ID GPX3_YEAST Reviewed; 163 AA. AC P40581; D6VVW8; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1995, sequence version 1. DT 27-MAR-2024, entry version 192. DE RecName: Full=Glutathione peroxidase-like peroxiredoxin HYR1 {ECO:0000305}; DE EC=1.11.1.24 {ECO:0000269|PubMed:12437921, ECO:0000269|PubMed:18767166}; DE AltName: Full=Glutathione peroxidase homolog 3 {ECO:0000303|PubMed:10480913}; DE Short=GPx 3; DE AltName: Full=Hydrogen peroxide resistance protein 1 {ECO:0000303|Ref.1}; DE AltName: Full=Oxidant receptor peroxidase 1 {ECO:0000303|PubMed:17720812}; DE AltName: Full=Phospholipid hydroperoxide glutathione peroxidase 3 {ECO:0000303|PubMed:9315326}; DE Short=PHGPx3; GN Name=HYR1 {ECO:0000303|Ref.1}; GN Synonyms=GPX3 {ECO:0000303|PubMed:10480913}, ORP1 GN {ECO:0000303|PubMed:17720812}; GN OrderedLocusNames=YIR037W {ECO:0000312|SGD:S000001476}; OS Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast). OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes; OC Saccharomycetales; Saccharomycetaceae; Saccharomyces. OX NCBI_TaxID=559292; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=ATCC 38626 / AH22 / NRRL Y-12843; RA Budde E., Stahl U.; RT "Cloning and phenotypic characterization of a glutathione-peroxidase like RT gene involved in the oxidative stress response of Saccharomyces RT cerevisiae."; RL Submitted (MAR-1995) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=ATCC 204508 / S288c; RX PubMed=9169870; RA Churcher C.M., Bowman S., Badcock K., Bankier A.T., Brown D., RA Chillingworth T., Connor R., Devlin K., Gentles S., Hamlin N., Harris D.E., RA Horsnell T., Hunt S., Jagels K., Jones M., Lye G., Moule S., Odell C., RA Pearson D., Rajandream M.A., Rice P., Rowley N., Skelton J., Smith V., RA Walsh S.V., Whitehead S., Barrell B.G.; RT "The nucleotide sequence of Saccharomyces cerevisiae chromosome IX."; RL Nature 387:84-87(1997). RN [3] RP GENOME REANNOTATION. RC STRAIN=ATCC 204508 / S288c; RX PubMed=24374639; DOI=10.1534/g3.113.008995; RA Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R., RA Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S., RA Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.; RT "The reference genome sequence of Saccharomyces cerevisiae: Then and now."; RL G3 (Bethesda) 4:389-398(2014). RN [4] RP FUNCTION. RX PubMed=9315326; RA Ursini F., Maiorino M., Roveri A.; RT "Phospholipid hydroperoxide glutathione peroxidase (PHGPx): more than an RT antioxidant enzyme?"; RL Biomed. Environ. Sci. 10:327-332(1997). RN [5] RP FUNCTION, INDUCTION, AND DISRUPTION PHENOTYPE. RX PubMed=10480913; DOI=10.1074/jbc.274.38.27002; RA Inoue Y., Matsuda T., Sugiyama K., Izawa S., Kimura A.; RT "Genetic analysis of glutathione peroxidase in oxidative stress response of RT Saccharomyces cerevisiae."; RL J. Biol. Chem. 274:27002-27009(1999). RN [6] RP FUNCTION. RX PubMed=11445588; DOI=10.1074/jbc.m105672200; RA Avery A.M., Avery S.V.; RT "Saccharomyces cerevisiae expresses three phospholipid hydroperoxide RT glutathione peroxidases."; RL J. Biol. Chem. 276:33730-33735(2001). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, AND OXIDATION OF YAP1. RX PubMed=12437921; DOI=10.1016/s0092-8674(02)01048-6; RA Delaunay A., Pflieger D., Barrault M.-B., Vinh J., Toledano M.B.; RT "A thiol peroxidase is an H2O2 receptor and redox-transducer in gene RT activation."; RL Cell 111:471-481(2002). RN [8] RP FUNCTION, AND INTERACTION WITH YBP1. RX PubMed=12743123; DOI=10.1074/jbc.m303542200; RA Veal E.A., Ross S.J., Malakasi P., Peacock E., Morgan B.A.; RT "Ybp1 is required for the hydrogen peroxide-induced oxidation of the Yap1 RT transcription factor."; RL J. Biol. Chem. 278:30896-30904(2003). RN [9] RP FUNCTION, AND ACTIVATING SUBSTANCES. RX PubMed=14556853; DOI=10.1016/s0891-5849(03)00434-9; RA Azevedo D., Tacnet F., Delaunay A., Rodrigues-Pousada C., Toledano M.B.; RT "Two redox centers within Yap1 for H2O2 and thiol-reactive chemicals RT signaling."; RL Free Radic. Biol. Med. 35:889-900(2003). RN [10] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RX PubMed=14562095; DOI=10.1038/nature02026; RA Huh W.-K., Falvo J.V., Gerke L.C., Carroll A.S., Howson R.W., RA Weissman J.S., O'Shea E.K.; RT "Global analysis of protein localization in budding yeast."; RL Nature 425:686-691(2003). RN [11] RP LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS]. RX PubMed=14562106; DOI=10.1038/nature02046; RA Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N., RA O'Shea E.K., Weissman J.S.; RT "Global analysis of protein expression in yeast."; RL Nature 425:737-741(2003). RN [12] RP FUNCTION. RX PubMed=15337745; DOI=10.1074/jbc.m408340200; RA Avery A.M., Willetts S.A., Avery S.V.; RT "Genetic dissection of the phospholipid hydroperoxidase activity of yeast RT gpx3 reveals its functional importance."; RL J. Biol. Chem. 279:46652-46658(2004). RN [13] RP FUNCTION, AND ACTIVE SITE. RX PubMed=17720812; DOI=10.1074/jbc.m705953200; RA Ma L.H., Takanishi C.L., Wood M.J.; RT "Molecular mechanism of oxidative stress perception by the Orp1 protein."; RL J. Biol. Chem. 282:31429-31436(2007). RN [14] RP FUNCTION. RX PubMed=19230722; DOI=10.1016/j.chembiol.2009.01.003; RA Paulsen C.E., Carroll K.S.; RT "Chemical dissection of an essential redox switch in yeast."; RL Chem. Biol. 16:217-225(2009). RN [15] RP SUBCELLULAR LOCATION. RX PubMed=22659048; DOI=10.1016/j.bbalip.2012.05.004; RA Ohdate T., Inoue Y.; RT "Involvement of glutathione peroxidase 1 in growth and peroxisome formation RT in Saccharomyces cerevisiae in oleic acid medium."; RL Biochim. Biophys. Acta 1821:1295-1305(2012). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION [LARGE SCALE RP ANALYSIS]. RX PubMed=22984289; DOI=10.1074/mcp.m112.021105; RA Voegtle F.N., Burkhart J.M., Rao S., Gerbeth C., Hinrichs J., RA Martinou J.C., Chacinska A., Sickmann A., Zahedi R.P., Meisinger C.; RT "Intermembrane space proteome of yeast mitochondria."; RL Mol. Cell. Proteomics 11:1840-1852(2012). RN [17] RP X-RAY CRYSTALLOGRAPHY (2.02 ANGSTROMS), CATALYTIC ACTIVITY, AND MUTAGENESIS RP OF CYS-82. RX PubMed=18767166; DOI=10.1002/prot.22220; RA Zhang W.J., He Y.-X., Yang Z., Yu J., Chen Y., Zhou C.-Z.; RT "Crystal structure of glutathione-dependent phospholipid peroxidase Hyr1 RT from the yeast Saccharomyces cerevisiae."; RL Proteins 73:1058-1062(2008). CC -!- FUNCTION: Involved in oxidative stress response and redox homeostasis. CC Functions as a sensor and transducer of hydroperoxide stress. In CC response to hydroperoxide stress it oxidizes (activates) the CC transcription activator YAP1, which is involved in transcription CC activation of genes of the oxidative stress response pathway. May also CC play a direct role in hydroperoxide scavenging, being the most active CC of three closely related S.cerevisiae peroxiredoxins (GPX1, GPX2, and CC HYR1/GPX3) with respect to peroxide and lipid hydroperoxide reduction. CC The three enzymes are not required for the glutaredoxin-mediated CC antioxidant function. In the presence of peroxides, HYR1/GPX3 is CC directly oxidized at Cys-36 to form a cysteine sulfenic acid (-SOH). CC Cys-36-SOH then forms either an intramolecular disulfide bond (Cys-36 CC with Cys-82) or a transient, intermolecular disulfide bond with 'Cys- CC 598' of YAP1, which is further resolved into a YAP1 intramolecular CC disulfide bond ('Cys-303' with 'Cys-598'), which causes its nuclear CC accumulation and activation, and a reduced Cys-36 in HYR1/GPX3. CC {ECO:0000269|PubMed:10480913, ECO:0000269|PubMed:11445588, CC ECO:0000269|PubMed:12437921, ECO:0000269|PubMed:12743123, CC ECO:0000269|PubMed:14556853, ECO:0000269|PubMed:15337745, CC ECO:0000269|PubMed:17720812, ECO:0000269|PubMed:19230722, CC ECO:0000269|PubMed:9315326}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[thioredoxin]-dithiol + a hydroperoxide = [thioredoxin]- CC disulfide + an alcohol + H2O; Xref=Rhea:RHEA:62620, Rhea:RHEA- CC COMP:10698, Rhea:RHEA-COMP:10700, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:29950, ChEBI:CHEBI:30879, ChEBI:CHEBI:35924, CC ChEBI:CHEBI:50058; EC=1.11.1.24; CC Evidence={ECO:0000269|PubMed:12437921, ECO:0000269|PubMed:18767166}; CC -!- SUBUNIT: Interacts with YAP1 and probably YBP1. CC {ECO:0000269|PubMed:12743123}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14562095}. CC Mitochondrion intermembrane space {ECO:0000269|PubMed:22984289}. CC Peroxisome matrix {ECO:0000269|PubMed:22659048}. CC -!- INDUCTION: In contrast to the other two peroxiredoxins, HYR1/GPX3 CC expression is constitutive, not stress-induced. CC {ECO:0000269|PubMed:10480913}. CC -!- DISRUPTION PHENOTYPE: Sensitive to hydrogen peroxide and tert-butyl CC hydroperoxide (t-BHP). {ECO:0000269|PubMed:10480913}. CC -!- MISCELLANEOUS: Present with 8000 molecules/cell in log phase SD medium. CC {ECO:0000269|PubMed:14562106}. CC -!- MISCELLANEOUS: The active site is a conserved redox-active cysteine CC residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic CC attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to CC cysteine sulfenic acid (C(P)-SOH), which then reacts with another CC cysteine residue, the resolving cysteine (C(R)), to form a disulfide CC bridge. The disulfide is subsequently reduced by an appropriate CC electron donor to complete the catalytic cycle. In this atypical 2-Cys CC peroxiredoxin, C(R) is present in the same subunit to form an CC intramolecular disulfide. {ECO:0000305|PubMed:17720812}. CC -!- SIMILARITY: Belongs to the glutathione peroxidase family. CC {ECO:0000305}. CC -!- CAUTION: Was originally thought to be a glutathione peroxidase CC (PubMed:10480913) or a phospholipid hydroperoxide glutathione CC peroxidase (PubMed:11445588), but functions as an atypical 2-Cys CC peroxiredoxin using thioredoxin as reducing power instead CC (PubMed:12437921). {ECO:0000305|PubMed:10480913, CC ECO:0000305|PubMed:11445588, ECO:0000305|PubMed:12437921}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U22446; AAA64283.1; -; Genomic_DNA. DR EMBL; Z38061; CAA86197.1; -; Genomic_DNA. DR EMBL; BK006942; DAA08584.1; -; Genomic_DNA. DR PIR; S48499; S48499. DR RefSeq; NP_012303.1; NM_001179559.1. DR PDB; 3CMI; X-ray; 2.02 A; A=1-163. DR PDBsum; 3CMI; -. DR AlphaFoldDB; P40581; -. DR SMR; P40581; -. DR BioGRID; 35028; 105. DR DIP; DIP-1275N; -. DR IntAct; P40581; 14. DR MINT; P40581; -. DR STRING; 4932.YIR037W; -. DR PeroxiBase; 3742; SceGPx03. DR iPTMnet; P40581; -. DR MaxQB; P40581; -. DR PaxDb; 4932-YIR037W; -. DR PeptideAtlas; P40581; -. DR TopDownProteomics; P40581; -. DR EnsemblFungi; YIR037W_mRNA; YIR037W; YIR037W. DR GeneID; 854855; -. DR KEGG; sce:YIR037W; -. DR AGR; SGD:S000001476; -. DR SGD; S000001476; HYR1. DR VEuPathDB; FungiDB:YIR037W; -. DR eggNOG; KOG1651; Eukaryota. DR GeneTree; ENSGT00940000165680; -. DR HOGENOM; CLU_029507_2_2_1; -. DR InParanoid; P40581; -. DR OMA; TFPMTEK; -. DR OrthoDB; 67394at2759; -. DR BioCyc; YEAST:YIR037W-MONOMER; -. DR BioGRID-ORCS; 854855; 3 hits in 10 CRISPR screens. DR EvolutionaryTrace; P40581; -. DR PRO; PR:P40581; -. DR Proteomes; UP000002311; Chromosome IX. DR RNAct; P40581; Protein. DR GO; GO:0005829; C:cytosol; HDA:SGD. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:SGD. DR GO; GO:0005739; C:mitochondrion; HDA:SGD. DR GO; GO:0005782; C:peroxisomal matrix; IDA:SGD. DR GO; GO:0004602; F:glutathione peroxidase activity; IDA:SGD. DR GO; GO:0047066; F:phospholipid-hydroperoxide glutathione peroxidase activity; IDA:SGD. DR GO; GO:0140824; F:thioredoxin-dependent peroxiredoxin activity; IEA:UniProtKB-EC. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:SGD. DR CDD; cd00340; GSH_Peroxidase; 1. DR Gene3D; 3.40.30.10; Glutaredoxin; 1. DR InterPro; IPR000889; Glutathione_peroxidase. DR InterPro; IPR029759; GPX_AS. DR InterPro; IPR029760; GPX_CS. DR InterPro; IPR036249; Thioredoxin-like_sf. DR InterPro; IPR013766; Thioredoxin_domain. DR PANTHER; PTHR11592; GLUTATHIONE PEROXIDASE; 1. DR PANTHER; PTHR11592:SF78; PHOSPHOLIPID HYDROPEROXIDE GLUTATHIONE PEROXIDASE; 1. DR Pfam; PF00255; GSHPx; 1. DR PIRSF; PIRSF000303; Glutathion_perox; 1. DR PRINTS; PR01011; GLUTPROXDASE. DR SUPFAM; SSF52833; Thioredoxin-like; 1. DR PROSITE; PS00460; GLUTATHIONE_PEROXID_1; 1. DR PROSITE; PS00763; GLUTATHIONE_PEROXID_2; 1. DR PROSITE; PS51355; GLUTATHIONE_PEROXID_3; 1. PE 1: Evidence at protein level; KW 3D-structure; Antioxidant; Cytoplasm; Disulfide bond; Mitochondrion; KW Oxidoreductase; Peroxidase; Peroxisome; Redox-active center; KW Reference proteome. FT CHAIN 1..163 FT /note="Glutathione peroxidase-like peroxiredoxin HYR1" FT /id="PRO_0000066643" FT ACT_SITE 36 FT /note="Cysteine sulfenic acid (-SOH) intermediate" FT /evidence="ECO:0000269|PubMed:17720812, FT ECO:0000305|PubMed:18767166" FT DISULFID 36..82 FT /note="Redox-active" FT /evidence="ECO:0000305|PubMed:18767166" FT DISULFID 36 FT /note="Interchain (with C-598 in YAP1); transient" FT /evidence="ECO:0000269|PubMed:12437921, FT ECO:0000269|PubMed:17720812" FT MUTAGEN 82 FT /note="C->S: Loss of enzyme activity." FT /evidence="ECO:0000269|PubMed:18767166" FT HELIX 3..6 FT /evidence="ECO:0007829|PDB:3CMI" FT HELIX 19..22 FT /evidence="ECO:0007829|PDB:3CMI" FT STRAND 26..36 FT /evidence="ECO:0007829|PDB:3CMI" FT HELIX 39..52 FT /evidence="ECO:0007829|PDB:3CMI" FT HELIX 53..55 FT /evidence="ECO:0007829|PDB:3CMI" FT STRAND 57..64 FT /evidence="ECO:0007829|PDB:3CMI" FT STRAND 97..100 FT /evidence="ECO:0007829|PDB:3CMI" FT HELIX 105..113 FT /evidence="ECO:0007829|PDB:3CMI" FT STRAND 117..119 FT /evidence="ECO:0007829|PDB:3CMI" FT STRAND 129..132 FT /evidence="ECO:0007829|PDB:3CMI" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:3CMI" FT STRAND 138..142 FT /evidence="ECO:0007829|PDB:3CMI" FT HELIX 148..151 FT /evidence="ECO:0007829|PDB:3CMI" FT HELIX 152..159 FT /evidence="ECO:0007829|PDB:3CMI" SQ SEQUENCE 163 AA; 18641 MW; 46C42B81E895C1A3 CRC64; MSEFYKLAPV DKKGQPFPFD QLKGKVVLIV NVASKCGFTP QYKELEALYK RYKDEGFTII GFPCNQFGHQ EPGSDEEIAQ FCQLNYGVTF PIMKKIDVNG GNEDPVYKFL KSQKSGMLGL RGIKWNFEKF LVDKKGKVYE RYSSLTKPSS LSETIEELLK EVE //