AK1A1_RAT
ID AK1A1_RAT Reviewed; 325 AA.
AC P51635;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Aldo-keto reductase family 1 member A1;
DE EC=1.1.1.2 {ECO:0000269|PubMed:22820017, ECO:0000269|PubMed:8500767};
DE EC=1.1.1.33 {ECO:0000269|PubMed:4463942};
DE EC=1.1.1.372 {ECO:0000269|PubMed:22820017};
DE EC=1.1.1.54 {ECO:0000269|PubMed:25152401};
DE AltName: Full=3-DG-reducing enzyme {ECO:0000303|PubMed:8500767};
DE AltName: Full=Alcohol dehydrogenase [NADP(+)];
DE AltName: Full=Aldehyde reductase {ECO:0000303|PubMed:7827091};
DE AltName: Full=Glucuronate reductase {ECO:0000303|PubMed:22820017};
DE EC=1.1.1.19 {ECO:0000269|PubMed:22820017};
DE AltName: Full=Glucuronolactone reductase {ECO:0000303|PubMed:22820017};
DE EC=1.1.1.20 {ECO:0000269|PubMed:22820017};
GN Name=Akr1a1; Synonyms=Alr;
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], PARTIAL PROTEIN SEQUENCE, TISSUE SPECIFICITY,
RP FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Kidney, and Liver;
RX PubMed=8500767; DOI=10.1016/0378-1119(93)90728-l;
RA Takahashi M., Fujii J., Teshima T., Suzuki K., Shiba T., Taniguchi N.;
RT "Identity of a major 3-deoxyglucosone-reducing enzyme with aldehyde
RT reductase in rat liver established by amino acid sequencing and cDNA
RT expression.";
RL Gene 127:249-253(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pituitary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PROTEIN SEQUENCE OF 14-30; 62-77; 81-97; 135-145 AND 146-157, GLYCATION AT
RP LYS-23; LYS-68; LYS-85; LYS-141 AND LYS-153, AND ABSENCE OF GLYCATION AT
RP LYS-13; LYS-30; LYS-34; LYS-61; LYS-80; LYS-97; LYS-127; LYS-134; LYS-145;
RP LYS-157; LYS-240; LYS-257; LYS-263; LYS-287; LYS-294 AND LYS-308.
RX PubMed=7827091; DOI=10.1021/bi00004a038;
RA Takahashi M., Lu Y.B., Myint T., Fujii J., Wada Y., Taniguchi N.;
RT "In vivo glycation of aldehyde reductase, a major 3-deoxyglucosone reducing
RT enzyme: identification of glycation sites.";
RL Biochemistry 34:1433-1438(1995).
RN [4]
RP PROTEIN SEQUENCE OF 204-218; 222-240; 270-287 AND 313-325, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=Sprague-Dawley; TISSUE=Spinal cord;
RA Lubec G., Afjehi-Sadat L.;
RL Submitted (NOV-2006) to UniProtKB.
RN [5]
RP CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=4463942; DOI=10.1042/bj1390205;
RA Beedle A.S., Rees H.H., Goodwin T.W.;
RT "Some properties and a suggested reclassification of mevaldate reductase.";
RL Biochem. J. 139:205-209(1974).
RN [6]
RP ACETYLATION AT THR-2, AND IDENTIFICATION BY MASS SPECTROMETRY.
RA Lubec G., Chen W.-Q.;
RL Submitted (FEB-2007) to UniProtKB.
RN [7]
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE SPECIFICITY,
RP AND FUNCTION.
RX PubMed=22820017; DOI=10.1016/j.bbagen.2012.07.003;
RA Takahashi M., Miyata S., Fujii J., Inai Y., Ueyama S., Araki M., Soga T.,
RA Fujinawa R., Nishitani C., Ariki S., Shimizu T., Abe T., Ihara Y.,
RA Nishikimi M., Kozutsumi Y., Taniguchi N., Kuroki Y.;
RT "In vivo role of aldehyde reductase.";
RL Biochim. Biophys. Acta 1820:1787-1796(2012).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-4, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [9]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=25152401; DOI=10.1016/j.bbrc.2014.08.072;
RA Kurahashi T., Kwon M., Homma T., Saito Y., Lee J., Takahashi M., Yamada K.,
RA Miyata S., Fujii J.;
RT "Reductive detoxification of acrolein as a potential role for aldehyde
RT reductase (AKR1A) in mammals.";
RL Biochem. Biophys. Res. Commun. 452:136-141(2014).
CC -!- FUNCTION: Catalyzes the NADPH-dependent reduction of a wide variety of
CC carbonyl-containing compounds to their corresponding alcohols. Displays
CC enzymatic activity towards endogenous metabolites such as aromatic and
CC aliphatic aldehydes, ketones, monosaccharides and bile acids (By
CC similarity) (PubMed:22820017, PubMed:25152401). Plays an important role
CC in ascorbic acid biosynthesis by catalyzing the reduction of D-
CC glucuronic acid and D-glucurono-gamma-lactone (PubMed:22820017).
CC Functions as a detoxifiying enzyme by reducing a range of toxic
CC aldehydes. Reduces methylglyoxal and 3-deoxyglucosone, which are
CC present at elevated levels under hyperglycemic conditions and are
CC cytotoxic (PubMed:8500767, PubMed:25152401). Involved also in the
CC detoxification of lipid-derived aldehydes like acrolein
CC (PubMed:25152401). Plays a role in the activation of procarcinogens,
CC such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the
CC metabolism of various xenobiotics and drugs (By similarity). Displays
CC no reductase activity towards retinoids (By similarity).
CC {ECO:0000250|UniProtKB:P14550, ECO:0000250|UniProtKB:P50578,
CC ECO:0000269|PubMed:22820017, ECO:0000269|PubMed:25152401,
CC ECO:0000269|PubMed:8500767}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a primary alcohol + NADP(+) = an aldehyde + H(+) + NADPH;
CC Xref=Rhea:RHEA:15937, ChEBI:CHEBI:15378, ChEBI:CHEBI:15734,
CC ChEBI:CHEBI:17478, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.2;
CC Evidence={ECO:0000269|PubMed:8500767};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-gulonate + NADP(+) = aldehydo-D-glucuronate + H(+) + NADPH;
CC Xref=Rhea:RHEA:14909, ChEBI:CHEBI:13115, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:142686;
CC EC=1.1.1.19; Evidence={ECO:0000269|PubMed:22820017};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-gulono-1,4-lactone + NADP(+) = D-glucurono-3,6-lactone +
CC H(+) + NADPH; Xref=Rhea:RHEA:18925, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17587, ChEBI:CHEBI:18268, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.1.1.20;
CC Evidence={ECO:0000269|PubMed:22820017};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=allyl alcohol + NADP(+) = acrolein + H(+) + NADPH;
CC Xref=Rhea:RHEA:12168, ChEBI:CHEBI:15368, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16605, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.54;
CC Evidence={ECO:0000269|PubMed:25152401};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glycerol + NADP(+) = D-glyceraldehyde + H(+) + NADPH;
CC Xref=Rhea:RHEA:23592, ChEBI:CHEBI:15378, ChEBI:CHEBI:17378,
CC ChEBI:CHEBI:17754, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC EC=1.1.1.372; Evidence={ECO:0000269|PubMed:22820017};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glycerol + NADP(+) = H(+) + L-glyceraldehyde + NADPH;
CC Xref=Rhea:RHEA:38111, ChEBI:CHEBI:15378, ChEBI:CHEBI:17754,
CC ChEBI:CHEBI:27975, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC EC=1.1.1.372; Evidence={ECO:0000269|PubMed:22820017};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=hydroxyacetone + NADP(+) = H(+) + methylglyoxal + NADPH;
CC Xref=Rhea:RHEA:27986, ChEBI:CHEBI:15378, ChEBI:CHEBI:17158,
CC ChEBI:CHEBI:27957, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000269|PubMed:22820017};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3-deoxyfructose + NADP(+) = 3-deoxyglucosone + H(+) + NADPH;
CC Xref=Rhea:RHEA:58668, ChEBI:CHEBI:15378, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:60777, ChEBI:CHEBI:142685;
CC Evidence={ECO:0000269|PubMed:22820017, ECO:0000269|PubMed:8500767};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + NADP(+) = H(+) + mevaldate + NADPH;
CC Xref=Rhea:RHEA:20193, ChEBI:CHEBI:15378, ChEBI:CHEBI:36464,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58219, ChEBI:CHEBI:58349; EC=1.1.1.33;
CC Evidence={ECO:0000269|PubMed:4463942};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NADP(+) + pyridine 3-methanol = H(+) + NADPH + pyridine-3-
CC carbaldehyde; Xref=Rhea:RHEA:58776, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:28345, ChEBI:CHEBI:45213, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; Evidence={ECO:0000269|PubMed:8500767};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.9 mM for D,L glyceraldehyde {ECO:0000269|PubMed:22820017};
CC KM=1.8 mM for D-glucuronic acid {ECO:0000269|PubMed:22820017};
CC KM=0.31 mM for methylglyoxal {ECO:0000269|PubMed:22820017};
CC KM=0.63 mM for 3-deoxyglucosone {ECO:0000269|PubMed:22820017};
CC KM=11 mM for D-glucurono-gamma-lactone {ECO:0000269|PubMed:22820017};
CC KM=2.4 mM for acrolein {ECO:0000269|PubMed:25152401};
CC KM=0.260 mM for mevaldate {ECO:0000269|PubMed:4463942};
CC Note=kcat is 3.0 sec(-1) for D,L glyceraldehyde as substrate
CC (PubMed:22820017). kcat is 3.0 sec(-1) for methylglyoxal as substrate
CC (PubMed:22820017). kcat is 3.4 sec(-1) for 3-deoxyglucosone as
CC substrate (PubMed:22820017). kcat is 3.1 sec(-1) for D-glucuronic
CC acid as substrate (PubMed:22820017). kcat is 3.7 sec(-1) for D-
CC glucurono-gamma-lactone acid as substrate (PubMed:22820017).
CC {ECO:0000269|PubMed:22820017};
CC -!- SUBUNIT: Monomer. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9JII6}. Apical cell membrane
CC {ECO:0000250|UniProtKB:Q9JII6}.
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:8500767}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; D10854; BAA01627.1; -; mRNA.
DR EMBL; BC059133; AAH59133.1; -; mRNA.
DR PIR; JN0629; JN0629.
DR RefSeq; NP_112262.1; NM_031000.3.
DR AlphaFoldDB; P51635; -.
DR SMR; P51635; -.
DR IntAct; P51635; 1.
DR STRING; 10116.ENSRNOP00000023072; -.
DR BindingDB; P51635; -.
DR ChEMBL; CHEMBL3871; -.
DR DrugCentral; P51635; -.
DR iPTMnet; P51635; -.
DR PhosphoSitePlus; P51635; -.
DR SwissPalm; P51635; -.
DR World-2DPAGE; 0004:P51635; -.
DR jPOST; P51635; -.
DR PaxDb; P51635; -.
DR PRIDE; P51635; -.
DR Ensembl; ENSRNOT00000023072; ENSRNOP00000023072; ENSRNOG00000016727.
DR GeneID; 78959; -.
DR KEGG; rno:78959; -.
DR UCSC; RGD:68346; rat.
DR CTD; 10327; -.
DR RGD; 68346; Akr1a1.
DR eggNOG; KOG1577; Eukaryota.
DR GeneTree; ENSGT00940000156539; -.
DR HOGENOM; CLU_023205_0_0_1; -.
DR InParanoid; P51635; -.
DR OMA; WRHPDEP; -.
DR OrthoDB; 1016440at2759; -.
DR PhylomeDB; P51635; -.
DR TreeFam; TF106492; -.
DR BRENDA; 1.1.1.2; 5301.
DR Reactome; R-RNO-156590; Glutathione conjugation.
DR Reactome; R-RNO-5661270; Formation of xylulose-5-phosphate.
DR SABIO-RK; P51635; -.
DR PRO; PR:P51635; -.
DR Proteomes; UP000002494; Chromosome 5.
DR Bgee; ENSRNOG00000016727; Expressed in adult mammalian kidney and 19 other tissues.
DR Genevisible; P51635; RN.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; ISO:RGD.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; ISO:RGD.
DR GO; GO:0047655; F:allyl-alcohol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047941; F:glucuronolactone reductase activity; IDA:UniProtKB.
DR GO; GO:0047956; F:glycerol dehydrogenase [NADP+] activity; IEA:RHEA.
DR GO; GO:0047939; F:L-glucuronate reductase activity; IDA:UniProtKB.
DR GO; GO:1990002; F:methylglyoxal reductase (NADPH-dependent, acetol producing); IEA:RHEA.
DR GO; GO:0019726; F:mevaldate reductase (NADPH) activity; IEA:UniProtKB-EC.
DR GO; GO:0016657; F:oxidoreductase activity, acting on NAD(P)H, nitrogenous group as acceptor; IEA:Ensembl.
DR GO; GO:0046185; P:aldehyde catabolic process; ISO:RGD.
DR GO; GO:0110095; P:cellular detoxification of aldehyde; IDA:UniProtKB.
DR GO; GO:0042840; P:D-glucuronate catabolic process; IMP:UniProtKB.
DR GO; GO:0044597; P:daunorubicin metabolic process; ISO:RGD.
DR GO; GO:0044598; P:doxorubicin metabolic process; ISO:RGD.
DR GO; GO:0019853; P:L-ascorbic acid biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR CDD; cd19106; AKR_AKR1A1-4; 1.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR020471; AKR.
DR InterPro; IPR044481; AKR1A.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR InterPro; IPR036812; NADP_OxRdtase_dom_sf.
DR Pfam; PF00248; Aldo_ket_red; 1.
DR PIRSF; PIRSF000097; AKR; 1.
DR PRINTS; PR00069; ALDKETRDTASE.
DR SUPFAM; SSF51430; SSF51430; 1.
DR PROSITE; PS00798; ALDOKETO_REDUCTASE_1; 1.
DR PROSITE; PS00062; ALDOKETO_REDUCTASE_2; 1.
DR PROSITE; PS00063; ALDOKETO_REDUCTASE_3; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cell membrane; Cytoplasm; Direct protein sequencing;
KW Glycation; Glycoprotein; Lipid metabolism; Membrane; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|Ref.6"
FT CHAIN 2..325
FT /note="Aldo-keto reductase family 1 member A1"
FT /id="PRO_0000124620"
FT ACT_SITE 50
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT BINDING 11..20
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000255"
FT BINDING 113
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT BINDING 211..273
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT SITE 13
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 30
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 34
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 61
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 80
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT SITE 80
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 97
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 127
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 134
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 145
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 157
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 240
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 257
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 263
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 287
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 294
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT SITE 308
FT /note="Not glycated"
FT /evidence="ECO:0000269|PubMed:7827091"
FT MOD_RES 2
FT /note="N-acetylthreonine"
FT /evidence="ECO:0000269|Ref.6"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 38
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT MOD_RES 127
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9JII6"
FT MOD_RES 127
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9JII6"
FT MOD_RES 145
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9JII6"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT CARBOHYD 23
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000269|PubMed:7827091"
FT CARBOHYD 68
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000269|PubMed:7827091"
FT CARBOHYD 85
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000269|PubMed:7827091"
FT CARBOHYD 141
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000269|PubMed:7827091"
FT CARBOHYD 153
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000269|PubMed:7827091"
SQ SEQUENCE 325 AA; 36506 MW; F95573B7411884DA CRC64;
MTASSVLLHT GQKMPLIGLG TWKSEPGQVK AAIKYALSVG YRHIDCASVY GNETEIGEAL
KESVGAGKAV PREELFVTSK LWNTKHHPED VEPAVRKTLA DLQLEYLDLY LMHWPYAFER
GDNPFPKNAD GTVKYDSTHY KETWKALEAL VAKGLVKALG LSNFSSRQID DVLSVASVRP
AVLQVECHPY LAQNELIAHC QARGLEVTAY SPLGSSDRAW RHPDEPVLLE EPVVLALAEK
HGRSPAQILL RWQVQRKVIC IPKSITPSRI LQNIQVFDFT FSPEEMKQLD ALNKNWRYIV
PMITVDGKRV PRDAGHPLYP FNDPY
