as a principal H2O2-scavenging enzyme; tpx1 deletion causes extreme peroxide
      sensitivity, directly demonstrating its role in cellular H2O2 detoxification.
    action: ACCEPT
    reason: Strong IMP evidence corroborated by falcon deep research; a core function of the gene.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Experimentally, *tpx1* deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo.
      reference_section_type: OTHER
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22344694
  review:
    summary: |-
      Cytoplasmic localization, consistent with Tpx1 acting in the cytosol as the upstream
      redox transmitter for the cytosolic Pap1 transcription factor. The more specific cytosol
      term is also annotated.
    action: ACCEPT
    reason: Direct localization evidence corroborated by falcon deep research; cytosol is the more specific term.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
      reference_section_type: OTHER
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:20356456
  review:
    summary: |-
      Recombinant TPx (Tpx1) inhibited thermal aggregation of citrate synthase, demonstrating
      molecular chaperone (holdase) activity in vitro, a known moonlighting property of typical
      2-Cys peroxiredoxins. The activity is better captured by the MF term protein folding
      chaperone (GO:0044183) than by the binding-only term unfolded protein binding. Both terms
      are molecular function, so this is a within-aspect refinement.
    action: MODIFY
    reason: In-vitro chaperone (anti-aggregation) activity is more precisely a protein folding chaperone MF than a binding term; supported by the original IDA reference.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: PMID:20356456
      supporting_text: >-
        to inhibit the aggregation. The chaperone activities of PMP20 and GPx were
- term:
    id: GO:0140824
    label: thioredoxin-dependent peroxiredoxin activity
  evidence_type: IDA
  original_reference_id: PMID:20356456
  review:
    summary: |-
      Core molecular function, directly demonstrated (IDA): recombinant TPx reduces peroxides
      using the thioredoxin system, matching EC 1.11.1.24. This is the most specific and
      best-supported MF term for Tpx1.
    action: ACCEPT
    reason: Direct in-vitro demonstration corroborated by falcon deep research; the primary core MF of the gene.
    supported_by:
    - reference_id: PMID:20356456
      supporting_text: >-
        TPx (thioredoxin peroxidase) exhibited a capacity for peroxide reduction
        with the thioredoxin system.
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 functions as a **thioredoxin-dependent peroxidase** that detoxifies **hydrogen peroxide** and can also reduce **organic peroxides**, consistent with its classification as a typical 2‑Cys peroxiredoxin.
      reference_section_type: OTHER
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IMP
  original_reference_id: PMID:24268782
  review:
    summary: |-
      Core molecular function supported by mutational/genetic evidence. Tpx1 reduces peroxides
      via its thioredoxin-coupled cycle; the catalytic mechanism uses peroxidatic Cys48 and
      resolving Cys169. Notably, Brown et al. show the only essential function of this
      thioredoxin peroxidase activity in H2O2 resistance is to inhibit the thioredoxin family
      protein Txl1 by oxidizing it, i.e. the peroxidase activity also drives an oxidative redox
      relay rather than acting purely as a reductive detoxifier.
    action: ACCEPT
    reason: Supported by IMP evidence and falcon deep research; a core function of the gene.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        catalytic cycle in *S. pombe* involves a **peroxidatic cysteine (Cys48)** and **resolving cysteine (Cys169)**, consistent with typical 2‑Cys Prx chemistry.
      reference_section_type: OTHER
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:24268782
  review:
    summary: |-
      Reflects the Tpx1->Pap1 redox relay: under mild H2O2, Tpx1 is required for Pap1
      oxidation/activation, driving Pap1-dependent antioxidant gene transcription. Mechanistically
      this relay operates by Tpx1 transferring oxidizing equivalents to partner proteins (Brown
      et al. show the essential relay in H2O2 resistance is oxidation/inhibition of the
      thioredoxin family protein Txl1), amplifying the H2O2 signal. This is an indirect,
      signaling-mediated effect on transcription (Tpx1 is not itself a transcription factor), so
      it is kept as a non-core consequence of the H2O2-sensor role.
    action: KEEP_AS_NON_CORE
    reason: Genuine but indirect/signaling-mediated effect on transcription via Pap1; non-core relative to the primary peroxidase function. Reinforced by falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is reported to be required for **Pap1 oxidation/activation** under mild peroxide stress, acting as the primary peroxide sensor/transducer for this pathway; Pap1 nuclear accumulation and downstream gene induction depend on Tpx1-mediated redox control.
      reference_section_type: OTHER
- term:
    id: GO:0042744
    label: hydrogen peroxide catabolic process
  evidence_type: IMP
  original_reference_id: PMID:24521463
  review:
    summary: |-
      Core process, IMP-supported. Genetic dissection of H2O2 scavenging shows Tpx1 is a
      principal peroxide-catabolizing enzyme during aerobic growth alongside catalase.
    action: ACCEPT
    reason: Strong IMP evidence corroborated by falcon deep research; a core function of the gene.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is central to peroxide defense during aerobic growth: loss of Tpx1 yields strong peroxide sensitivity and evidence of increased oxidative damage, consistent with a major antioxidant role.
      reference_section_type: OTHER
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IMP
  original_reference_id: PMID:24521463
  review:
    summary: |-
      Core process, IMP-supported. By scavenging peroxides through the thioredoxin-coupled
      cycle, Tpx1 maintains intracellular redox balance during aerobic growth and peroxide
      stress.
    action: ACCEPT
    reason: Supported by IMP evidence and falcon deep research; a core function of the gene.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Trx1 is described as the main electron donor for Tpx1, with **Trx3** reported as partially compensatory when Trx1 is absent; thioredoxin reductase (**Trr1**) maintains the thioredoxin pool using NADPH.
      reference_section_type: OTHER
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:22245228
  review:
    summary: |-
      Reflects signal gating by Tpx1 hyperoxidation: at high H2O2, Tpx1 is hyperoxidized
      (Cys-sulfinic acid) and inactivated, which redirects thioredoxin reducing capacity to
      repair oxidized proteins and reset the transcriptional response. The effect on
      transcription is indirect and signaling-mediated, so it is kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: Indirect, signaling-mediated transcriptional effect via the hyperoxidation switch; non-core relative to the primary peroxidase function. Reinforced by falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        which **inactivates thioredoxin-dependent peroxidase activity** because thioredoxin cannot directly reduce the sulfinic form. Hyperoxidized typical 2‑Cys Prxs can be repaired by **sulfiredoxin (Srx)** via an **ATP-dependent** reaction, restoring catalytic competence and changing signaling capacity over time.
      reference_section_type: OTHER
- term:
    id: GO:0042744
    label: hydrogen peroxide catabolic process
  evidence_type: IMP
  original_reference_id: PMID:22245228
  review:
    summary: |-
      Core process. Confirms Tpx1 as a major H2O2-catabolizing enzyme whose
      peroxidase activity (and its reversible inactivation by hyperoxidation) governs cellular
      peroxide levels.
    action: ACCEPT
    reason: Supported by IMP evidence and falcon deep research; a core function of the gene.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Experimentally, *tpx1* deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo.
      reference_section_type: OTHER
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22245228
  review:
    summary: |-
      Directly observed cytoplasmic localization, consistent with the predominantly cytosolic
      site where Tpx1 detoxifies peroxides and controls cytosolic thioredoxin/Pap1 signaling.
    action: ACCEPT
    reason: Direct localization evidence corroborated by falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
      reference_section_type: OTHER
- term:
    id: GO:0004601
    label: peroxidase activity
  evidence_type: IDA
  original_reference_id: PMID:17409354
  review:
    summary: |-
      Directly demonstrated peroxidase activity. Tpx1 is essential as the H2O2 scavenger during
      aerobic growth. The specific thioredoxin-dependent peroxiredoxin activity term is the
      preferred core MF; this is the accurate parent.
    action: ACCEPT
    reason: Direct experimental evidence; accurate parent of the specific peroxiredoxin MF. Corroborated by falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 functions as a **thioredoxin-dependent peroxidase** that detoxifies **hydrogen peroxide** and can also reduce **organic peroxides**, consistent with its classification as a typical 2‑Cys peroxiredoxin.
      reference_section_type: OTHER
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17409354
  review:
    summary: |-
      Uninformative per curation guidelines. Tpx1 does form functionally meaningful
      interactions (homodimer, transient mixed disulfides with thioredoxins, Pap1, Pka1, Csn5,
      and Srx1), but these are captured by more specific MF terms such as
      thioredoxin-dependent peroxiredoxin activity and protein-disulfide reductase activity.
      The bare protein binding term adds no information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative; specific MF terms (peroxiredoxin/disulfide-relay activities) capture the actual interactions.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IMP
  original_reference_id: PMID:17409354
  review:
    summary: |-
      Core process. As the essential H2O2 scavenger during aerobic growth, Tpx1 is central to
      maintaining cellular redox balance.
    action: ACCEPT
    reason: Supported by IMP evidence and falcon deep research; a core function of the gene.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is central to peroxide defense during aerobic growth: loss of Tpx1 yields strong peroxide sensitivity and evidence of increased oxidative damage, consistent with a major antioxidant role.
      reference_section_type: OTHER
- term:
    id: GO:0051920
    label: peroxiredoxin activity
  evidence_type: IDA
  original_reference_id: PMID:17409354
  review:
    summary: |-
      Directly demonstrated peroxiredoxin activity. The more specific
      thioredoxin-dependent peroxiredoxin activity (GO:0140824) term is the preferred core MF.
    action: ACCEPT
    reason: Direct experimental evidence corroborated by falcon deep research; specific peroxiredoxin MF is preferred.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        catalytic cycle in *S. pombe* involves a **peroxidatic cysteine (Cys48)** and **resolving cysteine (Cys169)**, consistent with typical 2‑Cys Prx chemistry.
      reference_section_type: OTHER
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:16823372
  review:
    summary: |-
      Nuclear signal from a genome-wide GFP localization screen. Plausible given Tpx1 influence
      on Pap1 activation, but Tpx1 is predominantly cytosolic and executes its core function in
      the cytosol; retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: High-throughput localization signal; secondary to the predominant cytosolic site of function per falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
      reference_section_type: OTHER
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: HDA
  original_reference_id: PMID:16823372
  review:
    summary: |-
      Cytosolic localization from a genome-wide GFP localization screen, concordant with the
      predominant cytosolic site where Tpx1 detoxifies peroxides and controls thioredoxin/Pap1
      signaling. This is the principal site of function.
    action: ACCEPT
    reason: High-throughput localization consistent with the predominant cytosolic site of function per falcon deep research.
    supported_by:
    - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
      supporting_text: |-
        Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
      reference_section_type: OTHER
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15824112
  review:
    summary: |-
      Uninformative per curation guidelines. This IPI derives from the Tpx1-Srx1 interaction
      (sulfiredoxin-mediated repair of hyperoxidized Tpx1) and the Tpx1-Pap1 redox switch, but
      the bare protein binding term conveys none of this. The specific redox-relay/peroxidase
      MF terms and the regulatory process terms capture the biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative; the Srx1/Pap1 interactions are better captured by specific MF/process terms.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15824112
  title: Oxidation of a eukaryotic 2-Cys peroxiredoxin is a molecular switch controlling the transcriptional response to increasing levels of hydrogen peroxide.
  findings: []
- id: PMID:16823372
  title: ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe.
  findings: []
- id: PMID:17409354
  title: The peroxiredoxin Tpx1 is essential as a H2O2 scavenger during aerobic growth in fission yeast.
  findings: []
- id: PMID:20356456
  title: Distinct functional roles of peroxiredoxin isozymes and glutathione peroxidase from fission yeast, Schizosaccharomyces pombe.
  findings: []
- id: PMID:22245228
  title: Inactivation of a peroxiredoxin by hydrogen peroxide is critical for thioredoxin-mediated repair of oxidized proteins and cell survival.
  findings: []
- id: PMID:22344694
  title: The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2.
  findings: []
- id: PMID:24268782
  title: A peroxiredoxin promotes H2O2 signaling and oxidative stress resistance by oxidizing a thioredoxin family protein.
  findings: []
- id: PMID:24521463
  title: A genetic approach to study H2O2 scavenging in fission yeast--distinct roles of peroxiredoxin and catalase.
  findings: []
- id: PMID:37572670
  title: A peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms.
  findings: []
- id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
  title: Falcon deep research report on tpx1 (Edison Scientific Literature)
  findings:
  - statement: |-
      Tpx1 (UniProt O74887) is the single typical 2-Cys peroxiredoxin (thioredoxin peroxidase,
      EC 1.11.1.24) of S. pombe, reducing hydrogen peroxide and organic peroxides via a
      peroxidatic Cys48 and resolving Cys169, recycled by the thioredoxin system.
    supporting_text: |-
      Tpx1 functions as a **thioredoxin-dependent peroxidase** that detoxifies **hydrogen peroxide** and can also reduce **organic peroxides**, consistent with its classification as a typical 2‑Cys peroxiredoxin. Experimentally, *tpx1* deletion causes extreme peroxide sensitivity and increased oxidative damage markers (e.g., protein carbonylation), supporting a central peroxide-detoxifying role in vivo.
    reference_section_type: OTHER
  - statement: |-
      Tpx1 is recycled primarily by the cytosolic thioredoxin system, with Trx1 the main
      electron donor (Trx3 partially compensatory) and Trr1/NADPH maintaining the reduced
      thioredoxin pool.
    supporting_text: |-
      Trx1 is described as the main electron donor for Tpx1, with **Trx3** reported as partially compensatory when Trx1 is absent; thioredoxin reductase (**Trr1**) maintains the thioredoxin pool using NADPH.
    reference_section_type: OTHER
  - statement: |-
      Beyond detoxification, Tpx1 is a central H2O2 sensor/redox relay that routes peroxide
      information to two major stress branches: the Pap1 (AP-1-like) transcription factor and
      the Sty1/Atf1 stress-activated MAPK pathway.
    supporting_text: |-
      A defining feature of *S. pombe* Tpx1 is that it is not only an antioxidant enzyme but also a **central peroxide sensor/transducer** that routes H2O2 information to at least two major oxidative stress response branches: **Pap1** (AP‑1-like) and the **Sty1/Atf1** stress-activated MAPK pathway.
    reference_section_type: OTHER
  - statement: |-
      Under mild H2O2 (~0.2 mM), Tpx1 is required for Pap1 oxidation/activation, nuclear
      accumulation and downstream antioxidant gene induction, acting as the primary peroxide
      sensor/transducer for the Pap1 pathway.
    supporting_text: |-
      Tpx1 is reported to be required for **Pap1 oxidation/activation** under mild peroxide stress, acting as the primary peroxide sensor/transducer for this pathway; Pap1 nuclear accumulation and downstream gene induction depend on Tpx1-mediated redox control.
    reference_section_type: OTHER
  - statement: |-
      The Tpx1 signaling (Sty1) role can be genetically uncoupled from its peroxidase activity
      using separation-of-function alleles such as tpx1C169S, which disrupts thioredoxin
      peroxidase activity while leaving Sty1 regulation intact.
    supporting_text: |-
      role in Sty1 pathway signaling can be genetically separated from its thioredoxin peroxidase activity using alleles such as **tpx1C169S**, described as disrupting thioredoxin peroxidase activity while leaving Sty1 regulation intact.
    reference_section_type: OTHER
  - statement: |-
      At high peroxide flux Tpx1 is hyperoxidized to a sulfinic acid, which inactivates its
      thioredoxin-dependent peroxidase activity; sulfiredoxin (Srx1) repairs the hyperoxidized
      form in an ATP-dependent reaction, gating signaling over time.
    supporting_text: |-
      which **inactivates thioredoxin-dependent peroxidase activity** because thioredoxin cannot directly reduce the sulfinic form. Hyperoxidized typical 2‑Cys Prxs can be repaired by **sulfiredoxin (Srx)** via an **ATP-dependent** reaction, restoring catalytic competence and changing signaling capacity over time.
    reference_section_type: OTHER
  - statement: |-
      Tpx1 directly relays peroxide signals to regulatory proteins, forming protein-protein
      disulfide complexes with partners such as Pka1 and Csn5 in response to 0.2 mM H2O2.
    supporting_text: |-
      Pka1 and Csn5 form **protein–protein disulfide complexes with Tpx1** in response to **0.2 mM H2O2**, consistent with Tpx1 functioning as a redox relay to regulatory proteins.
    reference_section_type: OTHER
  - statement: |-
      Tpx1 is predominantly cytosolic before and after H2O2 exposure, with a minor
      mitochondrial intermembrane-space (IMS) pool detected under oxidative conditions.
    supporting_text: |-
      Tpx1 is primarily described as **cytosolic** before and after H2O2 exposure, consistent with its roles in controlling cytosolic thioredoxins and transcription factor signaling.
    reference_section_type: OTHER
core_functions:
- description: >-
    Thioredoxin-dependent peroxiredoxin activity that detoxifies H2O2 and
    maintains cellular redox balance during aerobic growth and peroxide stress.
  supported_by:
  - reference_id: PMID:17409354
    supporting_text: >-
      The peroxiredoxin Tpx1 is essential as a H2O2 scavenger during aerobic
      growth in fission yeast.
  - reference_id: PMID:20356456
    supporting_text: >-
      TPx (thioredoxin peroxidase) exhibited a capacity for peroxide reduction
      with the thioredoxin system.
  molecular_function:
    id: GO:0140824
    label: thioredoxin-dependent peroxiredoxin activity
  directly_involved_in:
  - id: GO:0042744
    label: hydrogen peroxide catabolic process
  - id: GO:0045454
    label: cell redox homeostasis
  locations:
  - id: GO:0005829
    label: cytosol
- description: >-
    H2O2 sensor and redox relay driven by the same thioredoxin-dependent
    peroxiredoxin chemistry: the peroxidatic cysteine, once oxidized by H2O2,
    transfers oxidizing equivalents to partner proteins via transient mixed
    disulfides, thereby transducing peroxide signals to the Pap1 (AP-1-like)
    transcription factor and the Sty1/Atf1 (p38/SAPK) MAPK pathway. In H2O2
    resistance this relay works by oxidizing (and thus inhibiting) the thioredoxin
    family protein Txl1, amplifying the H2O2 signal. This signaling role is
    genetically separable from bulk detoxification (e.g., via the tpx1C169S allele).
  supported_by:
  - reference_id: file:SCHPO/tpx1/tpx1-deep-research-falcon.md
    supporting_text: |-
      A defining feature of *S. pombe* Tpx1 is that it is not only an antioxidant enzyme but also a **central peroxide sensor/transducer** that routes H2O2 information to at least two major oxidative stress response branches: **Pap1** (AP‑1-like) and the **Sty1/Atf1** stress-activated MAPK pathway.
  - reference_id: PMID:24268782
    supporting_text: >-
      a Prx amplifies an H2O2 signal by driving the oxidation of a
      thioredoxin-like protein
  molecular_function:
    id: GO:0140824
    label: thioredoxin-dependent peroxiredoxin activity
  directly_involved_in:
  - id: GO:1900745
    label: positive regulation of p38MAPK cascade
  - id: GO:0034599
    label: cellular response to oxidative stress
  locations:
  - id: GO:0005829
    label: cytosol

tpx1

Gene Description

Existing Annotations Review

Core Functions

Thioredoxin-dependent peroxiredoxin activity that detoxifies H2O2 and maintains cellular redox balance during aerobic growth and peroxide stress.

References

Deep Research

Falcon

Research Report: Functional Annotation of Schizosaccharomyces pombe tpx1 (UniProt O74887)

Scope and identity verification

1) Key concepts, definitions, and current understanding

1.1 Typical 2-Cys peroxiredoxins (Prx) / thioredoxin peroxidases (Tpx)

1.2 Hyperoxidation and sulfiredoxin repair (signal gating)

1.3 Peroxiredoxins as H2O2 sensors and redox relays

2) Molecular function of Tpx1 (enzyme reaction and substrate specificity)

2.1 Primary enzymatic function

2.2 Electron donor specificity: thioredoxin system

3) Biological processes and pathways involving Tpx1

3.1 Oxidative stress defense (detoxification and homeostasis)

3.2 H2O2 signaling: Pap1 transcription factor pathway

3.3 H2O2 signaling: Sty1 MAPK / Atf1 pathway

4) Subcellular localization and cellular context

4.1 Cytosolic localization

4.2 Mitochondrial/IMS-associated pool

5) Key experimental evidence, mutants, and interaction partners

5.1 Catalytic cysteine mutants and mechanistic trapping

5.2 Thioredoxin partners and redox-network wiring

5.3 Expanded redox interaction landscape (proteomics/genetics)

6) Recent developments and latest research (prioritizing 2023–2024)

6.1 2024 high-impact evidence for peroxiredoxin-gated TF programs

6.2 Limitations in 2023–2024 Tpx1-specific retrieval

7) Current applications and real-world implementations

8) Relevant statistics and data (selected)

9) Expert analysis / synthesis (functional annotation summary)

Key sources (URLs and publication dates where available)

Notes on evidence limitations

Artifacts

Citations

📚 Additional Documentation

Bioreason Rl Predictions

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Bioreason Rl Review

BioReason-Pro RL Review: tpx1 (S. pombe)

Functional Summary Review

Notes on thinking trace

📄 View Raw YAML