AK1A1_HUMAN
ID AK1A1_HUMAN Reviewed; 325 AA.
AC P14550; A8KAL8; D3DQ04; Q6IAZ4;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 213.
DE RecName: Full=Aldo-keto reductase family 1 member A1;
DE EC=1.1.1.2 {ECO:0000269|PubMed:10510318};
DE EC=1.1.1.372 {ECO:0000269|PubMed:10510318};
DE EC=1.1.1.54 {ECO:0000269|PubMed:10510318};
DE AltName: Full=Alcohol dehydrogenase [NADP(+)];
DE AltName: Full=Aldehyde reductase;
DE AltName: Full=Glucuronate reductase;
DE EC=1.1.1.19 {ECO:0000250|UniProtKB:P51635};
DE AltName: Full=Glucuronolactone reductase;
DE EC=1.1.1.20 {ECO:0000250|UniProtKB:P51635};
GN Name=AKR1A1; Synonyms=ALDR1, ALR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2498333; DOI=10.1016/s0021-9258(18)60566-6;
RA Bohren K.M., Bullock B., Wermuth B., Gabbay K.H.;
RT "The aldo-keto reductase superfamily. cDNAs and deduced amino acid
RT sequences of human aldehyde and aldose reductases.";
RL J. Biol. Chem. 264:9547-9551(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10393438; DOI=10.1159/000015265;
RA Fujii J., Hamaoka R., Matsumoto A., Fujii T., Yamaguchi Y., Egashira M.,
RA Miyoshi O., Niikawa N., Taniguchi N.;
RT "The structural organization of the human aldehyde reductase gene, AKR1A1,
RT and mapping to chromosome 1p33-->p32.";
RL Cytogenet. Cell Genet. 84:230-232(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RX PubMed=10486210; DOI=10.1006/geno.1999.5915;
RA Barski O.A., Gabbay K.H., Bohren K.M.;
RT "Characterization of the human aldehyde reductase gene and promoter.";
RL Genomics 60:188-198(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Kidney;
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 [10]
RP PROTEIN SEQUENCE OF 2-325.
RC TISSUE=Liver;
RX PubMed=3615425;
RA Wermuth B., Omar A., Forster A., di Francesco C., Wolf M.,
RA von Wartburg J.-P., Bullock B., Gabbay K.H.;
RT "Primary structure of aldehyde reductase from human liver.";
RL Prog. Clin. Biol. Res. 232:297-307(1987).
RN [11]
RP MUTAGENESIS OF TYR-50; LYS-80; HIS-113; ILE-299 AND VAL-300.
RX PubMed=7669785; DOI=10.1021/bi00035a036;
RA Barski O.A., Gabbay K.H., Grimshaw C.E., Bohren K.M.;
RT "Mechanism of human aldehyde reductase: characterization of the active site
RT pocket.";
RL Biochemistry 34:11264-11275(1995).
RN [12]
RP FUNCTION, TISSUE SPECIFICITY, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND SUBSTRATE SPECIFICITY.
RX PubMed=10510318; DOI=10.1042/bj3430487;
RA O'Connor T., Ireland L.S., Harrison D.J., Hayes J.D.;
RT "Major differences exist in the function and tissue-specific expression of
RT human aflatoxin B1 aldehyde reductase and the principal human aldo-keto
RT reductase AKR1 family members.";
RL Biochem. J. 343:487-504(1999).
RN [13]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=11306097; DOI=10.1016/s0009-2797(00)00237-4;
RA Palackal N.T., Burczynski M.E., Harvey R.G., Penning T.M.;
RT "Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols
RT by ubiquitously expressed aldehyde reductase (AKR1A1).";
RL Chem. Biol. Interact. 130:815-824(2001).
RN [14]
RP FUNCTION, AND CHARACTERIZATION OF VARIANTS SER-52 AND ASP-55.
RX PubMed=18276838; DOI=10.1124/dmd.107.018895;
RA Bains O.S., Takahashi R.H., Pfeifer T.A., Grigliatti T.A., Reid R.E.,
RA Riggs K.W.;
RT "Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro
RT metabolism of daunorubicin.";
RL Drug Metab. Dispos. 36:904-910(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-38, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS).
RX PubMed=15299353; DOI=10.1107/s0907444994005275;
RA El-Kabbani O., Green N.C., Lin G., Carson M., Narayana S.V.L., Moore K.M.,
RA Flynn T.G., DeLucas L.J.;
RT "Structures of human and porcine aldehyde reductase: an enzyme implicated
RT in diabetic complications.";
RL Acta Crystallogr. D 50:859-868(1994).
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, with a
CC preference for negatively charged substrates, such as glucuronate and
CC succinic semialdehyde (PubMed:10510318). Functions as a detoxifiying
CC enzyme by reducing a range of toxic aldehydes. Reduces methylglyoxal
CC and 3-deoxyglucosone, which are present at elevated levels under
CC hyperglycemic conditions and are cytotoxic. Involved also in the
CC detoxification of lipid-derived aldehydes like acrolein (By
CC similarity). Plays a role in the activation of procarcinogens, such as
CC polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the
CC metabolism of various xenobiotics and drugs, including the
CC anthracyclines doxorubicin (DOX) and daunorubicin (DAUN)
CC (PubMed:18276838, PubMed:11306097). Displays no reductase activity
CC towards retinoids (By similarity). {ECO:0000250|UniProtKB:P50578,
CC ECO:0000250|UniProtKB:P51635, ECO:0000269|PubMed:10510318,
CC ECO:0000269|PubMed:11306097, ECO:0000269|PubMed:18276838}.
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:10510318};
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:10510318};
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:10510318};
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:10510318};
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:10510318};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 4-hydroxynonen-1-ol + NADP(+) = a 4-hydroxynonenal + H(+) +
CC NADPH; Xref=Rhea:RHEA:58336, ChEBI:CHEBI:15378, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:142593, ChEBI:CHEBI:142606;
CC Evidence={ECO:0000269|PubMed:10510318};
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:0000250|UniProtKB:P51635};
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:10510318};
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:0000250|UniProtKB:P51635};
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:10510318};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=1426 nmol/min/mg enzyme for 4-hydroxynonenal
CC {ECO:0000269|PubMed:10510318};
CC Vmax=268 nmol/min/mg enzyme for acrolein
CC {ECO:0000269|PubMed:10510318};
CC Vmax=3460 nmol/min/mg enzyme for pyridine-3-carbaldehyde
CC {ECO:0000269|PubMed:10510318};
CC Vmax=4273 nmol/min/mg enzyme for methylglyoxal
CC {ECO:0000269|PubMed:10510318};
CC Vmax=1263 nmol/min/mg enzyme for D,L-glyceraldehyde
CC {ECO:0000269|PubMed:10510318};
CC Vmax=5562 nmol/min/mg enzyme for D-glucuronic acid
CC {ECO:0000269|PubMed:10510318};
CC Vmax=4983 nmol/min/mg enzyme for succinic semialdehyde
CC {ECO:0000269|PubMed:10510318};
CC -!- SUBUNIT: Monomer. {ECO:0000250}.
CC -!- INTERACTION:
CC P14550; P42858: HTT; NbExp=6; IntAct=EBI-372388, EBI-466029;
CC P14550; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-372388, EBI-750109;
CC P14550; O76024: WFS1; NbExp=3; IntAct=EBI-372388, EBI-720609;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9JII6}. Apical cell membrane
CC {ECO:0000250|UniProtKB:Q9JII6}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in kidney,
CC salivary gland and liver. Detected in trachea, stomach, brain, lung,
CC prostate, placenta, mammary gland, small intestine and lung.
CC {ECO:0000269|PubMed:10486210, ECO:0000269|PubMed:10510318,
CC ECO:0000269|PubMed:11306097}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; J04794; AAA51711.1; -; mRNA.
DR EMBL; AF036683; AAB92369.1; -; Genomic_DNA.
DR EMBL; AF036680; AAB92369.1; JOINED; Genomic_DNA.
DR EMBL; AF036681; AAB92369.1; JOINED; Genomic_DNA.
DR EMBL; AF036682; AAB92369.1; JOINED; Genomic_DNA.
DR EMBL; AF112485; AAF01260.1; -; Genomic_DNA.
DR EMBL; AF112484; AAF01260.1; JOINED; Genomic_DNA.
DR EMBL; AK293083; BAF85772.1; -; mRNA.
DR EMBL; CR457010; CAG33291.1; -; mRNA.
DR EMBL; BT007003; AAP35649.1; -; mRNA.
DR EMBL; AL355480; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471059; EAX06970.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX06971.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX06972.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX06974.1; -; Genomic_DNA.
DR EMBL; BC000670; AAH00670.1; -; mRNA.
DR EMBL; BC005394; AAH05394.1; -; mRNA.
DR CCDS; CCDS523.1; -.
DR PIR; A33851; A33851.
DR RefSeq; NP_001189342.1; NM_001202413.1.
DR RefSeq; NP_001189343.1; NM_001202414.1.
DR RefSeq; NP_006057.1; NM_006066.3.
DR RefSeq; NP_697021.1; NM_153326.2.
DR PDB; 2ALR; X-ray; 2.48 A; A=2-325.
DR PDBsum; 2ALR; -.
DR AlphaFoldDB; P14550; -.
DR SMR; P14550; -.
DR BioGRID; 115610; 44.
DR IntAct; P14550; 14.
DR MINT; P14550; -.
DR STRING; 9606.ENSP00000361140; -.
DR BindingDB; P14550; -.
DR ChEMBL; CHEMBL2246; -.
DR DrugBank; DB08904; Certolizumab pegol.
DR DrugBank; DB09130; Copper.
DR DrugBank; DB00997; Doxorubicin.
DR DrugBank; DB00898; Ethanol.
DR DrugBank; DB06077; Lumateperone.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB03461; Nicotinamide adenine dinucleotide phosphate.
DR DrugBank; DB06207; Silodosin.
DR DrugBank; DB02383; Tolrestat.
DR DrugCentral; P14550; -.
DR GlyGen; P14550; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P14550; -.
DR MetOSite; P14550; -.
DR PhosphoSitePlus; P14550; -.
DR SwissPalm; P14550; -.
DR BioMuta; AKR1A1; -.
DR DMDM; 113600; -.
DR REPRODUCTION-2DPAGE; IPI00220271; -.
DR REPRODUCTION-2DPAGE; P14550; -.
DR SWISS-2DPAGE; P14550; -.
DR UCD-2DPAGE; P14550; -.
DR CPTAC; CPTAC-10; -.
DR CPTAC; CPTAC-9; -.
DR EPD; P14550; -.
DR jPOST; P14550; -.
DR MassIVE; P14550; -.
DR PaxDb; P14550; -.
DR PeptideAtlas; P14550; -.
DR PRIDE; P14550; -.
DR ProteomicsDB; 53058; -.
DR Antibodypedia; 3338; 594 antibodies from 37 providers.
DR DNASU; 10327; -.
DR Ensembl; ENST00000351829.9; ENSP00000312606.4; ENSG00000117448.14.
DR Ensembl; ENST00000372070.7; ENSP00000361140.3; ENSG00000117448.14.
DR Ensembl; ENST00000621846.4; ENSP00000480713.1; ENSG00000117448.14.
DR GeneID; 10327; -.
DR KEGG; hsa:10327; -.
DR MANE-Select; ENST00000351829.9; ENSP00000312606.4; NM_153326.3; NP_697021.1.
DR CTD; 10327; -.
DR DisGeNET; 10327; -.
DR GeneCards; AKR1A1; -.
DR HGNC; HGNC:380; AKR1A1.
DR HPA; ENSG00000117448; Low tissue specificity.
DR MIM; 103830; gene.
DR neXtProt; NX_P14550; -.
DR OpenTargets; ENSG00000117448; -.
DR PharmGKB; PA24674; -.
DR VEuPathDB; HostDB:ENSG00000117448; -.
DR eggNOG; KOG1577; Eukaryota.
DR GeneTree; ENSGT00940000156539; -.
DR HOGENOM; CLU_023205_0_0_1; -.
DR InParanoid; P14550; -.
DR OMA; WRHPDEP; -.
DR OrthoDB; 1016440at2759; -.
DR PhylomeDB; P14550; -.
DR TreeFam; TF106492; -.
DR BRENDA; 1.1.1.2; 2681.
DR PathwayCommons; P14550; -.
DR Reactome; R-HSA-156590; Glutathione conjugation.
DR Reactome; R-HSA-5661270; Formation of xylulose-5-phosphate.
DR SABIO-RK; P14550; -.
DR SignaLink; P14550; -.
DR BioGRID-ORCS; 10327; 13 hits in 1080 CRISPR screens.
DR ChiTaRS; AKR1A1; human.
DR EvolutionaryTrace; P14550; -.
DR GeneWiki; Aldo-keto_reductase_family_1,_member_A1; -.
DR GenomeRNAi; 10327; -.
DR Pharos; P14550; Tchem.
DR PRO; PR:P14550; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P14550; protein.
DR Bgee; ENSG00000117448; Expressed in nephron tubule and 207 other tissues.
DR ExpressionAtlas; P14550; baseline and differential.
DR Genevisible; P14550; HS.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR GO; GO:0045202; C:synapse; IEA:Ensembl.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0004033; F:aldo-keto reductase (NADP) activity; TAS:Reactome.
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:0016657; F:oxidoreductase activity, acting on NAD(P)H, nitrogenous group as acceptor; IEA:Ensembl.
DR GO; GO:0046185; P:aldehyde catabolic process; IEA:Ensembl.
DR GO; GO:0110095; P:cellular detoxification of aldehyde; ISS:UniProtKB.
DR GO; GO:0042840; P:D-glucuronate catabolic process; IEA:Ensembl.
DR GO; GO:0044597; P:daunorubicin metabolic process; IDA:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IDA:UniProtKB.
DR GO; GO:0019640; P:glucuronate catabolic process to xylulose 5-phosphate; TAS:Reactome.
DR GO; GO:1901687; P:glutathione derivative biosynthetic process; TAS:Reactome.
DR GO; GO:0019853; P:L-ascorbic acid biosynthetic process; IEA:Ensembl.
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 3D-structure; Acetylation; Cell membrane; Cytoplasm;
KW Direct protein sequencing; Lipid metabolism; Membrane; NADP;
KW Oxidoreductase; Phosphoprotein; Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:3615425,
FT ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:25944712"
FT CHAIN 2..325
FT /note="Aldo-keto reductase family 1 member A1"
FT /id="PRO_0000124617"
FT ACT_SITE 50
FT /note="Proton donor"
FT /evidence="ECO:0000269|PubMed:7669785"
FT BINDING 21..23
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 45
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 113
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:7669785"
FT BINDING 162..163
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 184
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 210..217
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT BINDING 261..273
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:O60218"
FT SITE 80
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000269|PubMed:7669785"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:25944712"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P51635"
FT MOD_RES 38
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
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:0007744|PubMed:23186163"
FT VARIANT 52
FT /note="N -> S (reduced activity towards daunorubicin;
FT dbSNP:rs2229540)"
FT /evidence="ECO:0000269|PubMed:18276838"
FT /id="VAR_048212"
FT VARIANT 55
FT /note="E -> D (reduced activity towards daunorubicin;
FT dbSNP:rs6690497)"
FT /evidence="ECO:0000269|PubMed:18276838"
FT /id="VAR_058909"
FT MUTAGEN 50
FT /note="Y->F: Complete loss of enzymatic activity."
FT /evidence="ECO:0000269|PubMed:7669785"
FT MUTAGEN 50
FT /note="Y->H: Complete loss of enzymatic activity."
FT /evidence="ECO:0000269|PubMed:7669785"
FT MUTAGEN 80
FT /note="K->M: Complete loss of enzymatic activity."
FT /evidence="ECO:0000269|PubMed:7669785"
FT MUTAGEN 113
FT /note="H->Q: Strong decrease in enzymatic activity."
FT /evidence="ECO:0000269|PubMed:7669785"
FT MUTAGEN 299
FT /note="I->A: No change in enzymatic activity."
FT /evidence="ECO:0000269|PubMed:7669785"
FT MUTAGEN 299
FT /note="I->C: No change in enzymatic activity."
FT /evidence="ECO:0000269|PubMed:7669785"
FT MUTAGEN 300
FT /note="V->C: No change in enzymatic activity."
FT /evidence="ECO:0000269|PubMed:7669785"
FT CONFLICT 305
FT /note="V -> A (in Ref. 4; BAF85772)"
FT /evidence="ECO:0000305"
FT STRAND 5..7
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 13..17
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 26..39
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 43..45
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 48..50
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 53..63
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 68..70
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 72..74
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 76..81
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 88..102
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 107..113
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 115..118
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 120..122
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 140..153
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 155..163
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 166..173
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 182..186
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 194..203
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 206..210
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 232..241
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 245..255
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 267..274
FT /evidence="ECO:0007829|PDB:2ALR"
FT HELIX 283..290
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 302..305
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 308..313
FT /evidence="ECO:0007829|PDB:2ALR"
FT STRAND 320..323
FT /evidence="ECO:0007829|PDB:2ALR"
SQ SEQUENCE 325 AA; 36573 MW; F6B27517EB754E37 CRC64;
MAASCVLLHT GQKMPLIGLG TWKSEPGQVK AAVKYALSVG YRHIDCAAIY GNEPEIGEAL
KEDVGPGKAV PREELFVTSK LWNTKHHPED VEPALRKTLA DLQLEYLDLY LMHWPYAFER
GDNPFPKNAD GTICYDSTHY KETWKALEAL VAKGLVQALG LSNFNSRQID DILSVASVRP
AVLQVECHPY LAQNELIAHC QARGLEVTAY SPLGSSDRAW RDPDEPVLLE EPVVLALAEK
YGRSPAQILL RWQVQRKVIC IPKSITPSRI LQNIKVFDFT FSPEEMKQLN ALNKNWRYIV
PMLTVDGKRV PRDAGHPLYP FNDPY
