AK1CA_RAT
ID AK1CA_RAT Reviewed; 324 AA.
AC D3ZF77;
DT 10-OCT-2018, integrated into UniProtKB/Swiss-Prot.
DT 20-APR-2010, sequence version 1.
DT 03-AUG-2022, entry version 85.
DE RecName: Full=Aldo-keto reductase family 1 member C15 {ECO:0000305};
DE EC=1.1.1.- {ECO:0000269|PubMed:17574202, ECO:0000269|PubMed:21187079, ECO:0000269|PubMed:21187080};
DE EC=1.1.1.216 {ECO:0000269|PubMed:17574202, ECO:0000269|PubMed:21187079};
DE AltName: Full=RAKc {ECO:0000303|PubMed:7511002};
GN Name=Akr1c15 {ECO:0000303|PubMed:17574202, ECO:0000312|RGD:1307514};
GN Synonyms=Akr1cl {ECO:0000312|RGD:1307514};
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 {ECO:0000312|Proteomes:UP000002494};
RN [1] {ECO:0000312|Proteomes:UP000002494}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway {ECO:0000312|Proteomes:UP000002494};
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2] {ECO:0000312|EMBL:EDL78576.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3] {ECO:0000305}
RP IDENTIFICATION, AND TISSUE SPECIFICITY.
RX PubMed=7511002; DOI=10.1021/bi00177a012;
RA Qin K.N., Cheng K.C.;
RT "Structure and tissue-specific expression of the aldo-keto reductase
RT superfamily.";
RL Biochemistry 33:3223-3228(1994).
RN [4] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17574202; DOI=10.1016/j.abb.2007.05.008;
RA Endo S., Matsunaga T., Horie K., Tajima K., Bunai Y., Carbone V.,
RA El-Kabbani O., Hara A.;
RT "Enzymatic characteristics of an aldo-keto reductase family protein
RT (AKR1C15) and its localization in rat tissues.";
RL Arch. Biochem. Biophys. 465:136-147(2007).
RN [5] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=21187079; DOI=10.1016/j.cbi.2010.12.017;
RA Endo S., Matsunaga T., Ohta C., Soda M., Kanamori A., Kitade Y., Ohno S.,
RA Tajima K., El-Kabbani O., Hara A.;
RT "Roles of rat and human aldo-keto reductases in metabolism of farnesol and
RT geranylgeraniol.";
RL Chem. Biol. Interact. 191:261-268(2011).
RN [6] {ECO:0000305}
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=21187080; DOI=10.1016/j.cbi.2010.12.018;
RA Matsunaga T., Shinoda Y., Inoue Y., Endo S., El-Kabbani O., Hara A.;
RT "Protective effect of rat aldo-keto reductase (AKR1C15) on endothelial cell
RT damage elicited by 4-hydroxy-2-nonenal.";
RL Chem. Biol. Interact. 191:364-370(2011).
CC -!- FUNCTION: Catalyzes the NADPH-dependent reduction of a variety of
CC substrates including aromatic and aliphatic aldehydes, quinones,
CC ketones, dicarbonyl compounds and 17-ketosteroids (PubMed:17574202).
CC Catalyzes the NADP(+)-dependent oxidation of aromatic, alicyclic and
CC aliphatic alcohols, and 17beta-hydroxysteroids (PubMed:17574202). To a
CC lesser extent, can also catalyze the reduction of some aldoses and
CC ketoses and the oxidation of some sugar alcohols (PubMed:17574202). In
CC the stomach, lung and colon tissues, mediates the reduction of farnesal
CC and geranylgeranial into farnesol and geranylgeraniol respectively
CC (PubMed:21187079). By reducing 4-hydroxy-2-nonenal (HNE), produced
CC during lipid peroxidation, into 1,4-dihydro-2-nonene (DHN), protects
CC vascular endothelial cells from damage elicited by oxidized
CC lipoproteins (PubMed:21187080). {ECO:0000269|PubMed:17574202,
CC ECO:0000269|PubMed:21187079, ECO:0000269|PubMed:21187080}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E,6E)-farnesol + NADP(+) = (2E,6E)-farnesal + H(+) + NADPH;
CC Xref=Rhea:RHEA:14697, ChEBI:CHEBI:15378, ChEBI:CHEBI:15894,
CC ChEBI:CHEBI:16619, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC EC=1.1.1.216; Evidence={ECO:0000269|PubMed:17574202,
CC ECO:0000269|PubMed:21187079};
CC -!- ACTIVITY REGULATION: The dehydrogenase activity is inhibited by
CC 3',3'',5',5''-tetraiodophenolphthalein, phenolphthalein, genistein,
CC quercetin, zearalenone and diethylstilbestrol.
CC {ECO:0000269|PubMed:17574202}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.2 uM for 4-nitrobenzaldehyde {ECO:0000269|PubMed:17574202};
CC KM=3.1 uM for benzaldehyde {ECO:0000269|PubMed:17574202};
CC KM=20 uM for pyridine-4-aldehyde {ECO:0000269|PubMed:17574202};
CC KM=25 uM for 2-phenyl-2-propenal {ECO:0000269|PubMed:17574202};
CC KM=2.4 uM for NADP(+) {ECO:0000269|PubMed:17574202};
CC KM=1430 uM for NAD(+) {ECO:0000269|PubMed:17574202};
CC KM=0.6 uM for NADPH {ECO:0000269|PubMed:17574202};
CC KM=43 uM for NADH {ECO:0000269|PubMed:17574202};
CC KM=0.3 uM for 1-decanal {ECO:0000269|PubMed:17574202};
CC KM=0.9 uM for 1-nonanal {ECO:0000269|PubMed:17574202};
CC KM=1.1 uM for 1-octanal {ECO:0000269|PubMed:17574202};
CC KM=1.1 uM for 1-hexanal {ECO:0000269|PubMed:17574202};
CC KM=112 uM for D-lactoaldehyde {ECO:0000269|PubMed:17574202};
CC KM=125 uM for L-lactoaldehyde {ECO:0000269|PubMed:17574202};
CC KM=225 uM for 4-methylpentanal (isocaproaldehyde)
CC {ECO:0000269|PubMed:17574202};
CC KM=0.4 uM for all-trans-retinal {ECO:0000269|PubMed:17574202};
CC KM=3.5 uM for trans-2,4-nonadienal {ECO:0000269|PubMed:17574202};
CC KM=3.3 uM for trans-2-nonenal {ECO:0000269|PubMed:17574202};
CC KM=2.3 uM for 9-cis-retinal {ECO:0000269|PubMed:17574202};
CC KM=2.5 uM for 4-hydroxy-2-nonenal (HNE)
CC {ECO:0000269|PubMed:17574202};
CC KM=0.8 uM for 6-tert-butyl-2,3-epoxy-4-benzoquinone (TBE)
CC {ECO:0000269|PubMed:17574202};
CC KM=2.7 uM for 1,4-naphthoquinone {ECO:0000269|PubMed:17574202};
CC KM=14 uM for 5-hydroxy-1,4-naphthoquinone (juglone)
CC {ECO:0000269|PubMed:17574202};
CC KM=22 uM for 1-indanone {ECO:0000269|PubMed:17574202};
CC KM=22 uM for 3-hydroxy-2-butanone {ECO:0000269|PubMed:17574202};
CC KM=0.5 uM for 1H-indole-2,3-dione (isatin)
CC {ECO:0000269|PubMed:17574202};
CC KM=0.6 uM for 16-ketoestrone {ECO:0000269|PubMed:17574202};
CC KM=2 uM for 2,3-hexanedione {ECO:0000269|PubMed:17574202};
CC KM=5.5 uM for butane-2,3-dione (diacetyl)
CC {ECO:0000269|PubMed:17574202};
CC KM=16 uM for methylglyoxal {ECO:0000269|PubMed:17574202};
CC KM=30 uM for 21-dehydrocortisol {ECO:0000269|PubMed:17574202};
CC KM=12 uM for S-indan-1-ol {ECO:0000269|PubMed:17574202};
CC KM=32 uM for farnesol {ECO:0000269|PubMed:17574202};
CC KM=5.6 uM for farnesal {ECO:0000269|PubMed:17574202};
CC KM=16 uM for geranylgeraniol {ECO:0000269|PubMed:17574202};
CC KM=0.2 uM for geranylgeranial {ECO:0000269|PubMed:21187079};
CC KM=15 uM for 1-nonanol {ECO:0000269|PubMed:17574202};
CC KM=8.2 uM for 1-decanol {ECO:0000269|PubMed:17574202};
CC KM=11 uM for 5-beta-androstane-3,17-dione (etiocholanedione)
CC {ECO:0000269|PubMed:17574202};
CC KM=8.7 uM for 5-alpha-androstane-3,17-dione (androstanedione)
CC {ECO:0000269|PubMed:17574202};
CC KM=5.6 uM for 4-androstene-3,17-dione {ECO:0000269|PubMed:17574202};
CC KM=36 uM for 5-alpha-androstan-3alpha-ol-17-one
CC {ECO:0000269|PubMed:17574202};
CC KM=8.7 uM for 5-beta-androstan-3alpha-ol-17-one
CC {ECO:0000269|PubMed:17574202};
CC KM=8.5 uM for 5-beta-androstane-3alpha,17beta-diol
CC {ECO:0000269|PubMed:17574202};
CC KM=12 uM for 5-beta-androstan-17beta-ol-3-one
CC {ECO:0000269|PubMed:17574202};
CC KM=6.9 uM for 5-alpha-androstane-3-alpha,17-beta-diol
CC {ECO:0000269|PubMed:17574202};
CC KM=18 uM for testosterone {ECO:0000269|PubMed:17574202};
CC KM=18 uM for 5-alpha-androstan-17beta-ol-3-one
CC {ECO:0000269|PubMed:17574202};
CC pH dependence:
CC Optimum pH is 10.5 for the dehydrogenase activity. Optimum pH is 6
CC for the reductase activity. {ECO:0000269|PubMed:17574202};
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:17574202}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17574202,
CC ECO:0000269|PubMed:21187079}.
CC -!- TISSUE SPECIFICITY: Expressed in lung, specifically in bronchiolar
CC Clara cells, type II alveolar cells and epithelial cells of the duct of
CC the bronchial gland (at protein level) (PubMed:17574202,
CC PubMed:7511002, PubMed:21187079). Expressed in gastric parietal cells
CC and in epithelial cells of the large intestine and colon (at protein
CC level) (PubMed:17574202, PubMed:21187079). Expressed in brown
CC adipocytes (at protein level) (PubMed:17574202). Expressed in vascular
CC endothelial cells (at protein level) (PubMed:17574202).
CC {ECO:0000269|PubMed:17574202, ECO:0000269|PubMed:21187079,
CC ECO:0000269|PubMed:7511002}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; AABR07028443; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH473990; EDL78576.1; -; Genomic_DNA.
DR RefSeq; NP_001103370.1; NM_001109900.1.
DR AlphaFoldDB; D3ZF77; -.
DR SMR; D3ZF77; -.
DR STRING; 10116.ENSRNOP00000055113; -.
DR iPTMnet; D3ZF77; -.
DR PhosphoSitePlus; D3ZF77; -.
DR PaxDb; D3ZF77; -.
DR PeptideAtlas; D3ZF77; -.
DR PRIDE; D3ZF77; -.
DR Ensembl; ENSRNOT00000058312; ENSRNOP00000055113; ENSRNOG00000021735.
DR GeneID; 361267; -.
DR KEGG; rno:361267; -.
DR UCSC; RGD:1307514; rat.
DR CTD; 361267; -.
DR RGD; 1307514; Akr1c15.
DR eggNOG; KOG1577; Eukaryota.
DR GeneTree; ENSGT00940000163184; -.
DR HOGENOM; CLU_023205_0_0_1; -.
DR InParanoid; D3ZF77; -.
DR OMA; ECSPAIN; -.
DR OrthoDB; 1016440at2759; -.
DR PhylomeDB; D3ZF77; -.
DR TreeFam; TF106492; -.
DR PRO; PR:D3ZF77; -.
DR Proteomes; UP000002494; Chromosome 17.
DR Proteomes; UP000234681; Chromosome 17.
DR Bgee; ENSRNOG00000021735; Expressed in lung and 18 other tissues.
DR ExpressionAtlas; D3ZF77; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0004033; F:aldo-keto reductase (NADP) activity; IDA:UniProtKB.
DR GO; GO:0047886; F:farnesol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IBA:GO_Central.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IBA:GO_Central.
DR GO; GO:0008202; P:steroid metabolic process; IBA:GO_Central.
DR CDD; cd19108; AKR_AKR1C1-35; 1.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR020471; AKR.
DR InterPro; IPR044482; AKR1C.
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 Cytoplasm; NADP; Oxidoreductase; Reference proteome.
FT CHAIN 1..324
FT /note="Aldo-keto reductase family 1 member C15"
FT /id="PRO_0000445546"
FT ACT_SITE 56
FT /note="Proton donor"
FT /evidence="ECO:0000255|PIRSR:PIRSR000097-1"
FT BINDING 24..26
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 51
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 118
FT /ligand="substrate"
FT /evidence="ECO:0000255|PIRSR:PIRSR000097-2"
FT BINDING 167..168
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 191
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 217..225
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 269..281
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT SITE 85
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000255|PIRSR:PIRSR000097-3"
SQ SEQUENCE 324 AA; 37195 MW; 851BFF1FD9476B13 CRC64;
MDLKHSRSVK LNDGNLMPVL GFGTFASKEI PKSKAAEATK VAIDVGFRHI DAAYFYQNEE
EVGQALRDKM ADGTVKREDL FYTTKIWITF LRPELVRQCL ERSLKKLGLD YVDLCIIHIP
IAMKPGEELL PKDANGKFIF DTVDIRDTWE ALEKCKDAGL SKSIGVSNFN HKQLELILNK
PRLKYKPTCN QVECHPYLNQ SKLLEFCKSK DIVLVAYSAL GSHRDSSWVS SDSPYLLEDP
VLMTIAKKHN QTPGQVALRY QLQRGVVVLA KSFNEKRIKE NFQVFDFELT PEDMKTIDSL
NRNFRYSQMA FALDHPDYPF LEEY
