Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Tsa1 is the major cytosolic peroxiredoxin of budding yeast; the cytosol is where it executes its peroxidase, redox-signaling and chaperone functions. Consistent with IDA evidence (PMID:18271751) and falcon synthesis. Reason: Core localization. Tsa1 is one of the most abundant cytosolic proteins and acts as the primary cytosolic peroxide sink. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Tsa1 is repeatedly described as the major cytosolic peroxiredoxin in yeast.
GO:0006979 response to oxidative stress	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Response to oxidative stress is a true but high-level process for TSA1. The more specific child terms (cellular response to oxidative stress, hydrogen peroxide catabolic process) better capture the core function. Reason: Correct but general parent term; retained as non-core because more specific annotations represent the precise antioxidant function. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Tsa1 reduces H2O2 and organic hydroperoxides; in typical 2‑Cys Prxs this occurs via CP attack on the peroxide bond, generating water/alcohol products.
GO:0008379 thioredoxin peroxidase activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function. Tsa1 is a thioredoxin-dependent peroxidase that reduces H2O2 and organic hydroperoxides via the typical 2-Cys peroxiredoxin cycle (peroxidatic Cys48, resolving Cys171), with the disulfide reduced by thioredoxin (Trx1/Trx2). Directly supported by IDA evidence (PMID:7961686). Reason: Defining enzymatic activity of TSA1, well supported across phylogenetic inference, biochemistry and structural data. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Tsa1’s primary biochemical role is as a thioredoxin-dependent peroxidase that reduces peroxides (especially H2O2) via the typical 2‑Cys Prx redox cycle centered on Cys48/Cys171.
GO:0042744 hydrogen peroxide catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process. As the major abundant cytosolic peroxiredoxin, Tsa1 is responsible for decomposing the bulk of cellular H2O2. Reason: Direct downstream process of the peroxidase activity; central to TSA1 function. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Reviews also emphasize that Prxs decompose >90% of cellular hydroperoxides and can detoxify up to ~90% of cytosolic H2O2 due to abundance and fast reaction rates (general Prx second-order rates ~10^6–10^8 M−1 s−1).
GO:0045454 cell redox homeostasis	IBA GO_REF:0000033	ACCEPT	Summary: Core process. Beyond peroxide scavenging, Tsa1 buffers the redox state of the proteome by forming and resolving mixed disulfides with client proteins (via thioredoxin), maintaining cellular thiol redox balance. Reason: Well supported as a core function; Tsa1 is a central node of the cytosolic thioredoxin-peroxiredoxin redox network. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md This provides a mechanistic route for Tsa1 to act not only as a sink for H2O2 but also as a regulator/buffer of protein thiol redox state.
GO:0098869 cellular oxidant detoxification	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Manual review: cellular oxidant detoxification may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0004601 peroxidase activity	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: Peroxidase activity is correct but is a general parent of the more specific thioredoxin-dependent peroxiredoxin activity that defines TSA1. Reason: True but general; the specific term thioredoxin-dependent peroxiredoxin activity (GO:0140824) better represents the core function. (Note: GO_REF:0000043 SPKW keyword annotations are being retired upstream.) Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Tsa1’s primary biochemical role is as a thioredoxin-dependent peroxidase that reduces peroxides (especially H2O2) via the typical 2‑Cys Prx redox cycle centered on Cys48/Cys171.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Manual review: cytoplasm is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0008379 thioredoxin peroxidase activity	IEA GO_REF:0000117	ACCEPT	Summary: Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0016209 antioxidant activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Manual review: antioxidant activity may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Manual review: oxidoreductase activity may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0034599 cellular response to oxidative stress	IEA GO_REF:0000117	ACCEPT	Summary: Core process. Tsa1 is the principal cytosolic effector of the cellular response to oxidative stress, both detoxifying peroxides and relaying H2O2 signals (e.g. to Yap1 and via redox modulation of PKA). Also supported by multiple IDA/IMP annotations. Reason: Central process for TSA1; redundantly supported by experimental evidence. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md A major mechanistic insight from authoritative work is that Tsa1’s contribution to stress resistance and longevity can occur not simply by scavenging H2O2, but through redox modulation of nutrient signaling.
GO:0034605 cellular response to heat	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Tsa1 contributes to the heat-stress response via its chaperone/holdase switch: heat shock drives formation of high-MW oligomers that bind misfolded proteins and enhance heat-shock resistance (PMID:15163410). Reason: Genuine but downstream of the chaperone moonlighting function; the holdase MF and protein folding process capture the mechanism more directly. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md At higher oxidant loads, Tsa1’s peroxidatic cysteine can become hyperoxidized (sulfinic/sulfonic states), which inactivates peroxidase activity and promotes formation of higher-order oligomers associated with molecular chaperone/holdase activity.
GO:0045454 cell redox homeostasis	IEA GO_REF:0000117	ACCEPT	Summary: Manual review: cell redox homeostasis is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0050821 protein stabilization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Manual review: protein stabilization may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0051920 peroxiredoxin activity	IEA GO_REF:0000002	ACCEPT	Summary: Peroxiredoxin activity is correct for TSA1, the major 2-Cys peroxiredoxin of yeast. The thioredoxin-dependent child term (GO:0140824) is the most precise MF. Reason: Accurate MF supported by domain/family (AhpC/Prx1) inference and direct biochemistry. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md The research target is the budding yeast (Saccharomyces cerevisiae) protein Tsa1, consistently described across primary and review sources as the major cytosolic typical 2‑Cys peroxiredoxin (Prx) with canonical active-site cysteines Cys48 (peroxidatic, CP) and Cys171 (resolving, CR).
GO:0140824 thioredoxin-dependent peroxiredoxin activity	IEA GO_REF:0000120	ACCEPT	Summary: This is the most precise molecular function term for TSA1: catalysis of hydroperoxide reduction using thioredoxin as the electron donor. Matches the experimentally characterized thioredoxin-coupled peroxidase activity (PMID:7961686, PMID:9888818) and is selected as the core MF. Reason: Most specific and accurate MF term; designated the core molecular function. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Reduction of oxidized Tsa1 is primarily driven by the cytosolic thioredoxin system: Trx1/Trx2 reduce the Tsa1 disulfide, and oxidized thioredoxin is recycled by thioredoxin reductase using NADPH.
GO:0005515 protein binding	IPI PMID:16272220 A yeast two-hybrid knockout strain to explore thioredoxin-in...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation. Tsa1 does form extensive (often transient, redox-based) interactions with client proteins - it forms mixed-disulfide intermediates (peroxiredoxinylation) with hundreds of targets - but the bare "protein binding" term is uninformative and these interactions are better captured by the redox/chaperone functions. Reason: Uninformative generic binding term; the underlying interactions reflect redox-relay/chaperone biology better described by specific MF terms. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md A 2023 bioRxiv preprint reports that Tsa1 forms widespread covalent mixed disulfide intermediates with cellular proteins, termed Tsa1-Induced Mixed Disulfide Intermediates (TIMDIs), and frames this as a bona fide redox-linked post-translational modification termed peroxiredoxinylation.
GO:0005515 protein binding	IPI PMID:16554755 Global landscape of protein complexes in the yeast Saccharom...	MARK AS OVER ANNOTATED	Summary: Manual review: protein binding is too generic or over-extended for TSA1. Reason: Marked over-annotated because more specific terms capture the biology more accurately.
GO:0005515 protein binding	IPI PMID:18719252 High-quality binary protein interaction map of the yeast int...	MARK AS OVER ANNOTATED	Summary: Manual review: protein binding is too generic or over-extended for TSA1. Reason: Marked over-annotated because more specific terms capture the biology more accurately.
GO:0005515 protein binding	IPI PMID:37968396 The social and structural architecture of the yeast protein ...	MARK AS OVER ANNOTATED	Summary: Manual review: protein binding is too generic or over-extended for TSA1. Reason: Marked over-annotated because more specific terms capture the biology more accurately.
GO:0019207 kinase regulator activity	IMP PMID:27634403 Redox-dependent Regulation of Gluconeogenesis by a Novel Mec...	KEEP AS NON CORE	Summary: Tsa1 directly regulates the metabolic kinase Pyk1 (pyruvate kinase / Cdc19): it physically interacts with and suppresses Pyk1 activity via a peroxidatic-cysteine (Cys48)-dependent mechanism, and these interactions are augmented during the glycolysis-to-gluconeogenesis shift (PMID:27634403, Irokawa et al. 2016). This is a genuine but specialized, non-peroxidase target-modulator role distinct from the core peroxidase function. (Note: a separate, mechanistically distinct redox repression of the Ras-cAMP-PKA pathway is reported in Roger et al. 2020, eLife, which is not part of this GOA annotation.) Reason: Real direct kinase-regulation function (suppression of pyruvate kinase Pyk1), but peripheral to the core antioxidant/chaperone activities. Supporting Evidence: PMID:27634403 We found that the suppression of pyruvate kinase (Pyk1) via the interaction with Tsa1 contributes in part to gluconeogenic enhancement. PMID:27634403 a peroxidatic cysteine in the catalytic center of Tsa1 played an important role in the physical Tsa1-Pyk1 interactions.
GO:0005737 cytoplasm	HDA PMID:22842922 Dissecting DNA damage response pathways by analysing protein...	ACCEPT	Summary: Cytoplasmic localization, consistent with Tsa1 being the major cytosolic peroxiredoxin. Redundant with more precise cytosol (GO:0005829) annotations. Reason: Correct localization; the cytosol child term is preferred but cytoplasm is accurate. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Tsa1 is repeatedly described as the major cytosolic peroxiredoxin in yeast.
GO:0006111 regulation of gluconeogenesis	IMP PMID:27634403 Redox-dependent Regulation of Gluconeogenesis by a Novel Mec...	KEEP AS NON CORE	Summary: Tsa1 promotes efficient gluconeogenic flux via a direct, peroxidatic-cysteine (Cys48)-dependent physical interaction with and suppression of pyruvate kinase (Pyk1); the Tsa1-Pyk1 interaction is augmented during the glycolysis-to-gluconeogenesis shift (PMID:27634403, Irokawa et al. 2016). A specialized, context-specific metabolic output rather than a core function. Reason: Genuine but peripheral metabolic regulation arising from direct suppression of pyruvate kinase (Pyk1), not from PKA redox signaling. Supporting Evidence: PMID:27634403 we discovered that Tsa1, a major peroxiredoxin of budding yeast cells, is required for the efficient flux of gluconeogenesis. PMID:27634403 We found that the suppression of pyruvate kinase (Pyk1) via the interaction with Tsa1 contributes in part to gluconeogenic enhancement.
GO:0006457 protein folding	IDA PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	ACCEPT	Summary: Core moonlighting process. Upon oxidative/heat stress Tsa1 switches to a high-MW chaperone (holdase) that assists protein folding/prevents aggregation (PMID:15163410). Selected as one of the core functions. Reason: Well-supported chaperone function central to TSA1's dual-function biology. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md At higher oxidant loads, Tsa1’s peroxidatic cysteine can become hyperoxidized (sulfinic/sulfonic states), which inactivates peroxidase activity and promotes formation of higher-order oligomers associated with molecular chaperone/holdase activity.
GO:0006457 protein folding	IMP PMID:16251355 The thioredoxin system protects ribosomes against stress-ind...	ACCEPT	Summary: Manual review: protein folding is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0034599 cellular response to oxidative stress	IDA PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	ACCEPT	Summary: Manual review: cellular response to oxidative stress is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0034605 cellular response to heat	IDA PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	KEEP AS NON CORE	Summary: Manual review: cellular response to heat may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0051082 unfolded protein binding	IDA PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	MODIFY	Summary: Tsa1's holdase activity involves binding unfolded/misfolded proteins. The activity-style term protein folding chaperone (GO:0044183) is more informative than the simple binding term for this moonlighting function. Reason: Replace with the more specific chaperone activity term; both are MF so this is a same-aspect refinement, not a cross-aspect change. Proposed replacements: protein folding chaperone Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md This supports a functional switch where hyperoxidized Tsa1 acts as a stress-activated chaperone adaptor to recruit the protein quality control machinery.
GO:0072721 cellular response to dithiothreitol	IMP PMID:16251355 The thioredoxin system protects ribosomes against stress-ind...	KEEP AS NON CORE	Summary: Manual review: cellular response to dithiothreitol may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0006457 protein folding	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	ACCEPT	Summary: Manual review: protein folding is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0008379 thioredoxin peroxidase activity	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	ACCEPT	Summary: Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0034605 cellular response to heat	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	KEEP AS NON CORE	Summary: Manual review: cellular response to heat may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0042802 identical protein binding	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	MARK AS OVER ANNOTATED	Summary: Manual review: identical protein binding is too generic or over-extended for TSA1. Reason: Marked over-annotated because more specific terms capture the biology more accurately.
GO:0045454 cell redox homeostasis	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	ACCEPT	Summary: Manual review: cell redox homeostasis is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0050821 protein stabilization	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	KEEP AS NON CORE	Summary: Manual review: protein stabilization may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0051082 unfolded protein binding	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	MODIFY	Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for TSA1. Reason: Modified to align with current curation guidance and improve term specificity. Proposed replacements: protein folding chaperone
GO:0051258 protein polymerization	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	KEEP AS NON CORE	Summary: Manual review: protein polymerization may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0071447 cellular response to hydroperoxide	IMP PMID:15163410 Two enzymes in one; two yeast peroxiredoxins display oxidati...	KEEP AS NON CORE	Summary: Manual review: cellular response to hydroperoxide may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0006457 protein folding	IMP PMID:24022485 Peroxiredoxin chaperone activity is critical for protein hom...	ACCEPT	Summary: Manual review: protein folding is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0000077 DNA damage checkpoint signaling	IGI PMID:19851444 Loss of yeast peroxiredoxin Tsa1p induces genome instability...	KEEP AS NON CORE	Summary: Manual review: DNA damage checkpoint signaling may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0005737 cytoplasm	IDA PMID:10681558 Distinct physiological functions of thiol peroxidase isoenzy...	ACCEPT	Summary: Manual review: cytoplasm is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0005737 cytoplasm	IDA PMID:8344960 Cloning, sequencing, and mutation of thiol-specific antioxid...	ACCEPT	Summary: Manual review: cytoplasm is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0005829 cytosol	IDA PMID:18271751 The yeast Tsa1 peroxiredoxin is a ribosome-associated antiox...	ACCEPT	Summary: Manual review: cytosol is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0008379 thioredoxin peroxidase activity	IDA PMID:7961686 Thioredoxin-dependent peroxide reductase from yeast.	ACCEPT	Summary: Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0008379 thioredoxin peroxidase activity	IMP PMID:7961686 Thioredoxin-dependent peroxide reductase from yeast.	ACCEPT	Summary: Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0008379 thioredoxin peroxidase activity	IDA PMID:9799566 Thermosensitive phenotype of yeast mutant lacking thioredoxi...	ACCEPT	Summary: Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0008379 thioredoxin peroxidase activity	IMP PMID:9799566 Thermosensitive phenotype of yeast mutant lacking thioredoxi...	ACCEPT	Summary: Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0033194 response to hydroperoxide	IMP PMID:15210711 Cytosolic thioredoxin peroxidase I and II are important defe...	KEEP AS NON CORE	Summary: Manual review: response to hydroperoxide may be context-dependent or peripheral for TSA1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
GO:0034599 cellular response to oxidative stress	IGI PMID:15051715 Peroxiredoxin-null yeast cells are hypersensitive to oxidati...	ACCEPT	Summary: Manual review: cellular response to oxidative stress is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0034599 cellular response to oxidative stress	IMP PMID:18271751 The yeast Tsa1 peroxiredoxin is a ribosome-associated antiox...	ACCEPT	Summary: Manual review: cellular response to oxidative stress is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0034599 cellular response to oxidative stress	IDA PMID:8344960 Cloning, sequencing, and mutation of thiol-specific antioxid...	ACCEPT	Summary: Manual review: cellular response to oxidative stress is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0034599 cellular response to oxidative stress	IMP PMID:8344960 Cloning, sequencing, and mutation of thiol-specific antioxid...	ACCEPT	Summary: Manual review: cellular response to oxidative stress is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0042262 DNA protection	IMP PMID:19543365 Peroxiredoxin Tsa1 is the key peroxidase suppressing genome ...	KEEP AS NON CORE	Summary: Tsa1 is the strongest anti-mutator among yeast oxidant-defense genes; tsa1-null cells show a ~5-10-fold increased mutation rate and genome instability. This genome-protective role is partly peroxidase-dependent and partly via redox-network effects (e.g. thioredoxin/RNR), making it an important but non-core, indirect consequence of the antioxidant function. Reason: Well-documented but downstream/indirect protective effect rather than a direct molecular function of Tsa1 on DNA. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md Yeast lacking TSA1 show a mutator phenotype, with reported ~5–10‑fold increased mutation rates, and Tsa1 is described as the strongest suppressor of mutations among oxidant-defense genes in yeast.
GO:0043022 ribosome binding	IDA PMID:18271751 The yeast Tsa1 peroxiredoxin is a ribosome-associated antiox...	KEEP AS NON CORE	Summary: Tsa1 associates with translating ribosomes, acting as a ribosome-associated antioxidant that protects nascent polypeptides from oxidative damage and misfolding (PMID:18271751). A specialized localization-linked function. Reason: Genuine ribosome-associated antioxidant role, but ancillary to the core cytosolic peroxidase/chaperone activities. Supporting Evidence: file:yeast/TSA1/TSA1-deep-research-falcon.md In addition to a free cytosolic pool, one source reports Tsa1 is also found associated with translating ribosomes, suggesting functional proximity to nascent polypeptides and translation-linked proteostasis.
GO:0045454 cell redox homeostasis	IDA PMID:8344960 Cloning, sequencing, and mutation of thiol-specific antioxid...	ACCEPT	Summary: Manual review: cell redox homeostasis is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0045454 cell redox homeostasis	IMP PMID:8344960 Cloning, sequencing, and mutation of thiol-specific antioxid...	ACCEPT	Summary: Manual review: cell redox homeostasis is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0045454 cell redox homeostasis	IMP PMID:9799566 Thermosensitive phenotype of yeast mutant lacking thioredoxi...	ACCEPT	Summary: Manual review: cell redox homeostasis is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.
GO:0051082 unfolded protein binding	IMP PMID:16251355 The thioredoxin system protects ribosomes against stress-ind...	MODIFY	Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for TSA1. Reason: Modified to align with current curation guidance and improve term specificity. Proposed replacements: protein folding chaperone
GO:0051920 peroxiredoxin activity	IDA PMID:17210445 Reactions of yeast thioredoxin peroxidases I and II with hyd...	ACCEPT	Summary: Manual review: peroxiredoxin activity is consistent with known biology of TSA1. Reason: Retained as supported or plausible for this gene and evidence context.

Core Functions

Thioredoxin-dependent peroxidase that catalyzes reduction of hydrogen peroxide and organic hydroperoxides to water/alcohol using the typical 2-Cys peroxiredoxin cycle (peroxidatic Cys48 attacks the peroxide bond, forming an inter-subunit disulfide with resolving Cys171 that is reduced by thioredoxin). As the major, highly abundant cytosolic peroxiredoxin, Tsa1 is the primary peroxide sink of the yeast cytosol.

Molecular Function:

thioredoxin-dependent peroxiredoxin activity

Directly Involved In:

hydrogen peroxide catabolic process cell redox homeostasis

Cellular Locations:

cytosol

Supporting Evidence:

file:yeast/TSA1/TSA1-deep-research-falcon.md
Tsa1’s primary biochemical role is as a **thioredoxin-dependent peroxidase** that reduces peroxides (especially **H2O2**) via the typical 2‑Cys Prx redox cycle centered on **Cys48/Cys171**.
PMID:7961686
The 25-kDa enzyme is now shown to be a peroxidase that reduces H2O2 and alkyl hydroperoxides with the use of hydrogens provided by thioredoxin, thioredoxin reductase, and NADPH.

Stress-activated molecular chaperone (holdase). Upon hyperoxidation of the peroxidatic cysteine and oxidative/heat stress, Tsa1 undergoes a reversible switch from low-molecular-weight peroxidase species to high-molecular-weight oligomers with chaperone holdase activity, binding unfolded/misfolded proteins and recruiting Hsp70 (Ssa1/2) and Hsp104 to clear oxidatively damaged aggregates; reactivation requires reduction by sulfiredoxin Srx1.

Molecular Function:

protein folding chaperone

Directly Involved In:

protein folding

Cellular Locations:

cytosol

Supporting Evidence:

file:yeast/TSA1/TSA1-deep-research-falcon.md
At higher oxidant loads, Tsa1’s peroxidatic cysteine can become **hyperoxidized** (sulfinic/sulfonic states), which **inactivates peroxidase activity** and promotes formation of **higher-order oligomers** associated with **molecular chaperone/holdase activity**.
PMID:15163410
The peroxidase function predominates in the lower MW forms, whereas the chaperone function predominates in the higher MW complexes. Oxidative stress and heat shock exposure of yeasts causes the protein structures of cPrxI and II to shift from low MW species to high MW complexes. This triggers a peroxidase-to-chaperone functional switch.

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:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10681558

Distinct physiological functions of thiol peroxidase isoenzymes in Saccharomyces cerevisiae.

PMID:15051715

Peroxiredoxin-null yeast cells are hypersensitive to oxidative stress and are genomically unstable.

PMID:15163410

Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function.

PMID:15210711

Cytosolic thioredoxin peroxidase I and II are important defenses of yeast against organic hydroperoxide insult: catalases and peroxiredoxins cooperate in the decomposition of H2O2 by yeast.

PMID:16251355

The thioredoxin system protects ribosomes against stress-induced aggregation.

PMID:16272220

A yeast two-hybrid knockout strain to explore thioredoxin-interacting proteins in vivo.

PMID:16554755

Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.

PMID:17210445

Reactions of yeast thioredoxin peroxidases I and II with hydrogen peroxide and peroxynitrite: rate constants by competitive kinetics.

PMID:18271751

The yeast Tsa1 peroxiredoxin is a ribosome-associated antioxidant.

PMID:18719252

High-quality binary protein interaction map of the yeast interactome network.

PMID:19543365

Peroxiredoxin Tsa1 is the key peroxidase suppressing genome instability and protecting against cell death in Saccharomyces cerevisiae.

PMID:19851444

Loss of yeast peroxiredoxin Tsa1p induces genome instability through activation of the DNA damage checkpoint and elevation of dNTP levels.

PMID:22842922

Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress.

PMID:24022485

Peroxiredoxin chaperone activity is critical for protein homeostasis in zinc-deficient yeast.

PMID:27634403

Redox-dependent Regulation of Gluconeogenesis by a Novel Mechanism Mediated by a Peroxidatic Cysteine of Peroxiredoxin.

PMID:37968396

The social and structural architecture of the yeast protein interactome.

PMID:7961686

Thioredoxin-dependent peroxide reductase from yeast.

PMID:8344960

Cloning, sequencing, and mutation of thiol-specific antioxidant gene of Saccharomyces cerevisiae.

PMID:9799566

Thermosensitive phenotype of yeast mutant lacking thioredoxin peroxidase.

file:yeast/TSA1/TSA1-deep-research-falcon.md

Falcon deep research on TSA1 (Edison Scientific Literature)

Tsa1 is the major cytosolic typical 2-Cys peroxiredoxin of budding yeast, with peroxidatic Cys48 (CP) and resolving Cys171 (CR) forming an inter-subunit disulfide during the catalytic cycle.

"The research target is the budding yeast (*Saccharomyces cerevisiae*) protein **Tsa1**, consistently described across primary and review sources as the **major cytosolic typical 2‑Cys peroxiredoxin** (Prx) with canonical active-site cysteines **Cys48 (peroxidatic, CP)** and **Cys171 (resolving, CR)**."
Tsa1 is a thioredoxin-dependent peroxidase that reduces H2O2 and organic hydroperoxides; oxidized Tsa1 disulfide is reduced by the cytosolic thioredoxin system (Trx1/Trx2, recycled by thioredoxin reductase using NADPH).

"Tsa1 reduces **H2O2 and organic hydroperoxides**; in typical 2‑Cys Prxs this occurs via CP attack on the peroxide bond, generating water/alcohol products."
Reduction of oxidized Tsa1 is driven primarily by the cytosolic thioredoxin system.

"Reduction of oxidized Tsa1 is primarily driven by the **cytosolic thioredoxin system**: **Trx1/Trx2** reduce the Tsa1 disulfide, and oxidized thioredoxin is recycled by **thioredoxin reductase** using **NADPH**."
Because of high abundance (~1% of cytosolic protein, ~10-50 uM) and fast kinetics, peroxiredoxins decompose the majority of cellular hydroperoxides.

"Reviews also emphasize that Prxs decompose **>90% of cellular hydroperoxides** and can detoxify up to **~90% of cytosolic H2O2** due to abundance and fast reaction rates (general Prx second-order rates ~10^6–10^8 M−1 s−1)."
At high oxidant loads the peroxidatic cysteine hyperoxidizes (sulfinic/sulfonic), inactivating peroxidase activity and promoting higher-order oligomers with molecular chaperone/holdase activity.

"At higher oxidant loads, Tsa1’s peroxidatic cysteine can become **hyperoxidized** (sulfinic/sulfonic states), which **inactivates peroxidase activity** and promotes formation of **higher-order oligomers** associated with **molecular chaperone/holdase activity**."
Increased Tsa1 dosage extends replicative lifespan in a manner dependent on Hsp70 (Ssa1/2) and partly Hsp104, and requires reduction of hyperoxidized Tsa1 by sulfiredoxin Srx1, supporting a role as a stress-activated chaperone adaptor that recruits protein quality control machinery.

"Increased dosage of Tsa1 extends replicative lifespan in a manner dependent on **Hsp70 (Ssa1/2)** and partly on **Hsp104**, and requires reduction of hyperoxidized Tsa1 by **sulfiredoxin Srx1** for aggregate clearance/disaggregation."
Tsa1 contributes to stress resistance and longevity partly through redox repression of the Ras-cAMP-PKA pathway, oxidizing a conserved cysteine (Cys243) of the PKA catalytic subunit and blocking activation-loop Thr241 phosphorylation.

"Specifically, Tsa1 represses the **Ras–cAMP–PKA pathway** by promoting oxidative modifications of PKA catalytic subunits; redox modification of a conserved cysteine (reported as **Cys243** in the catalytic subunit) inhibits phosphorylation of **Thr241** in the activation loop and reduces kinase activity."
tsa1-null cells show a mutator phenotype (~5-10-fold increased mutation rates); Tsa1 is the strongest suppressor of mutations among oxidant-defense genes in yeast, with genome protection involving both peroxidase-dependent and peroxidase-independent (redox-network) facets.

"Yeast lacking TSA1 show a **mutator phenotype**, with reported **~5–10‑fold increased mutation rates**, and Tsa1 is described as the strongest suppressor of mutations among oxidant-defense genes in yeast."
Tsa1 is the major cytosolic peroxiredoxin and is additionally found associated with translating ribosomes, placing it near nascent polypeptides for translation-linked proteostasis.

"In addition to a free cytosolic pool, one source reports Tsa1 is also found **associated with translating ribosomes**, suggesting functional proximity to nascent polypeptides and translation-linked proteostasis."
Tsa1 forms widespread covalent mixed-disulfide intermediates (TIMDIs, "peroxiredoxinylation") with client proteins via the peroxidatic cysteine; thioredoxins directly remove these adducts, extending the thioredoxin-peroxiredoxin system into a proteome-thiol buffering circuit.

"A 2023 bioRxiv preprint reports that Tsa1 forms widespread covalent mixed disulfide intermediates with cellular proteins, termed **Tsa1-Induced Mixed Disulfide Intermediates (TIMDIs)**, and frames this as a bona fide redox-linked post-translational modification termed **peroxiredoxinylation**."

Deep Research

Falcon

(TSA1-deep-research-falcon.md)

Research Report: Functional Annotation of *Saccharomyces cerevisiae* **TSA1** (UniProt **P34760**, ORF **YML028W**) Falcon Edison Scientific Literature 31 citations 2 artifacts 2026-05-31T17:49:37.979622

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000032 Figure 2 shows the induction of Tsa1-Induced Mixed Disulfide Intermediates (TIMDIs) in response to hydrogen peroxide. Panel (a) dis (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.

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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 Saccharomyces cerevisiae TSA1 (UniProt P34760, ORF YML028W)

0) Target identity verification (critical disambiguation)

The research target is the budding yeast (Saccharomyces cerevisiae) protein Tsa1, consistently described across primary and review sources as the major cytosolic typical 2‑Cys peroxiredoxin (Prx) with canonical active-site cysteines Cys48 (peroxidatic, CP) and Cys171 (resolving, CR). (west2018piecingtogetherhow pages 1-3, hanzen2017proteostasisandaging pages 20-23)

1) Key concepts, definitions, and current mechanistic understanding

1.1 Peroxiredoxins and “typical 2‑Cys” mechanism

Peroxiredoxins (Prxs) are thiol-based peroxidases that reduce peroxides using a conserved peroxidatic cysteine (CP). In typical 2‑Cys Prxs, peroxide oxidizes CP to CP‑SOH, which then condenses with a resolving cysteine (CR) on the partner subunit to form an inter‑subunit disulfide; this disulfide is reduced to complete the catalytic cycle. (west2018piecingtogetherhow pages 1-3, santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4)

In yeast Tsa1 specifically, the key catalytic residues are Cys48 (CP) and Cys171 (CR). (hanzen2017proteostasisandaging pages 20-23, west2018piecingtogetherhow pages 1-3)

1.2 Substrates and reducing partners (thioredoxin system)

Tsa1 reduces H2O2 and organic hydroperoxides; in typical 2‑Cys Prxs this occurs via CP attack on the peroxide bond, generating water/alcohol products. (west2018piecingtogetherhow pages 1-3, santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4)

Reduction of oxidized Tsa1 is primarily driven by the cytosolic thioredoxin system: Trx1/Trx2 reduce the Tsa1 disulfide, and oxidized thioredoxin is recycled by thioredoxin reductase using NADPH. (west2018piecingtogetherhow pages 1-3, santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)

1.3 Hyperoxidation, “floodgate” behavior, and the chaperone switch

At higher oxidant loads, Tsa1’s peroxidatic cysteine can become hyperoxidized (sulfinic/sulfonic states), which inactivates peroxidase activity and promotes formation of higher-order oligomers associated with molecular chaperone/holdase activity. (west2018piecingtogetherhow pages 1-3, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15, ohira2024theperoxiredoxintsa1 pages 1-5)

1.4 Abundance and why peroxiredoxins dominate peroxide metabolism

Despite lower catalytic efficiency than catalases/GPxs on a per-molecule basis, Prxs are highly abundant. Reported values for Tsa1 include ~1% of cytosolic protein and ~10–50 µM cytosolic concentration. (west2018piecingtogetherhow pages 1-3)

Reviews also emphasize that Prxs decompose >90% of cellular hydroperoxides and can detoxify up to ~90% of cytosolic H2O2 due to abundance and fast reaction rates (general Prx second-order rates ~10^6–10^8 M−1 s−1). (santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4, seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)

2) Primary function: enzymology and substrate specificity

2.1 Enzymatic role

Tsa1’s primary biochemical role is as a thioredoxin-dependent peroxidase that reduces peroxides (especially H2O2) via the typical 2‑Cys Prx redox cycle centered on Cys48/Cys171. (west2018piecingtogetherhow pages 1-3, hanzen2017proteostasisandaging pages 20-23, roger2020peroxiredoxinpromoteslongevity pages 1-2)

2.2 Reaction-cycle integration with proteome redox buffering

Beyond detoxification, Tsa1 can enter redox-linked states that influence cellular thiol chemistry:

Mixed-disulfide intermediates between Tsa1 and target proteins can form via the peroxidatic cysteine, and thioredoxins directly remove these Tsa1–protein adducts. (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)

This provides a mechanistic route for Tsa1 to act not only as a sink for H2O2 but also as a regulator/buffer of protein thiol redox state. (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)

3) Subcellular localization and where function is executed

Tsa1 is repeatedly described as the major cytosolic peroxiredoxin in yeast. (hanzen2016lifespancontrolby pages 1-3, west2018piecingtogetherhow pages 1-3)

In addition to a free cytosolic pool, one source reports Tsa1 is also found associated with translating ribosomes, suggesting functional proximity to nascent polypeptides and translation-linked proteostasis. (hanzen2017proteostasisandaging pages 20-23)

4) Biological processes and pathways involving Tsa1

4.1 H2O2 signaling and nutrient signaling integration (Ras–cAMP–PKA)

A major mechanistic insight from authoritative work is that Tsa1’s contribution to stress resistance and longevity can occur not simply by scavenging H2O2, but through redox modulation of nutrient signaling.

Specifically, Tsa1 represses the Ras–cAMP–PKA pathway by promoting oxidative modifications of PKA catalytic subunits; redox modification of a conserved cysteine (reported as Cys243 in the catalytic subunit) inhibits phosphorylation of Thr241 in the activation loop and reduces kinase activity. (roger2020peroxiredoxinpromoteslongevity pages 1-2, roger2020peroxiredoxinpromoteslongevity pages 10-11)

4.2 Proteostasis: redox-dependent recruitment of chaperones to aggregates

A high-impact model places Tsa1 at the interface of redox and proteostasis:

Increased dosage of Tsa1 extends replicative lifespan in a manner dependent on Hsp70 (Ssa1/2) and partly on Hsp104, and requires reduction of hyperoxidized Tsa1 by sulfiredoxin Srx1 for aggregate clearance/disaggregation. (hanzen2016lifespancontrolby pages 1-3, hanzen2016lifespancontrolby pages 8-9)

This supports a functional switch where hyperoxidized Tsa1 acts as a stress-activated chaperone adaptor to recruit the protein quality control machinery. (hanzen2016lifespancontrolby pages 1-3, hanzen2017proteostasisandaging pages 50-54)

4.3 Genome stability (mutator suppression)

Yeast lacking TSA1 show a mutator phenotype, with reported ~5–10‑fold increased mutation rates, and Tsa1 is described as the strongest suppressor of mutations among oxidant-defense genes in yeast. (west2018piecingtogetherhow pages 1-3)

Mechanistic interpretation is nuanced: mutation of the peroxidatic cysteine disrupts mutation suppression, while some resolving-cysteine mutants can still suppress mutation rates, implying that genome protection may involve peroxidase-independent facets (e.g., redox network effects and thioredoxin availability). (west2018piecingtogetherhow pages 6-9)

5) Recent developments and latest research (prioritize 2023–2024)

5.1 2023: “Peroxiredoxinylation” (Tsa1-induced mixed disulfides) as a proteome-wide redox buffer

A 2023 bioRxiv preprint reports that Tsa1 forms widespread covalent mixed disulfide intermediates with cellular proteins, termed Tsa1-Induced Mixed Disulfide Intermediates (TIMDIs), and frames this as a bona fide redox-linked post-translational modification termed peroxiredoxinylation. (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15, seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)

Key quantitative findings include:

Under low H2O2 stress, TIMDIs rise to >20% of the Tsa1 pool; figure quantification indicates ~25% at 0.125 mM H2O2. (seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8, seisenbacher2023peroxiredoxinylationbuffersthe media ddb673cf)
In trx1Δ trx2Δ cells, TIMDIs can reach ~60% of the Tsa1 pool, consistent with thioredoxins being key “erasers” of these adducts. (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)
Proteomics identified 211 interactors with WT Tsa1 versus 599 with the C171S “trap” mutant, with a large fraction of redox-sensitive interactions. (seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8)

Functionally, the authors propose peroxiredoxinylation buffers proteome redox state and contributes to stress resistance; thioredoxins directly remove Tsa1-formed mixed disulfides, extending the thioredoxin–peroxiredoxin system into a proteome-thiol buffering circuit. (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)

5.2 2024: Tsa1 stabilizes the rDNA locus to extend lifespan

A 2024 bioRxiv preprint links Tsa1 to stability of the ribosomal DNA (rDNA) repeat array (∼150 copies). Tsa1 deficiency reduces rDNA replication initiation and increases recombination frequency, increases transcription from E‑pro toward the replication fork barrier, and is associated with shortened lifespan; importantly, rDNA instability and lifespan defects are largely suppressed by fob1 mutation. (ohira2024theperoxiredoxintsa1 pages 1-5)

This study integrates Tsa1’s “nonperoxidase” functions with a specific chromosomal maintenance outcome, suggesting Tsa1 participates in rDNA homeostasis under replication fork arrest conditions. (ohira2024theperoxiredoxintsa1 pages 1-5)

5.3 2024: Peroxiredoxin urmylation context (thesis-level work)

A 2024 doctoral dissertation explicitly addresses “peroxiredoxin urmylation” in yeast and includes a section on “Peroxiredoxin Tsa1 … search for additional Urm1 targets,” indicating active investigation of Tsa1 in the Urm1 conjugation landscape, though the accessible thesis excerpts do not provide direct quantitative results for Tsa1 modification. (brachmann2024strukturelleundredoxbasierte pages 1-6)

6) Current applications and real-world implementations

6.1 Industrial yeast robustness (stress tolerance, biomass propagation)

In wine yeast / industrial propagation contexts, deletion of TSA1 affects growth and stress physiology in molasses-based biomass propagation and alters carbohydrate storage metabolites:

TSA1 deletion diminishes growth in molasses and triggers metabolic changes impacting trehalose/glycogen accumulation. (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)

These observations support the practical view of Tsa1 as a target for improving industrial strain robustness and stress performance, although strain-background dependence is expected. (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)

6.2 Conceptual translational value

Tsa1 is orthologous to mammalian Prdx1-like proteins and is frequently used as a tractable model for redox signaling/proteostasis/genome stability, but the direct “real-world” implementations of TSA1 itself are largely in yeast biotechnology rather than clinical domains. (west2018piecingtogetherhow pages 1-3, seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)

7) Expert opinions and authoritative synthesis (what leading sources emphasize)

7.1 Multifunctionality (“moonlighting”) and state switching

Multiple authoritative sources converge on the view that typical 2‑Cys peroxiredoxins—especially Tsa1—are multifunctional: they couple peroxide detoxification, redox signaling, and conditional chaperone activity via reversible cysteine chemistry and oligomerization state changes. (west2018piecingtogetherhow pages 1-3, hanzen2016lifespancontrolby pages 1-3, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)

7.2 Genome stability remains mechanistically complex

A key expert-level message from genomic stability-focused review is that Tsa1’s mutation-suppression may not require full canonical peroxidase catalysis, and may involve redox-network effects such as thioredoxin sequestration and impacts on downstream thioredoxin clients (e.g., ribonucleotide reductase). (west2018piecingtogetherhow pages 6-9, west2018piecingtogetherhow pages 1-3)

8) Key statistics and data points (curated)

Localization/abundance: Cytosolic; ~1% of cytosolic protein; ~10–50 µM (west2018piecingtogetherhow pages 1-3)
Mutation phenotype: tsa1Δ mutation rates ~5–10× higher (west2018piecingtogetherhow pages 1-3)
Peroxiredoxinylation magnitude: TIMDIs >20% of Tsa1 pool under low H2O2; ~25% at 0.125 mM H2O2 (seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8, seisenbacher2023peroxiredoxinylationbuffersthe media ddb673cf)
Thioredoxin dependence: TIMDIs rise to ~60% of Tsa1 pool in trx1Δ trx2Δ (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)
Interactome breadth (TIMDI trapping): 211 WT vs 599 C171S interactors (seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8)
Longevity: Tsa1 overexpression increases lifespan by ~40% (roger2020peroxiredoxinpromoteslongevity pages 1-2)
Stress-dependent interaction change: Tsa1 co-purification with PKA catalytic subunit Tpk1 decreases after 0.4 mM (p=0.00012) and 0.8 mM (p=0.00016) H2O2 (roger2019peroxiredoxinpromoteslongevity pages 44-51)

9) Evidence map (compact summary table)

The table below consolidates key functional-annotation points with supporting sources and quantitative anchors.

Functional aspect	Key findings	Representative evidence with year and URL
Identity / aliases	• TSA1 / YML028W in Saccharomyces cerevisiae encodes the major cytosolic typical 2-Cys peroxiredoxin • Historical aliases include thiol-specific antioxidant protein 1, thioredoxin peroxidase, and cytoplasmic thiol peroxidase • Orthologous to mammalian PRDX1/Prdx1-like enzymes (santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4, west2018piecingtogetherhow pages 1-3, hanzen2016lifespancontrolby pages 1-3)	2018 West et al., Antioxidants — https://doi.org/10.3390/antiox7120177 (west2018piecingtogetherhow pages 1-3) ; 2017 Santos et al. — https://doi.org/10.5772/intechopen.70401 (santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4)
Enzymatic reaction	• Functions as a thioredoxin-dependent peroxidase reducing H2O2 and hydroperoxides to water/alcohol • Peroxidatic Cys attacks peroxide, forming Cys-SOH; typical 2-Cys cycle proceeds via inter-subunit disulfide • Peroxiredoxins can remove >90% of cytosolic/cellular hydroperoxides because of high abundance and fast kinetics (~10^6–10^8 M^-1 s^-1 for Prxs generally) (santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4, west2018piecingtogetherhow pages 1-3, seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)	2018 West et al. — https://doi.org/10.3390/antiox7120177 (west2018piecingtogetherhow pages 1-3) ; 2017 Santos et al. — https://doi.org/10.5772/intechopen.70401 (santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4) ; 2023 Seisenbacher et al. — https://doi.org/10.1101/2023.12.13.571451 (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)
Catalytic residues	• Cys48 is the peroxidatic cysteine (CP); Cys171 is the resolving cysteine (CR) • C48 is essential for peroxide reaction, H2O2 resistance, and many redox-regulatory outputs • Hyperoxidation of C48 to sulfinic/sulfonic states inactivates peroxidase function and promotes noncanonical activities (hanzen2017proteostasisandaging pages 20-23, west2018piecingtogetherhow pages 1-3, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)	2017 Hanzén thesis — no URL available in source set (hanzen2017proteostasisandaging pages 20-23) ; 2018 West et al. — https://doi.org/10.3390/antiox7120177 (west2018piecingtogetherhow pages 1-3) ; 2023 Seisenbacher et al. — https://doi.org/10.1101/2023.12.13.571451 (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)
Redox cycle partners	• Oxidized Tsa1 disulfide is reduced by thioredoxins Trx1/Trx2; oxidized thioredoxin is recycled by thioredoxin reductase (Trr) using NADPH • Tsa1 is a major substrate of the cytosolic thioredoxin system • Thioredoxins also directly resolve Tsa1 mixed-disulfide adducts with client proteins (west2018piecingtogetherhow pages 1-3, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15, west2018piecingtogetherhow pages 6-9)	2018 West et al. — https://doi.org/10.3390/antiox7120177 (west2018piecingtogetherhow pages 1-3) ; 2023 Seisenbacher et al. — https://doi.org/10.1101/2023.12.13.571451 (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)
Localization	• Tsa1 is the major cytosolic peroxiredoxin in budding yeast • Also reported as present associated with translating ribosomes in addition to free cytosolic pool • Cytosolic abundance estimated at ~10–50 µM and about ~1% of cytosolic protein (hanzen2017proteostasisandaging pages 20-23, west2018piecingtogetherhow pages 1-3, hanzen2016lifespancontrolby pages 1-3)	2018 West et al. — https://doi.org/10.3390/antiox7120177 (west2018piecingtogetherhow pages 1-3) ; 2016 Hanzén et al., Cell — https://doi.org/10.1016/j.cell.2016.05.006 (hanzen2016lifespancontrolby pages 1-3)
Redox signaling targets / pathways	• Tsa1 mediates redox repression of Ras–cAMP–PKA signaling, not just peroxide detoxification • Promotes oxidative modification of PKA catalytic subunits; Cys243 redox control blocks Thr241 activation-loop phosphorylation • This mechanism explains improved H2O2 resistance and longevity control beyond scavenging alone (roger2020peroxiredoxinpromoteslongevity pages 1-2, roger2020peroxiredoxinpromoteslongevity pages 10-11, roger2019peroxiredoxinpromoteslongevity pages 44-51)	2020 Roger et al., eLife — https://doi.org/10.7554/elife.60346 (roger2020peroxiredoxinpromoteslongevity pages 1-2) ; 2019 preprint data underlying 2020 paper — https://doi.org/10.1101/676270 (roger2019peroxiredoxinpromoteslongevity pages 44-51)
Proteostasis / chaperone switch	• Hyperoxidized Tsa1 forms higher-order assemblies and switches from peroxidase to molecular chaperone / holdase • Recruits Hsp70 (Ssa1/2) and Hsp104 to oxidatively damaged aggregates; Tsa1 appears early at aggregates • Mild Tsa1 overexpression extends lifespan by ~40% in yeast; Tsa1 overproduction lowers age-related aggregate burden without increasing scavenging (hanzen2017proteostasisandaging pages 50-54, roger2020peroxiredoxinpromoteslongevity pages 1-2, hanzen2016lifespancontrolby pages 1-3, hanzen2016lifespancontrolby pages 8-9)	2016 Hanzén et al., Cell — https://doi.org/10.1016/j.cell.2016.05.006 (hanzen2016lifespancontrolby pages 1-3) ; 2020 Roger et al., eLife — https://doi.org/10.7554/elife.60346 (roger2020peroxiredoxinpromoteslongevity pages 1-2)
Genome stability / rDNA	• tsa1Δ cells show a ~5–10-fold increase in mutation rates, establishing Tsa1 as a major anti-mutator oxidant-defense factor • Tsa1 suppresses genome instability partly through C48-dependent functions; full canonical peroxidase activity may not be strictly required for mutation suppression • 2024 work links Tsa1 to rDNA stability: tsa1Δ causes reduced rDNA origin firing, increased recombination, increased E-pro transcription, and shortened lifespan; many defects are suppressed by fob1 mutation (west2018piecingtogetherhow pages 1-3, west2018piecingtogetherhow pages 6-9, ohira2024theperoxiredoxintsa1 pages 1-5)	2018 West et al. — https://doi.org/10.3390/antiox7120177 (west2018piecingtogetherhow pages 1-3) ; 2024 Ohira et al. — https://doi.org/10.1101/2024.03.14.585068 (ohira2024theperoxiredoxintsa1 pages 1-5)
Peroxiredoxinylation	• 2023–2024 priority finding: Tsa1 forms widespread Tsa1-induced mixed disulfide intermediates (TIMDIs) with client proteins; authors term this peroxiredoxinylation • TIMDIs rise to >20% of the Tsa1 pool under low H2O2 stress and up to ~60% in trx1Δ trx2Δ cells • Proteomics identified 211 WT interactors and 599 C171S interactors; validated targets include Cdc19 and Gnd1; Y78A reduces TIMDI formation (seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8, seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15, seisenbacher2023peroxiredoxinylationbuffersthe pages 4-6, seisenbacher2023peroxiredoxinylationbuffersthe pages 15-17)	2023 Seisenbacher et al. — https://doi.org/10.1101/2023.12.13.571451 (seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8) ; 2023 same study, mechanistic/quantitative pages (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15)
Industrial / real-world applications	• In wine and biomass-propagation strains, TSA1 deletion alters trehalose/glycogen metabolism, stress performance, and fermentation-associated outputs • tsa1Δ reduces growth in molasses and lowers fermentative capacity; it also changes acetic acid/acetaldehyde production • These data support Tsa1 as a target for optimizing industrial yeast robustness, stress tolerance, and biomass production (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)	2020 Garrigós et al., Microorganisms — https://doi.org/10.3390/microorganisms8101537 (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)

Table: This table summarizes the main experimentally supported functional annotation points for yeast TSA1/P34760, emphasizing enzymatic mechanism, localization, signaling, proteostasis, genome stability, and recent 2023–2024 developments. It is useful as a compact evidence map for downstream gene-function annotation.

10) Visual evidence: TIMDI/peroxiredoxinylation induction

Figure evidence supporting stress-induced TIMDI formation and the quantitative ~25% TIMDI fraction at 0.125 mM H2O2 is available from Seisenbacher et al. 2023 Figure 2. (seisenbacher2023peroxiredoxinylationbuffersthe media ddb673cf, seisenbacher2023peroxiredoxinylationbuffersthe media ee1d8fd5)

11) Limitations and evidence-quality notes

Several 2023–2024 findings are currently available as bioRxiv preprints (peroxiredoxinylation; rDNA stability). Their claims are supported by presented experiments but may evolve upon peer review. (seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15, ohira2024theperoxiredoxintsa1 pages 1-5)
The Urm1/urmylation connection to Tsa1 is suggested by a 2024 thesis structure and context but the provided accessible pages do not include direct Tsa1-specific modification data; conclusions are therefore conservative. (brachmann2024strukturelleundredoxbasierte pages 1-6)

Key source URLs and publication dates (selected)

Seisenbacher et al. 2023-12 (bioRxiv): https://doi.org/10.1101/2023.12.13.571451 (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)
Ohira et al. 2024-03 (bioRxiv): https://doi.org/10.1101/2024.03.14.585068 (ohira2024theperoxiredoxintsa1 pages 1-5)
Roger et al. 2020-07 (eLife): https://doi.org/10.7554/elife.60346 (roger2020peroxiredoxinpromoteslongevity pages 1-2)
Hanzén et al. 2016-06 (Cell): https://doi.org/10.1016/j.cell.2016.05.006 (hanzen2016lifespancontrolby pages 1-3)
West et al. 2018-11 (Antioxidants): https://doi.org/10.3390/antiox7120177 (west2018piecingtogetherhow pages 1-3)
Garrigós et al. 2020-10 (Microorganisms): https://doi.org/10.3390/microorganisms8101537 (seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4)

References

(west2018piecingtogetherhow pages 1-3): James D. West, Trevor J. Roston, Joseph B. David, Kristin M. Allan, and Matthew A. Loberg. Piecing together how peroxiredoxins maintain genomic stability. Antioxidants, 7:177, Nov 2018. URL: https://doi.org/10.3390/antiox7120177, doi:10.3390/antiox7120177. This article has 24 citations.
(hanzen2017proteostasisandaging pages 20-23): S Hanzén. Proteostasis and aging in saccharomyces cerevisiae: the role of a peroxiredoxin. Unknown journal, 2017.
(santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4): Melina C. Santos, Carlos A. Breyer, Leonardo Schultz, Karen S. Romanello, Anderson F. Cunha, Carlos A. Tairum Jr, and Marcos Antonio de Oliveira. Saccharomyces cerevisiae peroxiredoxins in biological processes: antioxidant defense, signal transduction, circadian rhythm, and more. ArXiv, Dec 2017. URL: https://doi.org/10.5772/intechopen.70401, doi:10.5772/intechopen.70401. This article has 1 citations.
(seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15): Gerhard Seisenbacher, Zrinka Raguz Nakic, Eva Borràs, Eduard Sabidó, Uwe Sauer, Eulalia de Nadal, and Francesc Posas. Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.571451, doi:10.1101/2023.12.13.571451. This article has 1 citations.
(ohira2024theperoxiredoxintsa1 pages 1-5): Junno Ohira, Mariko Sasaki, and Takehiko Kobayashi. The peroxiredoxin tsa1 extends the lifespan of budding yeast by maintaining the stability of the ribosomal rna gene cluster. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.14.585068, doi:10.1101/2024.03.14.585068. This article has 0 citations.
(seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4): Gerhard Seisenbacher, Zrinka Raguz Nakic, Eva Borràs, Eduard Sabidó, Uwe Sauer, Eulalia de Nadal, and Francesc Posas. Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.571451, doi:10.1101/2023.12.13.571451. This article has 1 citations.
(roger2020peroxiredoxinpromoteslongevity pages 1-2): Friederike Roger, Cecilia Picazo, Wolfgang Reiter, Marouane Libiad, Chikako Asami, Sarah Hanzén, Chunxia Gao, Gilles Lagniel, Niek Welkenhuysen, Jean Labarre, Thomas Nyström, Morten Grøtli, Markus Hartl, Michel B Toledano, and Mikael Molin. Peroxiredoxin promotes longevity and h2o2-resistance in yeast through redox-modulation of protein kinase a. eLife, Jul 2020. URL: https://doi.org/10.7554/elife.60346, doi:10.7554/elife.60346. This article has 41 citations and is from a domain leading peer-reviewed journal.
(hanzen2016lifespancontrolby pages 1-3): Sarah Hanzén, Katarina Vielfort, Junsheng Yang, Friederike Roger, Veronica Andersson, Sara Zamarbide-Forés, Rebecca Andersson, Lisa Malm, Gael Palais, Benoît Biteau, Beidong Liu, Michel B. Toledano, Mikael Molin, and Thomas Nyström. Lifespan control by redox-dependent recruitment of chaperones to misfolded proteins. Cell, 166:140-151, Jun 2016. URL: https://doi.org/10.1016/j.cell.2016.05.006, doi:10.1016/j.cell.2016.05.006. This article has 190 citations and is from a highest quality peer-reviewed journal.
(roger2020peroxiredoxinpromoteslongevity pages 10-11): Friederike Roger, Cecilia Picazo, Wolfgang Reiter, Marouane Libiad, Chikako Asami, Sarah Hanzén, Chunxia Gao, Gilles Lagniel, Niek Welkenhuysen, Jean Labarre, Thomas Nyström, Morten Grøtli, Markus Hartl, Michel B Toledano, and Mikael Molin. Peroxiredoxin promotes longevity and h2o2-resistance in yeast through redox-modulation of protein kinase a. eLife, Jul 2020. URL: https://doi.org/10.7554/elife.60346, doi:10.7554/elife.60346. This article has 41 citations and is from a domain leading peer-reviewed journal.
(hanzen2016lifespancontrolby pages 8-9): Sarah Hanzén, Katarina Vielfort, Junsheng Yang, Friederike Roger, Veronica Andersson, Sara Zamarbide-Forés, Rebecca Andersson, Lisa Malm, Gael Palais, Benoît Biteau, Beidong Liu, Michel B. Toledano, Mikael Molin, and Thomas Nyström. Lifespan control by redox-dependent recruitment of chaperones to misfolded proteins. Cell, 166:140-151, Jun 2016. URL: https://doi.org/10.1016/j.cell.2016.05.006, doi:10.1016/j.cell.2016.05.006. This article has 190 citations and is from a highest quality peer-reviewed journal.
(hanzen2017proteostasisandaging pages 50-54): S Hanzén. Proteostasis and aging in saccharomyces cerevisiae: the role of a peroxiredoxin. Unknown journal, 2017.
(west2018piecingtogetherhow pages 6-9): James D. West, Trevor J. Roston, Joseph B. David, Kristin M. Allan, and Matthew A. Loberg. Piecing together how peroxiredoxins maintain genomic stability. Antioxidants, 7:177, Nov 2018. URL: https://doi.org/10.3390/antiox7120177, doi:10.3390/antiox7120177. This article has 24 citations.
(seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8): Gerhard Seisenbacher, Zrinka Raguz Nakic, Eva Borràs, Eduard Sabidó, Uwe Sauer, Eulalia de Nadal, and Francesc Posas. Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.571451, doi:10.1101/2023.12.13.571451. This article has 1 citations.
(seisenbacher2023peroxiredoxinylationbuffersthe media ddb673cf): Gerhard Seisenbacher, Zrinka Raguz Nakic, Eva Borràs, Eduard Sabidó, Uwe Sauer, Eulalia de Nadal, and Francesc Posas. Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.571451, doi:10.1101/2023.12.13.571451. This article has 1 citations.
(brachmann2024strukturelleundredoxbasierte pages 1-6): C Brachmann. Strukturelle und redox-basierte voraussetzungen für peroxiredoxin-urmylierung in der hefe saccharomyces cerevisiae. Unknown journal, 2024.
(roger2019peroxiredoxinpromoteslongevity pages 44-51): Friederike Roger, Cecilia Picazo, Wolfgang Reiter, Marouane Libiad, Chikako Asami, Sarah Hanzén, Chunxia Gao, Gilles Lagniel, Niek Welkenhuysen, Jean Labarre, Thomas Nyström, Morten Grøtli, Markus Hartl, Michel B. Toledano, and Mikael Molin. Peroxiredoxin promotes longevity and h₂o₂-resistance in yeast through redox-modulation of protein kinase a. Unknown journal, Jun 2019. URL: https://doi.org/10.1101/676270, doi:10.1101/676270.
(seisenbacher2023peroxiredoxinylationbuffersthe pages 4-6): Gerhard Seisenbacher, Zrinka Raguz Nakic, Eva Borràs, Eduard Sabidó, Uwe Sauer, Eulalia de Nadal, and Francesc Posas. Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.571451, doi:10.1101/2023.12.13.571451. This article has 1 citations.
(seisenbacher2023peroxiredoxinylationbuffersthe pages 15-17): Gerhard Seisenbacher, Zrinka Raguz Nakic, Eva Borràs, Eduard Sabidó, Uwe Sauer, Eulalia de Nadal, and Francesc Posas. Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.571451, doi:10.1101/2023.12.13.571451. This article has 1 citations.
(seisenbacher2023peroxiredoxinylationbuffersthe media ee1d8fd5): Gerhard Seisenbacher, Zrinka Raguz Nakic, Eva Borràs, Eduard Sabidó, Uwe Sauer, Eulalia de Nadal, and Francesc Posas. Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.571451, doi:10.1101/2023.12.13.571451. This article has 1 citations.

Artifacts

Edison artifact artifact-00

Citations

west2018piecingtogetherhow pages 1-3
seisenbacher2023peroxiredoxinylationbuffersthe pages 13-15
hanzen2017proteostasisandaging pages 20-23
west2018piecingtogetherhow pages 6-9
seisenbacher2023peroxiredoxinylationbuffersthe pages 6-8
brachmann2024strukturelleundredoxbasierte pages 1-6
seisenbacher2023peroxiredoxinylationbuffersthe pages 1-4
roger2020peroxiredoxinpromoteslongevity pages 1-2
roger2019peroxiredoxinpromoteslongevity pages 44-51
santos2017saccharomycescerevisiaeperoxiredoxins pages 1-4
hanzen2016lifespancontrolby pages 1-3
roger2020peroxiredoxinpromoteslongevity pages 10-11
hanzen2016lifespancontrolby pages 8-9
hanzen2017proteostasisandaging pages 50-54
seisenbacher2023peroxiredoxinylationbuffersthe pages 4-6
seisenbacher2023peroxiredoxinylationbuffersthe pages 15-17
https://doi.org/10.3390/antiox7120177
https://doi.org/10.5772/intechopen.70401
https://doi.org/10.1101/2023.12.13.571451
https://doi.org/10.1016/j.cell.2016.05.006
https://doi.org/10.7554/elife.60346
https://doi.org/10.1101/676270
https://doi.org/10.1101/2024.03.14.585068
https://doi.org/10.3390/microorganisms8101537
https://doi.org/10.3390/antiox7120177,
https://doi.org/10.5772/intechopen.70401,
https://doi.org/10.1101/2023.12.13.571451,
https://doi.org/10.1101/2024.03.14.585068,
https://doi.org/10.7554/elife.60346,
https://doi.org/10.1016/j.cell.2016.05.006,
https://doi.org/10.1101/676270,

📄 View Raw YAML

id: P34760
gene_symbol: TSA1
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  TSA1 encodes the major cytoplasmic thioredoxin peroxidase (peroxiredoxin),
  a dual-function protein that acts as both an antioxidant enzyme and a
  molecular chaperone. As a peroxidase, Tsa1p catalyzes the
  thioredoxin-dependent reduction of hydrogen peroxide and organic
  hydroperoxides, protecting cells against oxidative damage. It also serves
  as a hydrogen peroxide sensor and signal transducer, relaying the H2O2
  signal to the transcription factor Yap1p by inducing intramolecular
  disulfide bond formation that triggers Yap1p nuclear accumulation and
  activation. Under oxidative stress or heat shock, Tsa1p undergoes a
  reversible structural switch from low-molecular-weight peroxidase species to
  high-molecular-weight oligomeric complexes with chaperone holdase activity,
  enhancing resistance to proteotoxic stress. Tsa1p also associates with
  ribosomes as an antioxidant, protects against oxidative damage caused by
  nascent-protein misfolding, and is required for telomere length maintenance.
  Orthologous to human PRDX1/PRDX2.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Tsa1 is the major cytosolic peroxiredoxin of budding yeast; the cytosol is
      where it executes its peroxidase, redox-signaling and chaperone functions.
      Consistent with IDA evidence (PMID:18271751) and falcon synthesis.
    action: ACCEPT
    reason: |-
      Core localization. Tsa1 is one of the most abundant cytosolic proteins and
      acts as the primary cytosolic peroxide sink.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Tsa1 is repeatedly described as the **major cytosolic peroxiredoxin** in yeast.
- 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 true but high-level process for TSA1.
      The more specific child terms (cellular response to oxidative stress,
      hydrogen peroxide catabolic process) better capture the core function.
    action: KEEP_AS_NON_CORE
    reason: |-
      Correct but general parent term; retained as non-core because more specific
      annotations represent the precise antioxidant function.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Tsa1 reduces **H2O2 and organic hydroperoxides**; in typical 2‑Cys Prxs this occurs via CP attack on the peroxide bond, generating water/alcohol products.
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Core molecular function. Tsa1 is a thioredoxin-dependent peroxidase that
      reduces H2O2 and organic hydroperoxides via the typical 2-Cys peroxiredoxin
      cycle (peroxidatic Cys48, resolving Cys171), with the disulfide reduced by
      thioredoxin (Trx1/Trx2). Directly supported by IDA evidence (PMID:7961686).
    action: ACCEPT
    reason: |-
      Defining enzymatic activity of TSA1, well supported across phylogenetic
      inference, biochemistry and structural data.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Tsa1’s primary biochemical role is as a **thioredoxin-dependent peroxidase** that reduces peroxides (especially **H2O2**) via the typical 2‑Cys Prx redox cycle centered on **Cys48/Cys171**.
- 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 abundant cytosolic peroxiredoxin,
      Tsa1 is responsible for decomposing the bulk of cellular H2O2.
    action: ACCEPT
    reason: |-
      Direct downstream process of the peroxidase activity; central to TSA1
      function.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Reviews also emphasize that Prxs decompose **>90% of cellular hydroperoxides** and can detoxify up to **~90% of cytosolic H2O2** due to abundance and fast reaction rates (general Prx second-order rates ~10^6–10^8 M−1 s−1).
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: |-
      Core process. Beyond peroxide scavenging, Tsa1 buffers the redox state of
      the proteome by forming and resolving mixed disulfides with client proteins
      (via thioredoxin), maintaining cellular thiol redox balance.
    action: ACCEPT
    reason: |-
      Well supported as a core function; Tsa1 is a central node of the cytosolic
      thioredoxin-peroxiredoxin redox network.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        This provides a mechanistic route for Tsa1 to act not only as a sink for H2O2 but also as a **regulator/buffer of protein thiol redox state**.
- term:
    id: GO:0098869
    label: cellular oxidant detoxification
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Manual review: cellular oxidant detoxification may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0004601
    label: peroxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: |-
      Peroxidase activity is correct but is a general parent of the more specific
      thioredoxin-dependent peroxiredoxin activity that defines TSA1.
    action: KEEP_AS_NON_CORE
    reason: |-
      True but general; the specific term thioredoxin-dependent peroxiredoxin
      activity (GO:0140824) better represents the core function. (Note:
      GO_REF:0000043 SPKW keyword annotations are being retired upstream.)
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Tsa1’s primary biochemical role is as a **thioredoxin-dependent peroxidase** that reduces peroxides (especially **H2O2**) via the typical 2‑Cys Prx redox cycle centered on **Cys48/Cys171**.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Manual review: cytoplasm is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0016209
    label: antioxidant activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Manual review: antioxidant activity may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Manual review: oxidoreductase activity may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: |-
      Core process. Tsa1 is the principal cytosolic effector of the cellular
      response to oxidative stress, both detoxifying peroxides and relaying H2O2
      signals (e.g. to Yap1 and via redox modulation of PKA). Also supported by
      multiple IDA/IMP annotations.
    action: ACCEPT
    reason: |-
      Central process for TSA1; redundantly supported by experimental evidence.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        A major mechanistic insight from authoritative work is that Tsa1’s contribution to stress resistance and longevity can occur **not simply by scavenging H2O2**, but through **redox modulation of nutrient signaling**.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: |-
      Tsa1 contributes to the heat-stress response via its chaperone/holdase
      switch: heat shock drives formation of high-MW oligomers that bind
      misfolded proteins and enhance heat-shock resistance (PMID:15163410).
    action: KEEP_AS_NON_CORE
    reason: |-
      Genuine but downstream of the chaperone moonlighting function; the holdase
      MF and protein folding process capture the mechanism more directly.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        At higher oxidant loads, Tsa1’s peroxidatic cysteine can become **hyperoxidized** (sulfinic/sulfonic states), which **inactivates peroxidase activity** and promotes formation of **higher-order oligomers** associated with **molecular chaperone/holdase activity**.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'Manual review: cell redox homeostasis is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'Manual review: protein stabilization may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0051920
    label: peroxiredoxin activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: |-
      Peroxiredoxin activity is correct for TSA1, the major 2-Cys peroxiredoxin
      of yeast. The thioredoxin-dependent child term (GO:0140824) is the most
      precise MF.
    action: ACCEPT
    reason: |-
      Accurate MF supported by domain/family (AhpC/Prx1) inference and direct
      biochemistry.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        The research target is the budding yeast (*Saccharomyces cerevisiae*) protein **Tsa1**, consistently described across primary and review sources as the **major cytosolic typical 2‑Cys peroxiredoxin** (Prx) with canonical active-site cysteines **Cys48 (peroxidatic, CP)** and **Cys171 (resolving, CR)**.
- term:
    id: GO:0140824
    label: thioredoxin-dependent peroxiredoxin activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: |-
      This is the most precise molecular function term for TSA1: catalysis of
      hydroperoxide reduction using thioredoxin as the electron donor. Matches
      the experimentally characterized thioredoxin-coupled peroxidase activity
      (PMID:7961686, PMID:9888818) and is selected as the core MF.
    action: ACCEPT
    reason: |-
      Most specific and accurate MF term; designated the core molecular function.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Reduction of oxidized Tsa1 is primarily driven by the **cytosolic thioredoxin system**: **Trx1/Trx2** reduce the Tsa1 disulfide, and oxidized thioredoxin is recycled by **thioredoxin reductase** using **NADPH**.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16272220
  review:
    summary: |-
      Generic protein-binding annotation. Tsa1 does form extensive (often
      transient, redox-based) interactions with client proteins - it forms
      mixed-disulfide intermediates (peroxiredoxinylation) with hundreds of
      targets - but the bare "protein binding" term is uninformative and these
      interactions are better captured by the redox/chaperone functions.
    action: MARK_AS_OVER_ANNOTATED
    reason: |-
      Uninformative generic binding term; the underlying interactions reflect
      redox-relay/chaperone biology better described by specific MF terms.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        A 2023 bioRxiv preprint reports that Tsa1 forms widespread covalent mixed disulfide intermediates with cellular proteins, termed **Tsa1-Induced Mixed Disulfide Intermediates (TIMDIs)**, and frames this as a bona fide redox-linked post-translational modification termed **peroxiredoxinylation**.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554755
  review:
    summary: 'Manual review: protein binding is too generic or over-extended for TSA1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18719252
  review:
    summary: 'Manual review: protein binding is too generic or over-extended for TSA1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37968396
  review:
    summary: 'Manual review: protein binding is too generic or over-extended for TSA1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
    id: GO:0019207
    label: kinase regulator activity
  evidence_type: IMP
  original_reference_id: PMID:27634403
  review:
    summary: |-
      Tsa1 directly regulates the metabolic kinase Pyk1 (pyruvate kinase /
      Cdc19): it physically interacts with and suppresses Pyk1 activity via a
      peroxidatic-cysteine (Cys48)-dependent mechanism, and these interactions
      are augmented during the glycolysis-to-gluconeogenesis shift (PMID:27634403,
      Irokawa et al. 2016). This is a genuine but specialized, non-peroxidase
      target-modulator role distinct from the core peroxidase function. (Note: a
      separate, mechanistically distinct redox repression of the Ras-cAMP-PKA
      pathway is reported in Roger et al. 2020, eLife, which is not part of this
      GOA annotation.)
    action: KEEP_AS_NON_CORE
    reason: |-
      Real direct kinase-regulation function (suppression of pyruvate kinase
      Pyk1), but peripheral to the core antioxidant/chaperone activities.
    supported_by:
    - reference_id: PMID:27634403
      supporting_text: |-
        We found that the suppression of pyruvate kinase (Pyk1) via the interaction with Tsa1 contributes in part to gluconeogenic enhancement.
    - reference_id: PMID:27634403
      supporting_text: |-
        a peroxidatic cysteine in the catalytic center of Tsa1 played an important role in the physical Tsa1-Pyk1 interactions.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:22842922
  review:
    summary: |-
      Cytoplasmic localization, consistent with Tsa1 being the major cytosolic
      peroxiredoxin. Redundant with more precise cytosol (GO:0005829) annotations.
    action: ACCEPT
    reason: |-
      Correct localization; the cytosol child term is preferred but cytoplasm
      is accurate.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Tsa1 is repeatedly described as the **major cytosolic peroxiredoxin** in yeast.
- term:
    id: GO:0006111
    label: regulation of gluconeogenesis
  evidence_type: IMP
  original_reference_id: PMID:27634403
  review:
    summary: |-
      Tsa1 promotes efficient gluconeogenic flux via a direct,
      peroxidatic-cysteine (Cys48)-dependent physical interaction with and
      suppression of pyruvate kinase (Pyk1); the Tsa1-Pyk1 interaction is
      augmented during the glycolysis-to-gluconeogenesis shift (PMID:27634403,
      Irokawa et al. 2016). A specialized, context-specific metabolic output
      rather than a core function.
    action: KEEP_AS_NON_CORE
    reason: |-
      Genuine but peripheral metabolic regulation arising from direct
      suppression of pyruvate kinase (Pyk1), not from PKA redox signaling.
    supported_by:
    - reference_id: PMID:27634403
      supporting_text: |-
        we discovered that Tsa1, a major peroxiredoxin of budding yeast cells, is required for the efficient flux of gluconeogenesis.
    - reference_id: PMID:27634403
      supporting_text: |-
        We found that the suppression of pyruvate kinase (Pyk1) via the interaction with Tsa1 contributes in part to gluconeogenic enhancement.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:15163410
  review:
    summary: |-
      Core moonlighting process. Upon oxidative/heat stress Tsa1 switches to a
      high-MW chaperone (holdase) that assists protein folding/prevents
      aggregation (PMID:15163410). Selected as one of the core functions.
    action: ACCEPT
    reason: |-
      Well-supported chaperone function central to TSA1's dual-function biology.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        At higher oxidant loads, Tsa1’s peroxidatic cysteine can become **hyperoxidized** (sulfinic/sulfonic states), which **inactivates peroxidase activity** and promotes formation of **higher-order oligomers** associated with **molecular chaperone/holdase activity**.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:16251355
  review:
    summary: 'Manual review: protein folding is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IDA
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: cellular response to oxidative stress is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: cellular response to heat may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:15163410
  review:
    summary: |-
      Tsa1's holdase activity involves binding unfolded/misfolded proteins. The
      activity-style term protein folding chaperone (GO:0044183) is more
      informative than the simple binding term for this moonlighting function.
    action: MODIFY
    reason: |-
      Replace with the more specific chaperone activity term; both are MF so this
      is a same-aspect refinement, not a cross-aspect change.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        This supports a functional switch where hyperoxidized Tsa1 acts as a **stress-activated chaperone adaptor** to recruit the protein quality control machinery.
- term:
    id: GO:0072721
    label: cellular response to dithiothreitol
  evidence_type: IMP
  original_reference_id: PMID:16251355
  review:
    summary: 'Manual review: cellular response to dithiothreitol may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: protein folding is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: cellular response to heat may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: identical protein binding is too generic or over-extended for TSA1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Marked over-annotated because more specific terms capture the biology more accurately.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: cell redox homeostasis is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: protein stabilization may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: unfolded protein binding is better represented by a more specific replacement term for TSA1.'
    action: MODIFY
    reason: Modified to align with current curation guidance and improve term specificity.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0051258
    label: protein polymerization
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: protein polymerization may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0071447
    label: cellular response to hydroperoxide
  evidence_type: IMP
  original_reference_id: PMID:15163410
  review:
    summary: 'Manual review: cellular response to hydroperoxide may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:24022485
  review:
    summary: 'Manual review: protein folding is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0000077
    label: DNA damage checkpoint signaling
  evidence_type: IGI
  original_reference_id: PMID:19851444
  review:
    summary: 'Manual review: DNA damage checkpoint signaling may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10681558
  review:
    summary: 'Manual review: cytoplasm is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:8344960
  review:
    summary: 'Manual review: cytoplasm is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:18271751
  review:
    summary: 'Manual review: cytosol is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IDA
  original_reference_id: PMID:7961686
  review:
    summary: 'Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IMP
  original_reference_id: PMID:7961686
  review:
    summary: 'Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IDA
  original_reference_id: PMID:9799566
  review:
    summary: 'Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0008379
    label: thioredoxin peroxidase activity
  evidence_type: IMP
  original_reference_id: PMID:9799566
  review:
    summary: 'Manual review: thioredoxin peroxidase activity is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0033194
    label: response to hydroperoxide
  evidence_type: IMP
  original_reference_id: PMID:15210711
  review:
    summary: 'Manual review: response to hydroperoxide may be context-dependent or peripheral for TSA1.'
    action: KEEP_AS_NON_CORE
    reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IGI
  original_reference_id: PMID:15051715
  review:
    summary: 'Manual review: cellular response to oxidative stress is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:18271751
  review:
    summary: 'Manual review: cellular response to oxidative stress is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IDA
  original_reference_id: PMID:8344960
  review:
    summary: 'Manual review: cellular response to oxidative stress is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:8344960
  review:
    summary: 'Manual review: cellular response to oxidative stress is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0042262
    label: DNA protection
  evidence_type: IMP
  original_reference_id: PMID:19543365
  review:
    summary: |-
      Tsa1 is the strongest anti-mutator among yeast oxidant-defense genes;
      tsa1-null cells show a ~5-10-fold increased mutation rate and genome
      instability. This genome-protective role is partly peroxidase-dependent
      and partly via redox-network effects (e.g. thioredoxin/RNR), making it an
      important but non-core, indirect consequence of the antioxidant function.
    action: KEEP_AS_NON_CORE
    reason: |-
      Well-documented but downstream/indirect protective effect rather than a
      direct molecular function of Tsa1 on DNA.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        Yeast lacking TSA1 show a **mutator phenotype**, with reported **~5–10‑fold increased mutation rates**, and Tsa1 is described as the strongest suppressor of mutations among oxidant-defense genes in yeast.
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IDA
  original_reference_id: PMID:18271751
  review:
    summary: |-
      Tsa1 associates with translating ribosomes, acting as a ribosome-associated
      antioxidant that protects nascent polypeptides from oxidative damage and
      misfolding (PMID:18271751). A specialized localization-linked function.
    action: KEEP_AS_NON_CORE
    reason: |-
      Genuine ribosome-associated antioxidant role, but ancillary to the core
      cytosolic peroxidase/chaperone activities.
    additional_reference_ids:
    - file:yeast/TSA1/TSA1-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
      supporting_text: |-
        In addition to a free cytosolic pool, one source reports Tsa1 is also found **associated with translating ribosomes**, suggesting functional proximity to nascent polypeptides and translation-linked proteostasis.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IDA
  original_reference_id: PMID:8344960
  review:
    summary: 'Manual review: cell redox homeostasis is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IMP
  original_reference_id: PMID:8344960
  review:
    summary: 'Manual review: cell redox homeostasis is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IMP
  original_reference_id: PMID:9799566
  review:
    summary: 'Manual review: cell redox homeostasis is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IMP
  original_reference_id: PMID:16251355
  review:
    summary: 'Manual review: unfolded protein binding is better represented by a more specific replacement term for TSA1.'
    action: MODIFY
    reason: Modified to align with current curation guidance and improve term specificity.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0051920
    label: peroxiredoxin activity
  evidence_type: IDA
  original_reference_id: PMID:17210445
  review:
    summary: 'Manual review: peroxiredoxin activity is consistent with known biology of TSA1.'
    action: ACCEPT
    reason: Retained as supported or plausible for this gene and evidence context.
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: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:10681558
  title: Distinct physiological functions of thiol peroxidase isoenzymes in Saccharomyces cerevisiae.
  findings: []
- id: PMID:15051715
  title: Peroxiredoxin-null yeast cells are hypersensitive to oxidative stress and are genomically unstable.
  findings: []
- id: PMID:15163410
  title: Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function.
  findings: []
- id: PMID:15210711
  title: 'Cytosolic thioredoxin peroxidase I and II are important defenses of yeast against organic hydroperoxide insult: catalases and peroxiredoxins cooperate in the decomposition of H2O2 by yeast.'
  findings: []
- id: PMID:16251355
  title: The thioredoxin system protects ribosomes against stress-induced aggregation.
  findings: []
- id: PMID:16272220
  title: A yeast two-hybrid knockout strain to explore thioredoxin-interacting proteins in vivo.
  findings: []
- id: PMID:16554755
  title: Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
  findings: []
- id: PMID:17210445
  title: 'Reactions of yeast thioredoxin peroxidases I and II with hydrogen peroxide and peroxynitrite: rate constants by competitive kinetics.'
  findings: []
- id: PMID:18271751
  title: The yeast Tsa1 peroxiredoxin is a ribosome-associated antioxidant.
  findings: []
- id: PMID:18719252
  title: High-quality binary protein interaction map of the yeast interactome network.
  findings: []
- id: PMID:19543365
  title: Peroxiredoxin Tsa1 is the key peroxidase suppressing genome instability and protecting against cell death in Saccharomyces cerevisiae.
  findings: []
- id: PMID:19851444
  title: Loss of yeast peroxiredoxin Tsa1p induces genome instability through activation of the DNA damage checkpoint and elevation of dNTP levels.
  findings: []
- id: PMID:22842922
  title: Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress.
  findings: []
- id: PMID:24022485
  title: Peroxiredoxin chaperone activity is critical for protein homeostasis in zinc-deficient yeast.
  findings: []
- id: PMID:27634403
  title: Redox-dependent Regulation of Gluconeogenesis by a Novel Mechanism Mediated by a Peroxidatic Cysteine of Peroxiredoxin.
  findings: []
- id: PMID:37968396
  title: The social and structural architecture of the yeast protein interactome.
  findings: []
- id: PMID:7961686
  title: Thioredoxin-dependent peroxide reductase from yeast.
  findings: []
- id: PMID:8344960
  title: Cloning, sequencing, and mutation of thiol-specific antioxidant gene of Saccharomyces cerevisiae.
  findings: []
- id: PMID:9799566
  title: Thermosensitive phenotype of yeast mutant lacking thioredoxin peroxidase.
  findings: []
- id: file:yeast/TSA1/TSA1-deep-research-falcon.md
  title: Falcon deep research on TSA1 (Edison Scientific Literature)
  findings:
  - statement: |-
      Tsa1 is the major cytosolic typical 2-Cys peroxiredoxin of budding yeast,
      with peroxidatic Cys48 (CP) and resolving Cys171 (CR) forming an
      inter-subunit disulfide during the catalytic cycle.
    reference_section_type: OTHER
    supporting_text: |-
      The research target is the budding yeast (*Saccharomyces cerevisiae*) protein **Tsa1**, consistently described across primary and review sources as the **major cytosolic typical 2‑Cys peroxiredoxin** (Prx) with canonical active-site cysteines **Cys48 (peroxidatic, CP)** and **Cys171 (resolving, CR)**.
  - statement: |-
      Tsa1 is a thioredoxin-dependent peroxidase that reduces H2O2 and organic
      hydroperoxides; oxidized Tsa1 disulfide is reduced by the cytosolic
      thioredoxin system (Trx1/Trx2, recycled by thioredoxin reductase using
      NADPH).
    reference_section_type: OTHER
    supporting_text: |-
      Tsa1 reduces **H2O2 and organic hydroperoxides**; in typical 2‑Cys Prxs this occurs via CP attack on the peroxide bond, generating water/alcohol products.
  - statement: |-
      Reduction of oxidized Tsa1 is driven primarily by the cytosolic
      thioredoxin system.
    reference_section_type: OTHER
    supporting_text: |-
      Reduction of oxidized Tsa1 is primarily driven by the **cytosolic thioredoxin system**: **Trx1/Trx2** reduce the Tsa1 disulfide, and oxidized thioredoxin is recycled by **thioredoxin reductase** using **NADPH**.
  - statement: |-
      Because of high abundance (~1% of cytosolic protein, ~10-50 uM) and fast
      kinetics, peroxiredoxins decompose the majority of cellular hydroperoxides.
    reference_section_type: OTHER
    supporting_text: |-
      Reviews also emphasize that Prxs decompose **>90% of cellular hydroperoxides** and can detoxify up to **~90% of cytosolic H2O2** due to abundance and fast reaction rates (general Prx second-order rates ~10^6–10^8 M−1 s−1).
  - statement: |-
      At high oxidant loads the peroxidatic cysteine hyperoxidizes
      (sulfinic/sulfonic), inactivating peroxidase activity and promoting
      higher-order oligomers with molecular chaperone/holdase activity.
    reference_section_type: OTHER
    supporting_text: |-
      At higher oxidant loads, Tsa1’s peroxidatic cysteine can become **hyperoxidized** (sulfinic/sulfonic states), which **inactivates peroxidase activity** and promotes formation of **higher-order oligomers** associated with **molecular chaperone/holdase activity**.
  - statement: |-
      Increased Tsa1 dosage extends replicative lifespan in a manner dependent on
      Hsp70 (Ssa1/2) and partly Hsp104, and requires reduction of hyperoxidized
      Tsa1 by sulfiredoxin Srx1, supporting a role as a stress-activated
      chaperone adaptor that recruits protein quality control machinery.
    reference_section_type: OTHER
    supporting_text: |-
      Increased dosage of Tsa1 extends replicative lifespan in a manner dependent on **Hsp70 (Ssa1/2)** and partly on **Hsp104**, and requires reduction of hyperoxidized Tsa1 by **sulfiredoxin Srx1** for aggregate clearance/disaggregation.
  - statement: |-
      Tsa1 contributes to stress resistance and longevity partly through redox
      repression of the Ras-cAMP-PKA pathway, oxidizing a conserved cysteine
      (Cys243) of the PKA catalytic subunit and blocking activation-loop Thr241
      phosphorylation.
    reference_section_type: OTHER
    supporting_text: |-
      Specifically, Tsa1 represses the **Ras–cAMP–PKA pathway** by promoting oxidative modifications of PKA catalytic subunits; redox modification of a conserved cysteine (reported as **Cys243** in the catalytic subunit) inhibits phosphorylation of **Thr241** in the activation loop and reduces kinase activity.
  - statement: |-
      tsa1-null cells show a mutator phenotype (~5-10-fold increased mutation
      rates); Tsa1 is the strongest suppressor of mutations among oxidant-defense
      genes in yeast, with genome protection involving both peroxidase-dependent
      and peroxidase-independent (redox-network) facets.
    reference_section_type: OTHER
    supporting_text: |-
      Yeast lacking TSA1 show a **mutator phenotype**, with reported **~5–10‑fold increased mutation rates**, and Tsa1 is described as the strongest suppressor of mutations among oxidant-defense genes in yeast.
  - statement: |-
      Tsa1 is the major cytosolic peroxiredoxin and is additionally found
      associated with translating ribosomes, placing it near nascent
      polypeptides for translation-linked proteostasis.
    reference_section_type: OTHER
    supporting_text: |-
      In addition to a free cytosolic pool, one source reports Tsa1 is also found **associated with translating ribosomes**, suggesting functional proximity to nascent polypeptides and translation-linked proteostasis.
  - statement: |-
      Tsa1 forms widespread covalent mixed-disulfide intermediates (TIMDIs,
      "peroxiredoxinylation") with client proteins via the peroxidatic cysteine;
      thioredoxins directly remove these adducts, extending the
      thioredoxin-peroxiredoxin system into a proteome-thiol buffering circuit.
    reference_section_type: OTHER
    supporting_text: |-
      A 2023 bioRxiv preprint reports that Tsa1 forms widespread covalent mixed disulfide intermediates with cellular proteins, termed **Tsa1-Induced Mixed Disulfide Intermediates (TIMDIs)**, and frames this as a bona fide redox-linked post-translational modification termed **peroxiredoxinylation**.
core_functions:
- description: |-
    Thioredoxin-dependent peroxidase that catalyzes reduction of hydrogen
    peroxide and organic hydroperoxides to water/alcohol using the typical
    2-Cys peroxiredoxin cycle (peroxidatic Cys48 attacks the peroxide bond,
    forming an inter-subunit disulfide with resolving Cys171 that is reduced
    by thioredoxin). As the major, highly abundant cytosolic peroxiredoxin,
    Tsa1 is the primary peroxide sink of the yeast cytosol.
  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
  supported_by:
  - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
    supporting_text: |-
      Tsa1’s primary biochemical role is as a **thioredoxin-dependent peroxidase** that reduces peroxides (especially **H2O2**) via the typical 2‑Cys Prx redox cycle centered on **Cys48/Cys171**.
  - reference_id: PMID:7961686
    supporting_text: |-
      The 25-kDa enzyme is now shown to be a peroxidase that reduces H2O2 and alkyl hydroperoxides with the use of hydrogens provided by thioredoxin, thioredoxin reductase, and NADPH.
- description: |-
    Stress-activated molecular chaperone (holdase). Upon hyperoxidation of the
    peroxidatic cysteine and oxidative/heat stress, Tsa1 undergoes a reversible
    switch from low-molecular-weight peroxidase species to high-molecular-weight
    oligomers with chaperone holdase activity, binding unfolded/misfolded
    proteins and recruiting Hsp70 (Ssa1/2) and Hsp104 to clear oxidatively
    damaged aggregates; reactivation requires reduction by sulfiredoxin Srx1.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:yeast/TSA1/TSA1-deep-research-falcon.md
    supporting_text: |-
      At higher oxidant loads, Tsa1’s peroxidatic cysteine can become **hyperoxidized** (sulfinic/sulfonic states), which **inactivates peroxidase activity** and promotes formation of **higher-order oligomers** associated with **molecular chaperone/holdase activity**.
  - reference_id: PMID:15163410
    supporting_text: |-
      The peroxidase function predominates in the lower MW forms, whereas the chaperone function predominates in the higher MW complexes. Oxidative stress and heat shock exposure of yeasts causes the protein structures of cPrxI and II to shift from low MW species to high MW complexes. This triggers a peroxidase-to-chaperone functional switch.

TSA1

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Research Report: Functional Annotation of Saccharomyces cerevisiae TSA1 (UniProt P34760, ORF YML028W)

0) Target identity verification (critical disambiguation)

1) Key concepts, definitions, and current mechanistic understanding

1.1 Peroxiredoxins and “typical 2‑Cys” mechanism

1.2 Substrates and reducing partners (thioredoxin system)

1.3 Hyperoxidation, “floodgate” behavior, and the chaperone switch

1.4 Abundance and why peroxiredoxins dominate peroxide metabolism

2) Primary function: enzymology and substrate specificity

2.1 Enzymatic role

2.2 Reaction-cycle integration with proteome redox buffering

3) Subcellular localization and where function is executed

4) Biological processes and pathways involving Tsa1

4.1 H2O2 signaling and nutrient signaling integration (Ras–cAMP–PKA)

4.2 Proteostasis: redox-dependent recruitment of chaperones to aggregates

4.3 Genome stability (mutator suppression)

5) Recent developments and latest research (prioritize 2023–2024)

5.1 2023: “Peroxiredoxinylation” (Tsa1-induced mixed disulfides) as a proteome-wide redox buffer

5.2 2024: Tsa1 stabilizes the rDNA locus to extend lifespan

5.3 2024: Peroxiredoxin urmylation context (thesis-level work)

6) Current applications and real-world implementations

6.1 Industrial yeast robustness (stress tolerance, biomass propagation)

6.2 Conceptual translational value

7) Expert opinions and authoritative synthesis (what leading sources emphasize)

7.1 Multifunctionality (“moonlighting”) and state switching

7.2 Genome stability remains mechanistically complex

8) Key statistics and data points (curated)

9) Evidence map (compact summary table)

10) Visual evidence: TIMDI/peroxiredoxinylation induction

11) Limitations and evidence-quality notes

Key source URLs and publication dates (selected)

Artifacts

Citations

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