PRDX6_RAT
ID PRDX6_RAT Reviewed; 224 AA.
AC O35244;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 174.
DE RecName: Full=Peroxiredoxin-6;
DE EC=1.11.1.27 {ECO:0000269|PubMed:15004285};
DE AltName: Full=1-Cys peroxiredoxin;
DE Short=1-Cys PRX;
DE AltName: Full=Acidic calcium-independent phospholipase A2;
DE Short=aiPLA2;
DE EC=3.1.1.4 {ECO:0000269|PubMed:17652308, ECO:0000269|PubMed:8999971};
DE AltName: Full=Antioxidant protein 2;
DE AltName: Full=Glutathione-dependent peroxiredoxin {ECO:0000305};
DE AltName: Full=Lysophosphatidylcholine acyltransferase 5 {ECO:0000303|PubMed:26830860};
DE Short=LPC acyltransferase 5;
DE Short=LPCAT-5;
DE Short=Lyso-PC acyltransferase 5;
DE EC=2.3.1.23 {ECO:0000269|PubMed:26830860};
DE AltName: Full=Non-selenium glutathione peroxidase;
DE Short=NSGPx;
DE AltName: Full=Thiol-specific antioxidant protein;
GN Name=Prdx6; Synonyms=Aipla2, Aop2, Tsa;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Lung;
RA Kim T.-S., Feinstein S.I., Dodia C., Hennigan B.B., Fisher A.B.;
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Wistar; TISSUE=Olfactory epithelium;
RA Andreeva S.;
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PROTEIN SEQUENCE OF 2-41; 57-84; 98-118; 133-142; 156-162 AND 183-199, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=Sprague-Dawley; TISSUE=Hippocampus, and Spinal cord;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q.;
RL Submitted (APR-2007) to UniProtKB.
RN [4]
RP PROTEIN SEQUENCE OF 26-42 AND 146-163, FUNCTION, CATALYTIC ACTIVITY, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8999971; DOI=10.1074/jbc.272.4.2542;
RA Kim T.-S., Sundaresh C.S., Feinstein S.I., Dodia C., Skach W.R., Jain M.K.,
RA Nagase T., Seki N., Ishikawa K., Nomura N., Fisher A.B.;
RT "Identification of a human cDNA clone for lysosomal type Ca2+-independent
RT phospholipase A2 and properties of the expressed protein.";
RL J. Biol. Chem. 272:2542-2550(1997).
RN [5]
RP ERRATUM OF PUBMED:8999971.
RA Kim T.-S., Sundaresh C.S., Feinstein S.I., Dodia C., Skach W.R., Jain M.K.,
RA Nagase T., Seki N., Ishikawa K., Nomura N., Fisher A.B.;
RL J. Biol. Chem. 272:10981-10981(1997).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVATION BY GLUTATHIONE.
RX PubMed=15004285; DOI=10.1073/pnas.0400181101;
RA Manevich Y., Feinstein S.I., Fisher A.B.;
RT "Activation of the antioxidant enzyme 1-CYS peroxiredoxin requires
RT glutathionylation mediated by heterodimerization with pi GST.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:3780-3785(2004).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF HIS-26;
RP SER-32 AND ASP-140.
RX PubMed=17652308; DOI=10.1194/jlr.m700299-jlr200;
RA Manevich Y., Reddy K.S., Shuvaeva T., Feinstein S.I., Fisher A.B.;
RT "Structure and phospholipase function of peroxiredoxin 6: identification of
RT the catalytic triad and its role in phospholipid substrate binding.";
RL J. Lipid Res. 48:2306-2318(2007).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=19700648; DOI=10.1152/ajplung.00052.2009;
RA Sorokina E.M., Feinstein S.I., Milovanova T.N., Fisher A.B.;
RT "Identification of the amino acid sequence that targets peroxiredoxin 6 to
RT lysosome-like structures of lung epithelial cells.";
RL Am. J. Physiol. 297:L871-L880(2009).
RN [9]
RP PHOSPHORYLATION AT THR-177 BY MAPK.
RX PubMed=19140803; DOI=10.1042/bj20082061;
RA Wu Y., Feinstein S.I., Manevich Y., Chowdhury I., Pak J.H., Kazi A.,
RA Dodia C., Speicher D.W., Fisher A.B.;
RT "Mitogen-activated protein kinase-mediated phosphorylation of peroxiredoxin
RT 6 regulates its phospholipase A(2) activity.";
RL Biochem. J. 419:669-679(2009).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, AND PHOSPHORYLATION.
RX PubMed=26830860; DOI=10.1194/jlr.m064758;
RA Fisher A.B., Dodia C., Sorokina E.M., Li H., Zhou S., Raabe T.,
RA Feinstein S.I.;
RT "A novel lysophosphatidylcholine acyl transferase activity is expressed by
RT peroxiredoxin 6.";
RL J. Lipid Res. 57:587-596(2016).
CC -!- FUNCTION: Thiol-specific peroxidase that catalyzes the reduction of
CC hydrogen peroxide and organic hydroperoxides to water and alcohols,
CC respectively (PubMed:15004285). Can reduce H(2)O(2) and short chain
CC organic, fatty acid, and phospholipid hydroperoxides (By similarity).
CC Also has phospholipase activity, can therefore either reduce the
CC oxidized sn-2 fatty acyl group of phospholipids (peroxidase activity)
CC or hydrolyze the sn-2 ester bond of phospholipids (phospholipase
CC activity) (PubMed:8999971, PubMed:15004285, PubMed:17652308). These
CC activities are dependent on binding to phospholipids at acidic pH and
CC to oxidized phospholipds at cytosolic pH (By similarity). Plays a role
CC in cell protection against oxidative stress by detoxifying peroxides
CC and in phospholipid homeostasis (By similarity). Exhibits acyl-CoA-
CC dependent lysophospholipid acyltransferase which mediates the
CC conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-
CC phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-
CC 3-phosphocholine or PC) (PubMed:26830860). Shows a clear preference for
CC LPC as the lysophospholipid and for palmitoyl CoA as the fatty acyl
CC substrate (By similarity). {ECO:0000250|UniProtKB:P30041,
CC ECO:0000269|PubMed:15004285, ECO:0000269|PubMed:17652308,
CC ECO:0000269|PubMed:26830860, ECO:0000269|PubMed:8999971}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a hydroperoxide + 2 glutathione = an alcohol + glutathione
CC disulfide + H2O; Xref=Rhea:RHEA:62632, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:30879, ChEBI:CHEBI:35924, ChEBI:CHEBI:57925,
CC ChEBI:CHEBI:58297; EC=1.11.1.27;
CC Evidence={ECO:0000269|PubMed:15004285};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-
CC glycero-3-phosphocholine + a fatty acid + H(+); Xref=Rhea:RHEA:15801,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:28868,
CC ChEBI:CHEBI:57643, ChEBI:CHEBI:58168; EC=3.1.1.4;
CC Evidence={ECO:0000269|PubMed:17652308, ECO:0000269|PubMed:8999971};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1-acyl-sn-glycero-3-phosphocholine + an acyl-CoA = a 1,2-
CC diacyl-sn-glycero-3-phosphocholine + CoA; Xref=Rhea:RHEA:12937,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57643, ChEBI:CHEBI:58168,
CC ChEBI:CHEBI:58342; EC=2.3.1.23;
CC Evidence={ECO:0000269|PubMed:26830860};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-hexadecanoyl-sn-glycero-3-phosphocholine + hexadecanoyl-CoA
CC = 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + CoA;
CC Xref=Rhea:RHEA:35983, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379,
CC ChEBI:CHEBI:72998, ChEBI:CHEBI:72999;
CC Evidence={ECO:0000250|UniProtKB:P30041};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35984;
CC Evidence={ECO:0000250|UniProtKB:P30041};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1-
CC hexadecanoyl-sn-glycero-3-phosphocholine + H(+) + hexadecanoate;
CC Xref=Rhea:RHEA:41223, ChEBI:CHEBI:7896, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:72998, ChEBI:CHEBI:72999;
CC Evidence={ECO:0000250|UniProtKB:P30041};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41224;
CC Evidence={ECO:0000250|UniProtKB:P30041};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.25 mM for dipalmitoyl phosphatidylcholine
CC {ECO:0000269|PubMed:8999971};
CC Vmax=1.89 nmol/h/mg enzyme for dipalmitoyl phosphatidylcholine
CC {ECO:0000269|PubMed:8999971};
CC pH dependence:
CC Optimum pH is 4 (for phospholipase activity).
CC {ECO:0000269|PubMed:8999971};
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with GSTP1; mediates
CC PRDX6 glutathionylation and regeneration (Probable). Interacts with
CC APEX1. Interacts with STH. May interact with FAM168B (By similarity).
CC May interact with HTR2A (By similarity). {ECO:0000250|UniProtKB:O08709,
CC ECO:0000250|UniProtKB:P30041, ECO:0000305|PubMed:15004285}.
CC -!- INTERACTION:
CC O35244; P62259: Ywhae; Xeno; NbExp=2; IntAct=EBI-915490, EBI-356480;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19700648}. Lysosome
CC {ECO:0000269|PubMed:19700648}. Note=Also found in lung secretory
CC organelles (lamellar bodies). {ECO:0000269|PubMed:19700648}.
CC -!- PTM: Phosphorylation at Thr-177 by MAP kinases increases the
CC phospholipase activity of the enzyme (PubMed:19140803). Phosphorylated
CC form exhibits a greater lysophosphatidylcholine acyltransferase
CC activity compared to the non-phosphorylated form (PubMed:26830860).
CC {ECO:0000269|PubMed:19140803, ECO:0000269|PubMed:26830860}.
CC -!- PTM: Irreversibly inactivated by overoxidation of Cys-47 to sulfinic
CC acid (Cys-SO(2)H) and sulfonic acid (Cys-SO(3)H) forms upon oxidative
CC stress. {ECO:0000250|UniProtKB:P30041}.
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 1-Cys
CC peroxiredoxin, no C(R) is present and C(P) instead forms a disulfide
CC with a cysteine from another protein or with a small thiol molecule.
CC C(P) is reactivated by glutathionylation mediated by glutathione S-
CC transferase Pi, followed by spontaneous reduction of the enzyme with
CC glutathione. {ECO:0000305|PubMed:15004285}.
CC -!- SIMILARITY: Belongs to the peroxiredoxin family. Prx6 subfamily.
CC {ECO:0000305}.
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DR EMBL; AF014009; AAB66341.1; -; mRNA.
DR EMBL; Y17295; CAA76732.1; -; mRNA.
DR RefSeq; NP_446028.1; NM_053576.2.
DR AlphaFoldDB; O35244; -.
DR SMR; O35244; -.
DR BioGRID; 250165; 4.
DR IntAct; O35244; 6.
DR MINT; O35244; -.
DR STRING; 10116.ENSRNOP00000030323; -.
DR PeroxiBase; 4427; Rno1CysPrx.
DR iPTMnet; O35244; -.
DR PhosphoSitePlus; O35244; -.
DR SwissPalm; O35244; -.
DR World-2DPAGE; 0004:O35244; -.
DR jPOST; O35244; -.
DR PaxDb; O35244; -.
DR PRIDE; O35244; -.
DR GeneID; 94167; -.
DR KEGG; rno:94167; -.
DR UCSC; RGD:71005; rat.
DR CTD; 9588; -.
DR RGD; 71005; Prdx6.
DR eggNOG; KOG0854; Eukaryota.
DR HOGENOM; CLU_042529_4_1_1; -.
DR InParanoid; O35244; -.
DR OMA; RLTMLYP; -.
DR OrthoDB; 1129256at2759; -.
DR PhylomeDB; O35244; -.
DR TreeFam; TF105183; -.
DR BRENDA; 1.11.1.27; 5301.
DR BRENDA; 2.3.1.23; 5301.
DR BRENDA; 3.1.1.4; 5301.
DR Reactome; R-RNO-3299685; Detoxification of Reactive Oxygen Species.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR PRO; PR:O35244; -.
DR Proteomes; UP000002494; Chromosome 13.
DR Bgee; ENSRNOG00000002896; Expressed in lung and 19 other tissues.
DR Genevisible; O35244; RN.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0047184; F:1-acylglycerophosphocholine O-acyltransferase activity; IDA:UniProtKB.
DR GO; GO:0047499; F:calcium-independent phospholipase A2 activity; ISO:RGD.
DR GO; GO:0004602; F:glutathione peroxidase activity; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0004601; F:peroxidase activity; ISO:RGD.
DR GO; GO:0004623; F:phospholipase A2 activity; ISO:RGD.
DR GO; GO:0008379; F:thioredoxin peroxidase activity; IEA:InterPro.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
DR GO; GO:0032060; P:bleb assembly; ISO:RGD.
DR GO; GO:0045454; P:cell redox homeostasis; IBA:GO_Central.
DR GO; GO:0098869; P:cellular oxidant detoxification; ISO:RGD.
DR GO; GO:0046475; P:glycerophospholipid catabolic process; ISO:RGD.
DR GO; GO:0042744; P:hydrogen peroxide catabolic process; IDA:RGD.
DR GO; GO:0048026; P:positive regulation of mRNA splicing, via spliceosome; ISO:RGD.
DR GO; GO:0006979; P:response to oxidative stress; ISO:RGD.
DR GO; GO:0000302; P:response to reactive oxygen species; ISO:RGD.
DR CDD; cd03016; PRX_1cys; 1.
DR InterPro; IPR000866; AhpC/TSA.
DR InterPro; IPR024706; Peroxiredoxin_AhpC-typ.
DR InterPro; IPR019479; Peroxiredoxin_C.
DR InterPro; IPR045020; PRX_1cys.
DR InterPro; IPR036249; Thioredoxin-like_sf.
DR InterPro; IPR013766; Thioredoxin_domain.
DR Pfam; PF10417; 1-cysPrx_C; 1.
DR Pfam; PF00578; AhpC-TSA; 1.
DR PIRSF; PIRSF000239; AHPC; 1.
DR SUPFAM; SSF52833; SSF52833; 1.
DR PROSITE; PS51352; THIOREDOXIN_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Antioxidant; Cytoplasm; Direct protein sequencing; Hydrolase;
KW Lipid degradation; Lipid metabolism; Lysosome; Multifunctional enzyme;
KW Oxidoreductase; Peroxidase; Phosphoprotein; Redox-active center;
KW Reference proteome; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P30041"
FT CHAIN 2..224
FT /note="Peroxiredoxin-6"
FT /id="PRO_0000135104"
FT DOMAIN 5..169
FT /note="Thioredoxin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00691"
FT REGION 31..40
FT /note="Required and sufficient for targeting to lysosomes
FT and lamellar bodies"
FT /evidence="ECO:0000269|PubMed:19700648"
FT ACT_SITE 47
FT /note="Cysteine sulfenic acid (-SOH) intermediate; for
FT peroxidase activity"
FT /evidence="ECO:0000269|PubMed:17652308"
FT ACT_SITE 140
FT /note="For phospholipase activity"
FT /evidence="ECO:0000305|PubMed:17652308"
FT SITE 32
FT /note="Important for phospholipase activity"
FT /evidence="ECO:0000305|PubMed:17652308"
FT MOD_RES 44
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P30041"
FT MOD_RES 63
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P30041"
FT MOD_RES 89
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P30041"
FT MOD_RES 177
FT /note="Phosphothreonine; by MAPK"
FT /evidence="ECO:0000269|PubMed:19140803"
FT MOD_RES 209
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P30041"
FT MOD_RES 209
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08709"
FT MUTAGEN 26
FT /note="H->A: Abolishes lipid binding."
FT /evidence="ECO:0000269|PubMed:17652308"
FT MUTAGEN 32
FT /note="S->A: Abolishes lipid binding."
FT /evidence="ECO:0000269|PubMed:17652308"
FT MUTAGEN 140
FT /note="D->A: Abolishes phospholipase activity, but does not
FT impair lipid binding."
FT /evidence="ECO:0000269|PubMed:17652308"
SQ SEQUENCE 224 AA; 24819 MW; EE41D9079A708FD9 CRC64;
MPGGLLLGDE APNFEANTTI GHIRFHDFLG DSWGILFSHP RDFTPVCTTE LGRAAKLAPE
FAKRNVKLIA LSIDSVEDHF AWSKDINAYN GAAPTEKLPF PIIDDKDRDL AILLGMLDPA
EKDEKGMPVT ARVVFIFGPD KKLKLSILYP ATTGRNFDEI LRVVDSLQLT ASNPVATPVD
WKKGESVMVL PTLPEEEAKQ LFPKGVFTKE LPSGKKYLRY TPQP
