Full text data of AKR1B1
AKR1B1
(ALDR1)
[Confidence: low (only semi-automatic identification from reviews)]
Aldose reductase; AR; 1.1.1.21 (Aldehyde reductase; Aldo-keto reductase family 1 member B1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Aldose reductase; AR; 1.1.1.21 (Aldehyde reductase; Aldo-keto reductase family 1 member B1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P15121
ID ALDR_HUMAN Reviewed; 316 AA.
AC P15121; B2R8N3; Q5U031; Q6FGA4; Q6ICP2; Q9BS21; Q9UCI9;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Aldose reductase;
DE Short=AR;
DE EC=1.1.1.21;
DE AltName: Full=Aldehyde reductase;
DE AltName: Full=Aldo-keto reductase family 1 member B1;
GN Name=AKR1B1; Synonyms=ALDR1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2498333;
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 [MRNA].
RC TISSUE=Placenta;
RX PubMed=2504709;
RA Chung S., Lamendola J.;
RT "Cloning and sequence determination of human placental aldose
RT reductase gene.";
RL J. Biol. Chem. 264:14775-14777(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetus;
RX PubMed=2510130; DOI=10.1093/nar/17.20.8368;
RA Graham A., Hedge P.J., Powell S.J., Riley J., Brown L., Gammack A.,
RA Carey F., Markham A.F.;
RT "Nucleotide sequence of cDNA for human aldose reductase.";
RL Nucleic Acids Res. 17:8368-8368(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Placenta;
RX PubMed=2111143; DOI=10.1089/dna.1990.9.149;
RA Grundmann U., Bohn H., Obermeier R., Amann E.;
RT "Cloning and prokaryotic expression of a biologically active human
RT placental aldose reductase.";
RL DNA Cell Biol. 9:149-157(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2112546;
RA Nishimura C., Matsuura Y., Kokai Y., Akera T., Carper D., Morjana N.,
RA Lyons C., Flynn T.G.;
RT "Cloning and expression of human aldose reductase.";
RL J. Biol. Chem. 265:9788-9792(1990).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1901857;
RA Graham A., Brown L., Hedge P.J., Gammack A.J., Markham A.F.;
RT "Structure of the human aldose reductase gene.";
RL J. Biol. Chem. 266:6872-6877(1991).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9195951; DOI=10.1074/jbc.272.26.16431;
RA Ko B.C.B., Ruepp B., Bohren K.M., Gabbay K.H., Chung S.S.;
RT "Identification and characterization of multiple osmotic response
RT sequences in the human aldose reductase gene.";
RL J. Biol. Chem. 272:16431-16437(1997).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lymphoma;
RX PubMed=14996095; DOI=10.1111/j.1365-2133.2004.05651.x;
RA Hartmann T.B., Thiel D., Dummer R., Schadendorf D., Eichmueller S.;
RT "SEREX identification of new tumour-associated antigens in cutaneous
RT T-cell lymphoma.";
RL Br. J. Dermatol. 150:252-258(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [10]
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 [11]
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
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Eye, and Urinary bladder;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [15]
RP PROTEIN SEQUENCE OF 131-162, AND TISSUE SPECIFICITY.
RX PubMed=8435445; DOI=10.1016/0167-4889(93)90218-E;
RA Ferraretto A., Negri A., Giuliani A., De Grada L., Fuhrman Conti A.M.,
RA Ronchi S.;
RT "Aldose reductase is involved in long-term adaptation of EUE cells to
RT hyperosmotic stress.";
RL Biochim. Biophys. Acta 1175:283-288(1993).
RN [16]
RP PROTEIN SEQUENCE OF 244-275.
RX PubMed=2492527;
RA Morjana N.A., Lyons C., Flynn T.G.;
RT "Aldose reductase from human psoas muscle. Affinity labeling of an
RT active site lysine by pyridoxal 5'-phosphate and pyridoxal 5'-
RT diphospho-5'-adenosine.";
RL J. Biol. Chem. 264:2912-2919(1989).
RN [17]
RP PROTEIN SEQUENCE OF 276-294, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [18]
RP PROTEIN SEQUENCE OF 298-316, AND ENZYME REGULATION.
RX PubMed=8343525; DOI=10.1016/0167-4838(93)90258-S;
RA Liu S.Q., Bhatnagar A., Ansari N.H., Srivastava S.K.;
RT "Identification of the reactive cysteine residue in human placenta
RT aldose reductase.";
RL Biochim. Biophys. Acta 1164:268-272(1993).
RN [19]
RP PARTIAL PROTEIN SEQUENCE, AND ACETYLATION AT ALA-2.
RC TISSUE=Muscle;
RX PubMed=8281941; DOI=10.1111/j.1432-1033.1993.tb18445.x;
RA Jaquinod M., Potier N., Klarskov K., Reymann J.-M., Sorokine O.,
RA Kieffer S., Barth P., Andriantomanga V., Biellmann J.-F.,
RA van Dorsselaer A.;
RT "Sequence of pig lens aldose reductase and electrospray mass
RT spectrometry of non-covalent and covalent complexes.";
RL Eur. J. Biochem. 218:893-903(1993).
RN [20]
RP MUTAGENESIS OF ASP-44; TYR-49; LYS-78 AND HIS-111.
RX PubMed=8245005;
RA Tarle I., Borhani D.W., Wilson D.K., Quiocho F.A., Petrash J.M.;
RT "Probing the active site of human aldose reductase. Site-directed
RT mutagenesis of Asp-43, Tyr-48, Lys-77, and His-110.";
RL J. Biol. Chem. 268:25687-25693(1993).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-95; LYS-222 AND LYS-263, AND
RP MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [23]
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.,
RA Buerckstuemmer T., 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 [24]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS).
RX PubMed=1621098; DOI=10.1126/science.1621098;
RA Wilson D.K., Bohren K.M., Gabbay K.H., Quiocho F.A.;
RT "An unlikely sugar substrate site in the 1.65 A structure of the human
RT aldose reductase holoenzyme implicated in diabetic complications.";
RL Science 257:81-84(1992).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS).
RX PubMed=1447221;
RA Borhani D.W., Harter T.M., Pertrash J.M.;
RT "The crystal structure of the aldose reductase.NADPH binary complex.";
RL J. Biol. Chem. 267:24841-24847(1992).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=8234324; DOI=10.1073/pnas.90.21.9847;
RA Wilson D.K., Tarle I., Petrash J.M., Quiocho F.A.;
RT "Refined 1.8-A structure of human aldose reductase complexed with the
RT potent inhibitor zopolrestat.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:9847-9851(1993).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=9405046; DOI=10.1021/bi9717136;
RA Harrison D.H., Bohren K.M., Petsko G.A., Ringe D., Gabbay K.H.;
RT "The alrestatin double-decker: binding of two inhibitor molecules to
RT human aldose reductase reveals a new specificity determinant.";
RL Biochemistry 36:16134-16140(1997).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.0 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR, AND ACTIVE SITE.
RX PubMed=15272156; DOI=10.1107/S0907444904011370;
RA Ruiz F., Hazemann I., Mitschler A., Joachimiak A., Schneider T.,
RA Karplus M., Podjarny A.;
RT "The crystallographic structure of the aldose reductase-IDD552 complex
RT shows direct proton donation from tyrosine 48.";
RL Acta Crystallogr. D 60:1347-1354(2004).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (0.66 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR.
RX PubMed=15146478; DOI=10.1002/prot.20015;
RA Howard E.I., Sanishvili R., Cachau R.E., Mitschler A., Chevrier B.,
RA Barth P., Lamour V., Van Zandt M., Sibley E., Bon C., Moras D.,
RA Schneider T.R., Joachimiak A., Podjarny A.;
RT "Ultrahigh resolution drug design I: details of interactions in human
RT aldose reductase-inhibitor complex at 0.66 A.";
RL Proteins 55:792-804(2004).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (0.95 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SUBSTRATE ANALOG.
RX PubMed=16337231; DOI=10.1016/j.jmb.2005.10.067;
RA Steuber H., Zentgraf M., Podjarny A., Heine A., Klebe G.;
RT "High-resolution crystal structure of aldose reductase complexed with
RT the novel sulfonyl-pyridazinone inhibitor exhibiting an alternative
RT active site anchoring group.";
RL J. Mol. Biol. 356:45-56(2006).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (0.82 ANGSTROMS) IN COMPLEX WITH NADP.
RX PubMed=17505104; DOI=10.1107/S0907444907011997;
RA Biadene M., Hazemann I., Cousido A., Ginell S., Joachimiak A.,
RA Sheldrick G.M., Podjarny A., Schneider T.R.;
RT "The atomic resolution structure of human aldose reductase reveals
RT that rearrangement of a bound ligand allows the opening of the safety-
RT belt loop.";
RL Acta Crystallogr. D 63:665-672(2007).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR.
RX PubMed=17418233; DOI=10.1016/j.jmb.2007.03.021;
RA Steuber H., Zentgraf M., La Motta C., Sartini S., Heine A., Klebe G.;
RT "Evidence for a novel binding site conformer of aldose reductase in
RT ligand-bound state.";
RL J. Mol. Biol. 369:186-197(2007).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.43 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR.
RX PubMed=17368668; DOI=10.1016/j.jmb.2006.12.004;
RA Steuber H., Heine A., Klebe G.;
RT "Structural and thermodynamic study on aldose reductase: nitro-
RT substituted inhibitors with strong enthalpic binding contribution.";
RL J. Mol. Biol. 368:618-638(2007).
CC -!- FUNCTION: Catalyzes the NADPH-dependent reduction of a wide
CC variety of carbonyl-containing compounds to their corresponding
CC alcohols with a broad range of catalytic efficiencies.
CC -!- CATALYTIC ACTIVITY: Alditol + NAD(P)(+) = aldose + NAD(P)H.
CC -!- ENZYME REGULATION: Cys-299 may regulate the kinetic and inhibition
CC properties of the enzyme, but does not participate in catalysis.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Highly expressed in embryonic epithelial cells
CC (EUE) in response to osmotic stress.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family.
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DR EMBL; J04795; AAA51713.1; -; mRNA.
DR EMBL; J05017; AAA51714.1; -; mRNA.
DR EMBL; X15414; CAA33460.1; -; mRNA.
DR EMBL; M34720; AAA35560.1; -; mRNA.
DR EMBL; M34721; AAA35561.1; -; Genomic_DNA.
DR EMBL; J05474; AAA51715.1; -; mRNA.
DR EMBL; M59783; AAA51712.1; -; Genomic_DNA.
DR EMBL; M59856; AAA51712.1; JOINED; Genomic_DNA.
DR EMBL; AF032455; AAB88851.1; -; Genomic_DNA.
DR EMBL; AF328729; AAN09721.1; -; mRNA.
DR EMBL; AK313439; BAG36230.1; -; mRNA.
DR EMBL; CR450351; CAG29347.1; -; mRNA.
DR EMBL; CR542203; CAG47000.1; -; mRNA.
DR EMBL; BT019859; AAV38662.1; -; mRNA.
DR EMBL; CH236950; EAL24070.1; -; Genomic_DNA.
DR EMBL; CH471070; EAW83814.1; -; Genomic_DNA.
DR EMBL; BC000260; AAH00260.1; -; mRNA.
DR EMBL; BC005387; AAH05387.1; -; mRNA.
DR EMBL; BC010391; AAH10391.1; -; mRNA.
DR PIR; A39763; A39763.
DR RefSeq; NP_001619.1; NM_001628.2.
DR UniGene; Hs.521212; -.
DR PDB; 1ABN; X-ray; 2.40 A; A=2-316.
DR PDB; 1ADS; X-ray; 1.65 A; A=2-316.
DR PDB; 1AZ1; X-ray; 1.80 A; A=2-316.
DR PDB; 1AZ2; X-ray; 2.90 A; A=2-316.
DR PDB; 1EF3; X-ray; 2.80 A; A/B=2-315.
DR PDB; 1EL3; X-ray; 1.70 A; A=1-316.
DR PDB; 1IEI; X-ray; 2.50 A; A=1-316.
DR PDB; 1MAR; X-ray; 1.80 A; A=2-316.
DR PDB; 1PWL; X-ray; 1.10 A; A=1-316.
DR PDB; 1PWM; X-ray; 0.92 A; A=1-316.
DR PDB; 1T40; X-ray; 1.80 A; A=1-316.
DR PDB; 1T41; X-ray; 1.05 A; A=1-316.
DR PDB; 1US0; X-ray; 0.66 A; A=1-316.
DR PDB; 1X96; X-ray; 1.40 A; A=1-316.
DR PDB; 1X97; X-ray; 1.40 A; A=1-316.
DR PDB; 1X98; X-ray; 1.30 A; A=1-316.
DR PDB; 1XGD; X-ray; 2.10 A; A=2-315.
DR PDB; 1Z3N; X-ray; 1.04 A; A=1-316.
DR PDB; 1Z89; X-ray; 1.43 A; A=1-316.
DR PDB; 1Z8A; X-ray; 0.95 A; A=1-316.
DR PDB; 2ACQ; X-ray; 1.76 A; A=2-315.
DR PDB; 2ACR; X-ray; 1.76 A; A=2-315.
DR PDB; 2ACS; X-ray; 1.76 A; A=2-315.
DR PDB; 2ACU; X-ray; 1.76 A; A=2-315.
DR PDB; 2AGT; X-ray; 1.00 A; A=1-316.
DR PDB; 2DUX; X-ray; 1.60 A; A=1-316.
DR PDB; 2DUZ; X-ray; 1.60 A; A=1-316.
DR PDB; 2DV0; X-ray; 1.62 A; A=1-316.
DR PDB; 2F2K; X-ray; 1.94 A; A=1-316.
DR PDB; 2FZ8; X-ray; 1.48 A; A=1-316.
DR PDB; 2FZ9; X-ray; 1.60 A; A=1-316.
DR PDB; 2FZB; X-ray; 1.50 A; A=1-316.
DR PDB; 2FZD; X-ray; 1.08 A; A=1-316.
DR PDB; 2HV5; X-ray; 1.59 A; A=1-316.
DR PDB; 2HVN; X-ray; 1.58 A; A=1-316.
DR PDB; 2HVO; X-ray; 1.65 A; A=1-316.
DR PDB; 2I16; X-ray; 0.81 A; A=1-316.
DR PDB; 2I17; X-ray; 0.81 A; A=1-316.
DR PDB; 2IKG; X-ray; 1.43 A; A=1-316.
DR PDB; 2IKH; X-ray; 1.55 A; A=1-316.
DR PDB; 2IKI; X-ray; 1.47 A; A=1-316.
DR PDB; 2IKJ; X-ray; 1.55 A; A=1-316.
DR PDB; 2INE; X-ray; 1.90 A; A=2-315.
DR PDB; 2INZ; X-ray; 1.95 A; A=2-315.
DR PDB; 2IPW; X-ray; 2.00 A; A=2-315.
DR PDB; 2IQ0; X-ray; 1.95 A; A=2-315.
DR PDB; 2IQD; X-ray; 2.00 A; A=2-315.
DR PDB; 2IS7; X-ray; 1.70 A; A=2-315.
DR PDB; 2ISF; X-ray; 2.00 A; A=2-315.
DR PDB; 2J8T; X-ray; 0.82 A; A=1-316.
DR PDB; 2NVC; X-ray; 1.65 A; A=1-316.
DR PDB; 2NVD; X-ray; 1.55 A; A=1-316.
DR PDB; 2PD5; X-ray; 1.60 A; A=1-316.
DR PDB; 2PD9; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDB; X-ray; 1.60 A; A=1-316.
DR PDB; 2PDC; X-ray; 1.65 A; A=1-316.
DR PDB; 2PDF; X-ray; 1.56 A; A=1-316.
DR PDB; 2PDG; X-ray; 1.42 A; A=1-316.
DR PDB; 2PDH; X-ray; 1.45 A; A=1-316.
DR PDB; 2PDI; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDJ; X-ray; 1.57 A; A=1-316.
DR PDB; 2PDK; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDL; X-ray; 1.47 A; A=1-316.
DR PDB; 2PDM; X-ray; 1.75 A; A=1-316.
DR PDB; 2PDN; X-ray; 1.70 A; A=1-316.
DR PDB; 2PDP; X-ray; 1.65 A; A=1-316.
DR PDB; 2PDQ; X-ray; 1.73 A; A=1-316.
DR PDB; 2PDU; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDW; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDX; X-ray; 1.65 A; A=1-316.
DR PDB; 2PDY; X-ray; 1.65 A; A=1-316.
DR PDB; 2PEV; X-ray; 0.90 A; A=1-316.
DR PDB; 2PF8; X-ray; 0.85 A; A=1-316.
DR PDB; 2PFH; X-ray; 0.85 A; A=1-316.
DR PDB; 2PZN; X-ray; 1.00 A; A=1-316.
DR PDB; 2QXW; X-ray; 0.80 A; A=1-316.
DR PDB; 2R24; X-ray; 1.75 A; A=1-316.
DR PDB; 3BCJ; X-ray; 0.78 A; A=1-316.
DR PDB; 3DN5; X-ray; 1.45 A; A=1-316.
DR PDB; 3G5E; X-ray; 1.80 A; A=1-316.
DR PDB; 3GHR; X-ray; 1.00 A; A=1-316.
DR PDB; 3GHS; X-ray; 1.00 A; A=1-316.
DR PDB; 3GHT; X-ray; 1.10 A; A=1-316.
DR PDB; 3GHU; X-ray; 1.20 A; A=1-316.
DR PDB; 3LBO; X-ray; 1.10 A; A=1-316.
DR PDB; 3LD5; X-ray; 1.27 A; A=1-316.
DR PDB; 3LEN; X-ray; 1.21 A; A=1-316.
DR PDB; 3LEP; X-ray; 0.99 A; A=1-316.
DR PDB; 3LQG; X-ray; 1.35 A; A=1-316.
DR PDB; 3LQL; X-ray; 1.13 A; A=1-316.
DR PDB; 3LZ3; X-ray; 1.03 A; A=1-316.
DR PDB; 3LZ5; X-ray; 0.95 A; A=1-316.
DR PDB; 3M0I; X-ray; 1.07 A; A=1-316.
DR PDB; 3M4H; X-ray; 0.94 A; A=1-316.
DR PDB; 3M64; X-ray; 1.30 A; A=1-316.
DR PDB; 3MB9; X-ray; 1.65 A; A=1-316.
DR PDB; 3MC5; X-ray; 1.14 A; A=1-316.
DR PDB; 3ONB; X-ray; 1.45 A; A=2-316.
DR PDB; 3ONC; X-ray; 1.06 A; A=2-316.
DR PDB; 3P2V; X-ray; 1.69 A; A=1-316.
DR PDB; 3Q65; X-ray; 2.09 A; A/B=1-316.
DR PDB; 3Q67; X-ray; 1.55 A; A/B=1-316.
DR PDB; 3RX2; X-ray; 1.90 A; A=1-316.
DR PDB; 3RX3; X-ray; 1.90 A; A=1-316.
DR PDB; 3RX4; X-ray; 2.00 A; A=1-316.
DR PDB; 3S3G; X-ray; 1.80 A; A=1-316.
DR PDB; 3T42; X-ray; 1.28 A; A=1-316.
DR PDB; 3U2C; X-ray; 1.00 A; A=1-316.
DR PDB; 3V35; X-ray; 1.90 A; A=1-316.
DR PDB; 3V36; X-ray; 2.00 A; A=1-316.
DR PDB; 3V9Q; X-ray; 2.00 A; A=1-316.
DR PDB; 4GCA; X-ray; 0.90 A; A=2-316.
DR PDB; 4JIR; X-ray; 2.00 A; A=1-316.
DR PDBsum; 1ABN; -.
DR PDBsum; 1ADS; -.
DR PDBsum; 1AZ1; -.
DR PDBsum; 1AZ2; -.
DR PDBsum; 1EF3; -.
DR PDBsum; 1EL3; -.
DR PDBsum; 1IEI; -.
DR PDBsum; 1MAR; -.
DR PDBsum; 1PWL; -.
DR PDBsum; 1PWM; -.
DR PDBsum; 1T40; -.
DR PDBsum; 1T41; -.
DR PDBsum; 1US0; -.
DR PDBsum; 1X96; -.
DR PDBsum; 1X97; -.
DR PDBsum; 1X98; -.
DR PDBsum; 1XGD; -.
DR PDBsum; 1Z3N; -.
DR PDBsum; 1Z89; -.
DR PDBsum; 1Z8A; -.
DR PDBsum; 2ACQ; -.
DR PDBsum; 2ACR; -.
DR PDBsum; 2ACS; -.
DR PDBsum; 2ACU; -.
DR PDBsum; 2AGT; -.
DR PDBsum; 2DUX; -.
DR PDBsum; 2DUZ; -.
DR PDBsum; 2DV0; -.
DR PDBsum; 2F2K; -.
DR PDBsum; 2FZ8; -.
DR PDBsum; 2FZ9; -.
DR PDBsum; 2FZB; -.
DR PDBsum; 2FZD; -.
DR PDBsum; 2HV5; -.
DR PDBsum; 2HVN; -.
DR PDBsum; 2HVO; -.
DR PDBsum; 2I16; -.
DR PDBsum; 2I17; -.
DR PDBsum; 2IKG; -.
DR PDBsum; 2IKH; -.
DR PDBsum; 2IKI; -.
DR PDBsum; 2IKJ; -.
DR PDBsum; 2INE; -.
DR PDBsum; 2INZ; -.
DR PDBsum; 2IPW; -.
DR PDBsum; 2IQ0; -.
DR PDBsum; 2IQD; -.
DR PDBsum; 2IS7; -.
DR PDBsum; 2ISF; -.
DR PDBsum; 2J8T; -.
DR PDBsum; 2NVC; -.
DR PDBsum; 2NVD; -.
DR PDBsum; 2PD5; -.
DR PDBsum; 2PD9; -.
DR PDBsum; 2PDB; -.
DR PDBsum; 2PDC; -.
DR PDBsum; 2PDF; -.
DR PDBsum; 2PDG; -.
DR PDBsum; 2PDH; -.
DR PDBsum; 2PDI; -.
DR PDBsum; 2PDJ; -.
DR PDBsum; 2PDK; -.
DR PDBsum; 2PDL; -.
DR PDBsum; 2PDM; -.
DR PDBsum; 2PDN; -.
DR PDBsum; 2PDP; -.
DR PDBsum; 2PDQ; -.
DR PDBsum; 2PDU; -.
DR PDBsum; 2PDW; -.
DR PDBsum; 2PDX; -.
DR PDBsum; 2PDY; -.
DR PDBsum; 2PEV; -.
DR PDBsum; 2PF8; -.
DR PDBsum; 2PFH; -.
DR PDBsum; 2PZN; -.
DR PDBsum; 2QXW; -.
DR PDBsum; 2R24; -.
DR PDBsum; 3BCJ; -.
DR PDBsum; 3DN5; -.
DR PDBsum; 3G5E; -.
DR PDBsum; 3GHR; -.
DR PDBsum; 3GHS; -.
DR PDBsum; 3GHT; -.
DR PDBsum; 3GHU; -.
DR PDBsum; 3LBO; -.
DR PDBsum; 3LD5; -.
DR PDBsum; 3LEN; -.
DR PDBsum; 3LEP; -.
DR PDBsum; 3LQG; -.
DR PDBsum; 3LQL; -.
DR PDBsum; 3LZ3; -.
DR PDBsum; 3LZ5; -.
DR PDBsum; 3M0I; -.
DR PDBsum; 3M4H; -.
DR PDBsum; 3M64; -.
DR PDBsum; 3MB9; -.
DR PDBsum; 3MC5; -.
DR PDBsum; 3ONB; -.
DR PDBsum; 3ONC; -.
DR PDBsum; 3P2V; -.
DR PDBsum; 3Q65; -.
DR PDBsum; 3Q67; -.
DR PDBsum; 3RX2; -.
DR PDBsum; 3RX3; -.
DR PDBsum; 3RX4; -.
DR PDBsum; 3S3G; -.
DR PDBsum; 3T42; -.
DR PDBsum; 3U2C; -.
DR PDBsum; 3V35; -.
DR PDBsum; 3V36; -.
DR PDBsum; 3V9Q; -.
DR PDBsum; 4GCA; -.
DR PDBsum; 4JIR; -.
DR ProteinModelPortal; P15121; -.
DR SMR; P15121; 1-316.
DR IntAct; P15121; 2.
DR MINT; MINT-1196717; -.
DR STRING; 9606.ENSP00000285930; -.
DR BindingDB; P15121; -.
DR ChEMBL; CHEMBL1900; -.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB00605; Sulindac.
DR PhosphoSite; P15121; -.
DR DMDM; 113596; -.
DR DOSAC-COBS-2DPAGE; P15121; -.
DR REPRODUCTION-2DPAGE; IPI00413641; -.
DR REPRODUCTION-2DPAGE; P15121; -.
DR UCD-2DPAGE; P15121; -.
DR PaxDb; P15121; -.
DR PeptideAtlas; P15121; -.
DR PRIDE; P15121; -.
DR DNASU; 231; -.
DR Ensembl; ENST00000285930; ENSP00000285930; ENSG00000085662.
DR GeneID; 231; -.
DR KEGG; hsa:231; -.
DR UCSC; uc003vrp.1; human.
DR CTD; 231; -.
DR GeneCards; GC07M134127; -.
DR HGNC; HGNC:381; AKR1B1.
DR HPA; CAB018773; -.
DR HPA; CAB027391; -.
DR HPA; HPA026425; -.
DR MIM; 103880; gene.
DR neXtProt; NX_P15121; -.
DR PharmGKB; PA24675; -.
DR eggNOG; COG0656; -.
DR HOVERGEN; HBG000020; -.
DR InParanoid; P15121; -.
DR KO; K00011; -.
DR OMA; DFLDTWT; -.
DR OrthoDB; EOG70KGQF; -.
DR PhylomeDB; P15121; -.
DR BioCyc; MetaCyc:HS01502-MONOMER; -.
DR BRENDA; 1.1.1.21; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15493; Steroid hormones.
DR SABIO-RK; P15121; -.
DR ChiTaRS; AKR1B1; human.
DR EvolutionaryTrace; P15121; -.
DR GeneWiki; AKR1B1; -.
DR GenomeRNAi; 231; -.
DR NextBio; 938; -.
DR PRO; PR:P15121; -.
DR ArrayExpress; P15121; -.
DR Bgee; P15121; -.
DR CleanEx; HS_AKR1B1; -.
DR Genevestigator; P15121; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; TAS:ProtInc.
DR GO; GO:0009055; F:electron carrier activity; TAS:UniProtKB.
DR GO; GO:0043795; F:glyceraldehyde oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0006700; P:C21-steroid hormone biosynthetic process; TAS:Reactome.
DR GO; GO:0005975; P:carbohydrate metabolic process; TAS:ProtInc.
DR GO; GO:0044597; P:daunorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0006950; P:response to stress; TAS:UniProtKB.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR001395; Aldo/ket_red.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR020471; Aldo/keto_reductase_subgr.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR PANTHER; PTHR11732; PTHR11732; 1.
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; Complete proteome; Cytoplasm;
KW Direct protein sequencing; NADP; Oxidoreductase; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 316 Aldose reductase.
FT /FTId=PRO_0000124623.
FT NP_BIND 10 19 NADP (Potential).
FT NP_BIND 211 273 NADP.
FT ACT_SITE 49 49 Proton donor.
FT BINDING 111 111 Substrate.
FT SITE 78 78 Lowers pKa of active site Tyr.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 95 95 N6-acetyllysine.
FT MOD_RES 222 222 N6-acetyllysine.
FT MOD_RES 263 263 N6-acetyllysine.
FT VARIANT 15 15 I -> F (in dbSNP:rs5054).
FT /FTId=VAR_014743.
FT VARIANT 42 42 H -> L (in dbSNP:rs5056).
FT /FTId=VAR_014744.
FT VARIANT 73 73 L -> V (in dbSNP:rs5057).
FT /FTId=VAR_014745.
FT VARIANT 90 90 K -> E (in dbSNP:rs2229542).
FT /FTId=VAR_048213.
FT VARIANT 204 204 G -> S (in dbSNP:rs5061).
FT /FTId=VAR_014746.
FT VARIANT 288 288 T -> I (in dbSNP:rs5062).
FT /FTId=VAR_014747.
FT MUTAGEN 44 44 D->N: Reduced enzymatic activity.
FT MUTAGEN 49 49 Y->F: Complete loss of enzymatic
FT activity.
FT MUTAGEN 78 78 K->M: Reduced enzymatic activity.
FT MUTAGEN 111 111 H->N: Reduced enzymatic activity.
FT CONFLICT 5 5 L -> I (in Ref. 2; AAA51714).
FT CONFLICT 114 114 T -> I (in Ref. 10; CAG47000).
FT CONFLICT 117 117 K -> R (in Ref. 10; CAG29347).
FT CONFLICT 142 142 W -> R (in Ref. 14; AAH05387).
FT CONFLICT 172 172 N -> S (in Ref. 10; CAG29347).
FT CONFLICT 270 272 IAE -> EAA (in Ref. 16; AA sequence).
FT CONFLICT 307 307 H -> M (in Ref. 18; AA sequence).
FT STRAND 3 6
FT STRAND 12 16
FT HELIX 25 38
FT STRAND 42 44
FT HELIX 47 49
FT HELIX 52 64
FT HELIX 70 72
FT STRAND 74 79
FT HELIX 81 83
FT TURN 86 88
FT HELIX 89 100
FT STRAND 105 113
FT STRAND 118 120
FT STRAND 127 129
FT HELIX 138 150
FT STRAND 153 155
FT STRAND 157 161
FT HELIX 164 171
FT STRAND 181 186
FT HELIX 194 202
FT STRAND 206 211
FT STRAND 223 225
FT TURN 228 230
FT HELIX 232 241
FT HELIX 245 255
FT STRAND 259 261
FT HELIX 267 274
FT HELIX 283 290
FT HELIX 302 304
FT STRAND 307 309
FT STRAND 311 314
SQ SEQUENCE 316 AA; 35853 MW; 1852E8616B5DCEAE CRC64;
MASRLLLNNG AKMPILGLGT WKSPPGQVTE AVKVAIDVGY RHIDCAHVYQ NENEVGVAIQ
EKLREQVVKR EELFIVSKLW CTYHEKGLVK GACQKTLSDL KLDYLDLYLI HWPTGFKPGK
EFFPLDESGN VVPSDTNILD TWAAMEELVD EGLVKAIGIS NFNHLQVEMI LNKPGLKYKP
AVNQIECHPY LTQEKLIQYC QSKGIVVTAY SPLGSPDRPW AKPEDPSLLE DPRIKAIAAK
HNKTTAQVLI RFPMQRNLVV IPKSVTPERI AENFKVFDFE LSSQDMTTLL SYNRNWRVCA
LLSCTSHKDY PFHEEF
//
ID ALDR_HUMAN Reviewed; 316 AA.
AC P15121; B2R8N3; Q5U031; Q6FGA4; Q6ICP2; Q9BS21; Q9UCI9;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Aldose reductase;
DE Short=AR;
DE EC=1.1.1.21;
DE AltName: Full=Aldehyde reductase;
DE AltName: Full=Aldo-keto reductase family 1 member B1;
GN Name=AKR1B1; Synonyms=ALDR1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2498333;
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 [MRNA].
RC TISSUE=Placenta;
RX PubMed=2504709;
RA Chung S., Lamendola J.;
RT "Cloning and sequence determination of human placental aldose
RT reductase gene.";
RL J. Biol. Chem. 264:14775-14777(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetus;
RX PubMed=2510130; DOI=10.1093/nar/17.20.8368;
RA Graham A., Hedge P.J., Powell S.J., Riley J., Brown L., Gammack A.,
RA Carey F., Markham A.F.;
RT "Nucleotide sequence of cDNA for human aldose reductase.";
RL Nucleic Acids Res. 17:8368-8368(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Placenta;
RX PubMed=2111143; DOI=10.1089/dna.1990.9.149;
RA Grundmann U., Bohn H., Obermeier R., Amann E.;
RT "Cloning and prokaryotic expression of a biologically active human
RT placental aldose reductase.";
RL DNA Cell Biol. 9:149-157(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2112546;
RA Nishimura C., Matsuura Y., Kokai Y., Akera T., Carper D., Morjana N.,
RA Lyons C., Flynn T.G.;
RT "Cloning and expression of human aldose reductase.";
RL J. Biol. Chem. 265:9788-9792(1990).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1901857;
RA Graham A., Brown L., Hedge P.J., Gammack A.J., Markham A.F.;
RT "Structure of the human aldose reductase gene.";
RL J. Biol. Chem. 266:6872-6877(1991).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9195951; DOI=10.1074/jbc.272.26.16431;
RA Ko B.C.B., Ruepp B., Bohren K.M., Gabbay K.H., Chung S.S.;
RT "Identification and characterization of multiple osmotic response
RT sequences in the human aldose reductase gene.";
RL J. Biol. Chem. 272:16431-16437(1997).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lymphoma;
RX PubMed=14996095; DOI=10.1111/j.1365-2133.2004.05651.x;
RA Hartmann T.B., Thiel D., Dummer R., Schadendorf D., Eichmueller S.;
RT "SEREX identification of new tumour-associated antigens in cutaneous
RT T-cell lymphoma.";
RL Br. J. Dermatol. 150:252-258(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [10]
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 [11]
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
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Eye, and Urinary bladder;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [15]
RP PROTEIN SEQUENCE OF 131-162, AND TISSUE SPECIFICITY.
RX PubMed=8435445; DOI=10.1016/0167-4889(93)90218-E;
RA Ferraretto A., Negri A., Giuliani A., De Grada L., Fuhrman Conti A.M.,
RA Ronchi S.;
RT "Aldose reductase is involved in long-term adaptation of EUE cells to
RT hyperosmotic stress.";
RL Biochim. Biophys. Acta 1175:283-288(1993).
RN [16]
RP PROTEIN SEQUENCE OF 244-275.
RX PubMed=2492527;
RA Morjana N.A., Lyons C., Flynn T.G.;
RT "Aldose reductase from human psoas muscle. Affinity labeling of an
RT active site lysine by pyridoxal 5'-phosphate and pyridoxal 5'-
RT diphospho-5'-adenosine.";
RL J. Biol. Chem. 264:2912-2919(1989).
RN [17]
RP PROTEIN SEQUENCE OF 276-294, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [18]
RP PROTEIN SEQUENCE OF 298-316, AND ENZYME REGULATION.
RX PubMed=8343525; DOI=10.1016/0167-4838(93)90258-S;
RA Liu S.Q., Bhatnagar A., Ansari N.H., Srivastava S.K.;
RT "Identification of the reactive cysteine residue in human placenta
RT aldose reductase.";
RL Biochim. Biophys. Acta 1164:268-272(1993).
RN [19]
RP PARTIAL PROTEIN SEQUENCE, AND ACETYLATION AT ALA-2.
RC TISSUE=Muscle;
RX PubMed=8281941; DOI=10.1111/j.1432-1033.1993.tb18445.x;
RA Jaquinod M., Potier N., Klarskov K., Reymann J.-M., Sorokine O.,
RA Kieffer S., Barth P., Andriantomanga V., Biellmann J.-F.,
RA van Dorsselaer A.;
RT "Sequence of pig lens aldose reductase and electrospray mass
RT spectrometry of non-covalent and covalent complexes.";
RL Eur. J. Biochem. 218:893-903(1993).
RN [20]
RP MUTAGENESIS OF ASP-44; TYR-49; LYS-78 AND HIS-111.
RX PubMed=8245005;
RA Tarle I., Borhani D.W., Wilson D.K., Quiocho F.A., Petrash J.M.;
RT "Probing the active site of human aldose reductase. Site-directed
RT mutagenesis of Asp-43, Tyr-48, Lys-77, and His-110.";
RL J. Biol. Chem. 268:25687-25693(1993).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-95; LYS-222 AND LYS-263, AND
RP MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [23]
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.,
RA Buerckstuemmer T., 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 [24]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS).
RX PubMed=1621098; DOI=10.1126/science.1621098;
RA Wilson D.K., Bohren K.M., Gabbay K.H., Quiocho F.A.;
RT "An unlikely sugar substrate site in the 1.65 A structure of the human
RT aldose reductase holoenzyme implicated in diabetic complications.";
RL Science 257:81-84(1992).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS).
RX PubMed=1447221;
RA Borhani D.W., Harter T.M., Pertrash J.M.;
RT "The crystal structure of the aldose reductase.NADPH binary complex.";
RL J. Biol. Chem. 267:24841-24847(1992).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=8234324; DOI=10.1073/pnas.90.21.9847;
RA Wilson D.K., Tarle I., Petrash J.M., Quiocho F.A.;
RT "Refined 1.8-A structure of human aldose reductase complexed with the
RT potent inhibitor zopolrestat.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:9847-9851(1993).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=9405046; DOI=10.1021/bi9717136;
RA Harrison D.H., Bohren K.M., Petsko G.A., Ringe D., Gabbay K.H.;
RT "The alrestatin double-decker: binding of two inhibitor molecules to
RT human aldose reductase reveals a new specificity determinant.";
RL Biochemistry 36:16134-16140(1997).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.0 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR, AND ACTIVE SITE.
RX PubMed=15272156; DOI=10.1107/S0907444904011370;
RA Ruiz F., Hazemann I., Mitschler A., Joachimiak A., Schneider T.,
RA Karplus M., Podjarny A.;
RT "The crystallographic structure of the aldose reductase-IDD552 complex
RT shows direct proton donation from tyrosine 48.";
RL Acta Crystallogr. D 60:1347-1354(2004).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (0.66 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR.
RX PubMed=15146478; DOI=10.1002/prot.20015;
RA Howard E.I., Sanishvili R., Cachau R.E., Mitschler A., Chevrier B.,
RA Barth P., Lamour V., Van Zandt M., Sibley E., Bon C., Moras D.,
RA Schneider T.R., Joachimiak A., Podjarny A.;
RT "Ultrahigh resolution drug design I: details of interactions in human
RT aldose reductase-inhibitor complex at 0.66 A.";
RL Proteins 55:792-804(2004).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (0.95 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SUBSTRATE ANALOG.
RX PubMed=16337231; DOI=10.1016/j.jmb.2005.10.067;
RA Steuber H., Zentgraf M., Podjarny A., Heine A., Klebe G.;
RT "High-resolution crystal structure of aldose reductase complexed with
RT the novel sulfonyl-pyridazinone inhibitor exhibiting an alternative
RT active site anchoring group.";
RL J. Mol. Biol. 356:45-56(2006).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (0.82 ANGSTROMS) IN COMPLEX WITH NADP.
RX PubMed=17505104; DOI=10.1107/S0907444907011997;
RA Biadene M., Hazemann I., Cousido A., Ginell S., Joachimiak A.,
RA Sheldrick G.M., Podjarny A., Schneider T.R.;
RT "The atomic resolution structure of human aldose reductase reveals
RT that rearrangement of a bound ligand allows the opening of the safety-
RT belt loop.";
RL Acta Crystallogr. D 63:665-672(2007).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR.
RX PubMed=17418233; DOI=10.1016/j.jmb.2007.03.021;
RA Steuber H., Zentgraf M., La Motta C., Sartini S., Heine A., Klebe G.;
RT "Evidence for a novel binding site conformer of aldose reductase in
RT ligand-bound state.";
RL J. Mol. Biol. 369:186-197(2007).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.43 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SYNTHETIC INHIBITOR.
RX PubMed=17368668; DOI=10.1016/j.jmb.2006.12.004;
RA Steuber H., Heine A., Klebe G.;
RT "Structural and thermodynamic study on aldose reductase: nitro-
RT substituted inhibitors with strong enthalpic binding contribution.";
RL J. Mol. Biol. 368:618-638(2007).
CC -!- FUNCTION: Catalyzes the NADPH-dependent reduction of a wide
CC variety of carbonyl-containing compounds to their corresponding
CC alcohols with a broad range of catalytic efficiencies.
CC -!- CATALYTIC ACTIVITY: Alditol + NAD(P)(+) = aldose + NAD(P)H.
CC -!- ENZYME REGULATION: Cys-299 may regulate the kinetic and inhibition
CC properties of the enzyme, but does not participate in catalysis.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Highly expressed in embryonic epithelial cells
CC (EUE) in response to osmotic stress.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family.
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DR EMBL; J04795; AAA51713.1; -; mRNA.
DR EMBL; J05017; AAA51714.1; -; mRNA.
DR EMBL; X15414; CAA33460.1; -; mRNA.
DR EMBL; M34720; AAA35560.1; -; mRNA.
DR EMBL; M34721; AAA35561.1; -; Genomic_DNA.
DR EMBL; J05474; AAA51715.1; -; mRNA.
DR EMBL; M59783; AAA51712.1; -; Genomic_DNA.
DR EMBL; M59856; AAA51712.1; JOINED; Genomic_DNA.
DR EMBL; AF032455; AAB88851.1; -; Genomic_DNA.
DR EMBL; AF328729; AAN09721.1; -; mRNA.
DR EMBL; AK313439; BAG36230.1; -; mRNA.
DR EMBL; CR450351; CAG29347.1; -; mRNA.
DR EMBL; CR542203; CAG47000.1; -; mRNA.
DR EMBL; BT019859; AAV38662.1; -; mRNA.
DR EMBL; CH236950; EAL24070.1; -; Genomic_DNA.
DR EMBL; CH471070; EAW83814.1; -; Genomic_DNA.
DR EMBL; BC000260; AAH00260.1; -; mRNA.
DR EMBL; BC005387; AAH05387.1; -; mRNA.
DR EMBL; BC010391; AAH10391.1; -; mRNA.
DR PIR; A39763; A39763.
DR RefSeq; NP_001619.1; NM_001628.2.
DR UniGene; Hs.521212; -.
DR PDB; 1ABN; X-ray; 2.40 A; A=2-316.
DR PDB; 1ADS; X-ray; 1.65 A; A=2-316.
DR PDB; 1AZ1; X-ray; 1.80 A; A=2-316.
DR PDB; 1AZ2; X-ray; 2.90 A; A=2-316.
DR PDB; 1EF3; X-ray; 2.80 A; A/B=2-315.
DR PDB; 1EL3; X-ray; 1.70 A; A=1-316.
DR PDB; 1IEI; X-ray; 2.50 A; A=1-316.
DR PDB; 1MAR; X-ray; 1.80 A; A=2-316.
DR PDB; 1PWL; X-ray; 1.10 A; A=1-316.
DR PDB; 1PWM; X-ray; 0.92 A; A=1-316.
DR PDB; 1T40; X-ray; 1.80 A; A=1-316.
DR PDB; 1T41; X-ray; 1.05 A; A=1-316.
DR PDB; 1US0; X-ray; 0.66 A; A=1-316.
DR PDB; 1X96; X-ray; 1.40 A; A=1-316.
DR PDB; 1X97; X-ray; 1.40 A; A=1-316.
DR PDB; 1X98; X-ray; 1.30 A; A=1-316.
DR PDB; 1XGD; X-ray; 2.10 A; A=2-315.
DR PDB; 1Z3N; X-ray; 1.04 A; A=1-316.
DR PDB; 1Z89; X-ray; 1.43 A; A=1-316.
DR PDB; 1Z8A; X-ray; 0.95 A; A=1-316.
DR PDB; 2ACQ; X-ray; 1.76 A; A=2-315.
DR PDB; 2ACR; X-ray; 1.76 A; A=2-315.
DR PDB; 2ACS; X-ray; 1.76 A; A=2-315.
DR PDB; 2ACU; X-ray; 1.76 A; A=2-315.
DR PDB; 2AGT; X-ray; 1.00 A; A=1-316.
DR PDB; 2DUX; X-ray; 1.60 A; A=1-316.
DR PDB; 2DUZ; X-ray; 1.60 A; A=1-316.
DR PDB; 2DV0; X-ray; 1.62 A; A=1-316.
DR PDB; 2F2K; X-ray; 1.94 A; A=1-316.
DR PDB; 2FZ8; X-ray; 1.48 A; A=1-316.
DR PDB; 2FZ9; X-ray; 1.60 A; A=1-316.
DR PDB; 2FZB; X-ray; 1.50 A; A=1-316.
DR PDB; 2FZD; X-ray; 1.08 A; A=1-316.
DR PDB; 2HV5; X-ray; 1.59 A; A=1-316.
DR PDB; 2HVN; X-ray; 1.58 A; A=1-316.
DR PDB; 2HVO; X-ray; 1.65 A; A=1-316.
DR PDB; 2I16; X-ray; 0.81 A; A=1-316.
DR PDB; 2I17; X-ray; 0.81 A; A=1-316.
DR PDB; 2IKG; X-ray; 1.43 A; A=1-316.
DR PDB; 2IKH; X-ray; 1.55 A; A=1-316.
DR PDB; 2IKI; X-ray; 1.47 A; A=1-316.
DR PDB; 2IKJ; X-ray; 1.55 A; A=1-316.
DR PDB; 2INE; X-ray; 1.90 A; A=2-315.
DR PDB; 2INZ; X-ray; 1.95 A; A=2-315.
DR PDB; 2IPW; X-ray; 2.00 A; A=2-315.
DR PDB; 2IQ0; X-ray; 1.95 A; A=2-315.
DR PDB; 2IQD; X-ray; 2.00 A; A=2-315.
DR PDB; 2IS7; X-ray; 1.70 A; A=2-315.
DR PDB; 2ISF; X-ray; 2.00 A; A=2-315.
DR PDB; 2J8T; X-ray; 0.82 A; A=1-316.
DR PDB; 2NVC; X-ray; 1.65 A; A=1-316.
DR PDB; 2NVD; X-ray; 1.55 A; A=1-316.
DR PDB; 2PD5; X-ray; 1.60 A; A=1-316.
DR PDB; 2PD9; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDB; X-ray; 1.60 A; A=1-316.
DR PDB; 2PDC; X-ray; 1.65 A; A=1-316.
DR PDB; 2PDF; X-ray; 1.56 A; A=1-316.
DR PDB; 2PDG; X-ray; 1.42 A; A=1-316.
DR PDB; 2PDH; X-ray; 1.45 A; A=1-316.
DR PDB; 2PDI; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDJ; X-ray; 1.57 A; A=1-316.
DR PDB; 2PDK; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDL; X-ray; 1.47 A; A=1-316.
DR PDB; 2PDM; X-ray; 1.75 A; A=1-316.
DR PDB; 2PDN; X-ray; 1.70 A; A=1-316.
DR PDB; 2PDP; X-ray; 1.65 A; A=1-316.
DR PDB; 2PDQ; X-ray; 1.73 A; A=1-316.
DR PDB; 2PDU; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDW; X-ray; 1.55 A; A=1-316.
DR PDB; 2PDX; X-ray; 1.65 A; A=1-316.
DR PDB; 2PDY; X-ray; 1.65 A; A=1-316.
DR PDB; 2PEV; X-ray; 0.90 A; A=1-316.
DR PDB; 2PF8; X-ray; 0.85 A; A=1-316.
DR PDB; 2PFH; X-ray; 0.85 A; A=1-316.
DR PDB; 2PZN; X-ray; 1.00 A; A=1-316.
DR PDB; 2QXW; X-ray; 0.80 A; A=1-316.
DR PDB; 2R24; X-ray; 1.75 A; A=1-316.
DR PDB; 3BCJ; X-ray; 0.78 A; A=1-316.
DR PDB; 3DN5; X-ray; 1.45 A; A=1-316.
DR PDB; 3G5E; X-ray; 1.80 A; A=1-316.
DR PDB; 3GHR; X-ray; 1.00 A; A=1-316.
DR PDB; 3GHS; X-ray; 1.00 A; A=1-316.
DR PDB; 3GHT; X-ray; 1.10 A; A=1-316.
DR PDB; 3GHU; X-ray; 1.20 A; A=1-316.
DR PDB; 3LBO; X-ray; 1.10 A; A=1-316.
DR PDB; 3LD5; X-ray; 1.27 A; A=1-316.
DR PDB; 3LEN; X-ray; 1.21 A; A=1-316.
DR PDB; 3LEP; X-ray; 0.99 A; A=1-316.
DR PDB; 3LQG; X-ray; 1.35 A; A=1-316.
DR PDB; 3LQL; X-ray; 1.13 A; A=1-316.
DR PDB; 3LZ3; X-ray; 1.03 A; A=1-316.
DR PDB; 3LZ5; X-ray; 0.95 A; A=1-316.
DR PDB; 3M0I; X-ray; 1.07 A; A=1-316.
DR PDB; 3M4H; X-ray; 0.94 A; A=1-316.
DR PDB; 3M64; X-ray; 1.30 A; A=1-316.
DR PDB; 3MB9; X-ray; 1.65 A; A=1-316.
DR PDB; 3MC5; X-ray; 1.14 A; A=1-316.
DR PDB; 3ONB; X-ray; 1.45 A; A=2-316.
DR PDB; 3ONC; X-ray; 1.06 A; A=2-316.
DR PDB; 3P2V; X-ray; 1.69 A; A=1-316.
DR PDB; 3Q65; X-ray; 2.09 A; A/B=1-316.
DR PDB; 3Q67; X-ray; 1.55 A; A/B=1-316.
DR PDB; 3RX2; X-ray; 1.90 A; A=1-316.
DR PDB; 3RX3; X-ray; 1.90 A; A=1-316.
DR PDB; 3RX4; X-ray; 2.00 A; A=1-316.
DR PDB; 3S3G; X-ray; 1.80 A; A=1-316.
DR PDB; 3T42; X-ray; 1.28 A; A=1-316.
DR PDB; 3U2C; X-ray; 1.00 A; A=1-316.
DR PDB; 3V35; X-ray; 1.90 A; A=1-316.
DR PDB; 3V36; X-ray; 2.00 A; A=1-316.
DR PDB; 3V9Q; X-ray; 2.00 A; A=1-316.
DR PDB; 4GCA; X-ray; 0.90 A; A=2-316.
DR PDB; 4JIR; X-ray; 2.00 A; A=1-316.
DR PDBsum; 1ABN; -.
DR PDBsum; 1ADS; -.
DR PDBsum; 1AZ1; -.
DR PDBsum; 1AZ2; -.
DR PDBsum; 1EF3; -.
DR PDBsum; 1EL3; -.
DR PDBsum; 1IEI; -.
DR PDBsum; 1MAR; -.
DR PDBsum; 1PWL; -.
DR PDBsum; 1PWM; -.
DR PDBsum; 1T40; -.
DR PDBsum; 1T41; -.
DR PDBsum; 1US0; -.
DR PDBsum; 1X96; -.
DR PDBsum; 1X97; -.
DR PDBsum; 1X98; -.
DR PDBsum; 1XGD; -.
DR PDBsum; 1Z3N; -.
DR PDBsum; 1Z89; -.
DR PDBsum; 1Z8A; -.
DR PDBsum; 2ACQ; -.
DR PDBsum; 2ACR; -.
DR PDBsum; 2ACS; -.
DR PDBsum; 2ACU; -.
DR PDBsum; 2AGT; -.
DR PDBsum; 2DUX; -.
DR PDBsum; 2DUZ; -.
DR PDBsum; 2DV0; -.
DR PDBsum; 2F2K; -.
DR PDBsum; 2FZ8; -.
DR PDBsum; 2FZ9; -.
DR PDBsum; 2FZB; -.
DR PDBsum; 2FZD; -.
DR PDBsum; 2HV5; -.
DR PDBsum; 2HVN; -.
DR PDBsum; 2HVO; -.
DR PDBsum; 2I16; -.
DR PDBsum; 2I17; -.
DR PDBsum; 2IKG; -.
DR PDBsum; 2IKH; -.
DR PDBsum; 2IKI; -.
DR PDBsum; 2IKJ; -.
DR PDBsum; 2INE; -.
DR PDBsum; 2INZ; -.
DR PDBsum; 2IPW; -.
DR PDBsum; 2IQ0; -.
DR PDBsum; 2IQD; -.
DR PDBsum; 2IS7; -.
DR PDBsum; 2ISF; -.
DR PDBsum; 2J8T; -.
DR PDBsum; 2NVC; -.
DR PDBsum; 2NVD; -.
DR PDBsum; 2PD5; -.
DR PDBsum; 2PD9; -.
DR PDBsum; 2PDB; -.
DR PDBsum; 2PDC; -.
DR PDBsum; 2PDF; -.
DR PDBsum; 2PDG; -.
DR PDBsum; 2PDH; -.
DR PDBsum; 2PDI; -.
DR PDBsum; 2PDJ; -.
DR PDBsum; 2PDK; -.
DR PDBsum; 2PDL; -.
DR PDBsum; 2PDM; -.
DR PDBsum; 2PDN; -.
DR PDBsum; 2PDP; -.
DR PDBsum; 2PDQ; -.
DR PDBsum; 2PDU; -.
DR PDBsum; 2PDW; -.
DR PDBsum; 2PDX; -.
DR PDBsum; 2PDY; -.
DR PDBsum; 2PEV; -.
DR PDBsum; 2PF8; -.
DR PDBsum; 2PFH; -.
DR PDBsum; 2PZN; -.
DR PDBsum; 2QXW; -.
DR PDBsum; 2R24; -.
DR PDBsum; 3BCJ; -.
DR PDBsum; 3DN5; -.
DR PDBsum; 3G5E; -.
DR PDBsum; 3GHR; -.
DR PDBsum; 3GHS; -.
DR PDBsum; 3GHT; -.
DR PDBsum; 3GHU; -.
DR PDBsum; 3LBO; -.
DR PDBsum; 3LD5; -.
DR PDBsum; 3LEN; -.
DR PDBsum; 3LEP; -.
DR PDBsum; 3LQG; -.
DR PDBsum; 3LQL; -.
DR PDBsum; 3LZ3; -.
DR PDBsum; 3LZ5; -.
DR PDBsum; 3M0I; -.
DR PDBsum; 3M4H; -.
DR PDBsum; 3M64; -.
DR PDBsum; 3MB9; -.
DR PDBsum; 3MC5; -.
DR PDBsum; 3ONB; -.
DR PDBsum; 3ONC; -.
DR PDBsum; 3P2V; -.
DR PDBsum; 3Q65; -.
DR PDBsum; 3Q67; -.
DR PDBsum; 3RX2; -.
DR PDBsum; 3RX3; -.
DR PDBsum; 3RX4; -.
DR PDBsum; 3S3G; -.
DR PDBsum; 3T42; -.
DR PDBsum; 3U2C; -.
DR PDBsum; 3V35; -.
DR PDBsum; 3V36; -.
DR PDBsum; 3V9Q; -.
DR PDBsum; 4GCA; -.
DR PDBsum; 4JIR; -.
DR ProteinModelPortal; P15121; -.
DR SMR; P15121; 1-316.
DR IntAct; P15121; 2.
DR MINT; MINT-1196717; -.
DR STRING; 9606.ENSP00000285930; -.
DR BindingDB; P15121; -.
DR ChEMBL; CHEMBL1900; -.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB00605; Sulindac.
DR PhosphoSite; P15121; -.
DR DMDM; 113596; -.
DR DOSAC-COBS-2DPAGE; P15121; -.
DR REPRODUCTION-2DPAGE; IPI00413641; -.
DR REPRODUCTION-2DPAGE; P15121; -.
DR UCD-2DPAGE; P15121; -.
DR PaxDb; P15121; -.
DR PeptideAtlas; P15121; -.
DR PRIDE; P15121; -.
DR DNASU; 231; -.
DR Ensembl; ENST00000285930; ENSP00000285930; ENSG00000085662.
DR GeneID; 231; -.
DR KEGG; hsa:231; -.
DR UCSC; uc003vrp.1; human.
DR CTD; 231; -.
DR GeneCards; GC07M134127; -.
DR HGNC; HGNC:381; AKR1B1.
DR HPA; CAB018773; -.
DR HPA; CAB027391; -.
DR HPA; HPA026425; -.
DR MIM; 103880; gene.
DR neXtProt; NX_P15121; -.
DR PharmGKB; PA24675; -.
DR eggNOG; COG0656; -.
DR HOVERGEN; HBG000020; -.
DR InParanoid; P15121; -.
DR KO; K00011; -.
DR OMA; DFLDTWT; -.
DR OrthoDB; EOG70KGQF; -.
DR PhylomeDB; P15121; -.
DR BioCyc; MetaCyc:HS01502-MONOMER; -.
DR BRENDA; 1.1.1.21; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15493; Steroid hormones.
DR SABIO-RK; P15121; -.
DR ChiTaRS; AKR1B1; human.
DR EvolutionaryTrace; P15121; -.
DR GeneWiki; AKR1B1; -.
DR GenomeRNAi; 231; -.
DR NextBio; 938; -.
DR PRO; PR:P15121; -.
DR ArrayExpress; P15121; -.
DR Bgee; P15121; -.
DR CleanEx; HS_AKR1B1; -.
DR Genevestigator; P15121; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; TAS:ProtInc.
DR GO; GO:0009055; F:electron carrier activity; TAS:UniProtKB.
DR GO; GO:0043795; F:glyceraldehyde oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0006700; P:C21-steroid hormone biosynthetic process; TAS:Reactome.
DR GO; GO:0005975; P:carbohydrate metabolic process; TAS:ProtInc.
DR GO; GO:0044597; P:daunorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0006950; P:response to stress; TAS:UniProtKB.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR001395; Aldo/ket_red.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR020471; Aldo/keto_reductase_subgr.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR PANTHER; PTHR11732; PTHR11732; 1.
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; Complete proteome; Cytoplasm;
KW Direct protein sequencing; NADP; Oxidoreductase; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 316 Aldose reductase.
FT /FTId=PRO_0000124623.
FT NP_BIND 10 19 NADP (Potential).
FT NP_BIND 211 273 NADP.
FT ACT_SITE 49 49 Proton donor.
FT BINDING 111 111 Substrate.
FT SITE 78 78 Lowers pKa of active site Tyr.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 95 95 N6-acetyllysine.
FT MOD_RES 222 222 N6-acetyllysine.
FT MOD_RES 263 263 N6-acetyllysine.
FT VARIANT 15 15 I -> F (in dbSNP:rs5054).
FT /FTId=VAR_014743.
FT VARIANT 42 42 H -> L (in dbSNP:rs5056).
FT /FTId=VAR_014744.
FT VARIANT 73 73 L -> V (in dbSNP:rs5057).
FT /FTId=VAR_014745.
FT VARIANT 90 90 K -> E (in dbSNP:rs2229542).
FT /FTId=VAR_048213.
FT VARIANT 204 204 G -> S (in dbSNP:rs5061).
FT /FTId=VAR_014746.
FT VARIANT 288 288 T -> I (in dbSNP:rs5062).
FT /FTId=VAR_014747.
FT MUTAGEN 44 44 D->N: Reduced enzymatic activity.
FT MUTAGEN 49 49 Y->F: Complete loss of enzymatic
FT activity.
FT MUTAGEN 78 78 K->M: Reduced enzymatic activity.
FT MUTAGEN 111 111 H->N: Reduced enzymatic activity.
FT CONFLICT 5 5 L -> I (in Ref. 2; AAA51714).
FT CONFLICT 114 114 T -> I (in Ref. 10; CAG47000).
FT CONFLICT 117 117 K -> R (in Ref. 10; CAG29347).
FT CONFLICT 142 142 W -> R (in Ref. 14; AAH05387).
FT CONFLICT 172 172 N -> S (in Ref. 10; CAG29347).
FT CONFLICT 270 272 IAE -> EAA (in Ref. 16; AA sequence).
FT CONFLICT 307 307 H -> M (in Ref. 18; AA sequence).
FT STRAND 3 6
FT STRAND 12 16
FT HELIX 25 38
FT STRAND 42 44
FT HELIX 47 49
FT HELIX 52 64
FT HELIX 70 72
FT STRAND 74 79
FT HELIX 81 83
FT TURN 86 88
FT HELIX 89 100
FT STRAND 105 113
FT STRAND 118 120
FT STRAND 127 129
FT HELIX 138 150
FT STRAND 153 155
FT STRAND 157 161
FT HELIX 164 171
FT STRAND 181 186
FT HELIX 194 202
FT STRAND 206 211
FT STRAND 223 225
FT TURN 228 230
FT HELIX 232 241
FT HELIX 245 255
FT STRAND 259 261
FT HELIX 267 274
FT HELIX 283 290
FT HELIX 302 304
FT STRAND 307 309
FT STRAND 311 314
SQ SEQUENCE 316 AA; 35853 MW; 1852E8616B5DCEAE CRC64;
MASRLLLNNG AKMPILGLGT WKSPPGQVTE AVKVAIDVGY RHIDCAHVYQ NENEVGVAIQ
EKLREQVVKR EELFIVSKLW CTYHEKGLVK GACQKTLSDL KLDYLDLYLI HWPTGFKPGK
EFFPLDESGN VVPSDTNILD TWAAMEELVD EGLVKAIGIS NFNHLQVEMI LNKPGLKYKP
AVNQIECHPY LTQEKLIQYC QSKGIVVTAY SPLGSPDRPW AKPEDPSLLE DPRIKAIAAK
HNKTTAQVLI RFPMQRNLVV IPKSVTPERI AENFKVFDFE LSSQDMTTLL SYNRNWRVCA
LLSCTSHKDY PFHEEF
//
MIM
103880
*RECORD*
*FIELD* NO
103880
*FIELD* TI
*103880 ALDO-KETO REDUCTASE FAMILY 1, MEMBER B1; AKR1B1
;;ALDOSE REDUCTASE; AR;;
ALDEHYDE REDUCTASE 1; ALDR1
read more*FIELD* TX
DESCRIPTION
See aldehyde reductase (103830). Aldose reductase (EC 1.1.1.21) is a
member of the monomeric, NADPH-dependent aldo-keto reductase family and
participates in glucose metabolism and osmoregulation. It is believed to
play a protective role against toxic aldehydes derived from lipid
peroxidation and steroidogenesis that could affect cell
growth/differentiation when accumulated (Lefrancois-Martinez et al.,
2004). It is the first enzyme of the polyol pathway of sugar metabolism,
is most abundantly expressed in adrenal gland, and has been implicated
in diabetic complications (Shah et al., 1997).
CLONING
Chung and LaMendola (1989) cloned and sequenced the aldose reductase
gene from a human placental cDNA library using antibodies against the
bovine lens aldose reductase. The deduced amino acid sequence indicated
that maturation of aldose reductase involves removal of the N-terminal
methionine. Nishimura et al. (1990) also cloned the aldose reductase
gene using synthetic oligonucleotide probes based on partial amino acid
sequences of purified human psoas muscle aldose reductase. Bohren et al.
(1989) isolated aldose reductase and aldehyde reductase cDNAs. They
reported that the 2 proteins are 51% identical. Northern blot analysis
revealed that aldose reductase was expressed as an approximately 1.4-kb
mRNA in placenta.
Graham et al. (1991) determined the sequence of the ALDR1 gene by
analysis of cDNA and genomic clones. The gene codes for a 316-amino acid
protein with a molecular mass of 35,858 Da. A major site of
transcription initiation in liver was mapped to an adenine residue 31
nucleotides upstream from the A of the ATG initiation codon.
GENE STRUCTURE
Graham et al. (1991) determined that the ALDR1 gene extends over
approximately 18 kb and consists of 10 exons, giving rise to a 1,384
nucleotide mRNA, excluding the poly(A) tail. The exons range in size
from 82 to 168 bp, whereas the introns range from 325 to about 7,160 bp.
The promoter region of the gene contains a TATA (TATTTA) box and a CCAAT
box, located 37 and 104 nucleotides upstream, respectively, from the
transcription initiation site. Graham et al. (1991) found 4 Alu elements
in the ALDR1 gene: 2 in intron 1 and 1 each in introns 4 and 9.
GENE FUNCTION
Using specific antibodies, Northern blot analysis, and enzymatic assays,
Lefrancois-Martinez et al. (2004) presented evidence that AKR1B1
detectable in 15-week-old fetal glands is regulated by cAMP in human
adrenocortical cells and thus that AKR1B1 is functionally related to the
ACTH-responsive murine akr1b7/mvdp (mouse vas deferens protein) gene
rather than to its direct ortholog, the mouse aldose reductase akr1b3
gene.
BIOCHEMICAL FEATURES
Aldose reductase catalyzes the reduction of a number of aldehydes,
including the aldehyde form of glucose, which is reduced to the
corresponding sugar alcohol, sorbitol (Chung and LaMendola, 1989).
Sorbitol is subsequently metabolized to fructose by sorbitol
dehydrogenase. Under normal conditions, this pathway plays a minor role
in glucose metabolism in most tissues. In diabetic hyperglycemia,
however, cells undergoing insulin-independent uptake of glucose produce
significant quantities of sorbitol. The sorbitol accumulates in cells
because of its poor penetration across cellular membranes and its slow
metabolism by sorbitol dehydrogenase. The resulting hyperosmotic stress
to cells may be a cause of diabetic complications such as neuropathy,
retinopathy, and cataracts.
Epidemiology studies in patients with insulin-dependent diabetes (IDDM;
222100) and noninsulin-dependent diabetes mellitus (NIDDM; 125853) are
consistent with the hypothesis that a genetic factor influences the risk
for kidney disease of diabetes mellitus (see 603933). Aldose reductase,
the rate-limiting enzyme in the polyol pathway, catalyzes the
NADPH-dependent reduction of sugar aldehydes to their corresponding
sugar polyols. Shah et al. (1997) explored the hypothesis that increased
AR gene expression is a risk factor for nephropathy associated with
IDDM. They studied the following 4 groups: normal subjects, those with
IDDM and no evidence of nephropathy, those with IDDM and nephropathy,
and nondiabetics with nephropathy. They quantitated AR mRNA from
peripheral blood mononuclear cells by RNase protection assay. The
AR/beta-actin mRNA ratio was higher in the group with diabetic
nephropathy (603933) (0.088; CI, 0.06-80.108) than in the group of
normal subjects (0.045; CI, 0.033-0.057; P less than 0.01), the group
with IDDM without nephropathy (0.045; CI, 0.030-0.060; P less than
0.01), or the group of nondiabetics with kidney disease (0.019; CI,
0.011-0.027; P less than 0.001). In contrast, among nondiabetics, the
AR/beta-actin mRNA ratios were 2-fold lower in those with kidney disease
than in the group of normal subjects (P less than 0.01). The authors
concluded that the degree of AR gene expression modulates the risk for
nephropathy in IDDM subjects.
Lefrancois-Martinez et al. (2004) studied if changes in AKR1B1
expression could be associated with adrenal disorders. Relative
abundance of AKR1B1 mRNA was decreased in adrenocortical carcinomas when
compared with adenomas. Most (7 of 8) adrenocortical carcinomas had very
low relative AKR1B1 protein levels when compared with benign tumors
(cortisol-producing adenomas, nonfunctional adenomas,
aldosterone-producing adenomas), Cushing hyperplasia (see 219080), or
normal adrenals.
MAPPING
Using PCR to amplify specifically the human AR sequence in hamster/human
hybrid DNA and also in mouse/human monochromosome hybrids, Graham et al.
(1991) assigned the gene to chromosome 7. The assignment was confirmed
and regionalized to 7q35 by in situ hybridization to human metaphase
chromosomes using a novel, rapid method.
Using a cDNA clone encoding human aldose reductase, Bateman et al.
(1993) mapped gene sequences to human chromosomes 1, 3, 7, 9, 11, 13,
14, and 18 by analysis of somatic cell hybrids. By in situ
hybridization, sequences were localized to 1q32-q42, 3p12, 7q31-q35,
9q22, 11p14-p15, and 13q14-q21. As a putative functional ALDR1 gene had
been mapped to chromosome 7 and a putative pseudogene (ALDRP1) to
chromosome 3, the sequences on the other 7 chromosomes were thought to
represent other active genes, non-aldose reductase homologous sequences,
or pseudogenes.
- PSEUDOGENES
Brown et al. (1992) identified a putative pseudogene (ALDRP1) that
contained no intronic sequences; the functional aldose reductase has 9
introns. In addition, the homology was absent in the region 5-prime to
the transcription start site for the cDNA, implying that regulatory
elements such as the promoter were missing from the pseudogene. They
mapped the pseudogene to chromosome 3 by PCR, using amplimers specific
for it to amplify DNA from somatic cell hybrids.
*FIELD* RF
1. Bateman, J. B.; Kojis, T.; Heinzmann, C.; Klisak, I.; Diep, A.;
Carper, D.; Nishimura, C.; Mohandas, T.; Sparkes, R. S.: Mapping
of aldose reductase gene sequences to human chromosomes 1, 3, 7, 9,
11, and 13. Genomics 17: 560-565, 1993.
2. Bohren, K. M.; Bullock, B.; Wermuth, B.; Gabbay, K. H.: The aldo-keto
reductase superfamily: cDNAs and deduced amino acid sequences of human
aldehyde and aldose reductases. J. Biol. Chem. 264: 9547-9551, 1989.
3. Brown, L.; Hedge, P. J.; Markham, A. F.; Graham, A.: A human aldehyde
dehydrogenase (aldose reductase) pseudogene: nucleotide sequence analysis
and assignment to chromosome 3. Genomics 13: 465-468, 1992.
4. Chung, S.; LaMendola, J.: Cloning and sequence determination of
human placental aldose reductase gene. J. Biol. Chem. 264: 14775-14777,
1989.
5. Graham, A.; Brown, L.; Hedge, P. J.; Gammack, A. J.; Markham, A.
F.: Structure of the human aldose reductase gene. J. Biol. Chem. 266:
6872-6877, 1991.
6. Graham, A.; Heath, P.; Morten, J. E. N.; Markham, A. F.: The human
aldose reductase gene maps to chromosome region 7q35. Hum. Genet. 86:
509-514, 1991.
7. Lefrancois-Martinez, A.-M.; Bertherat, J.; Val, P.; Tournaire,
C.; Gallo-Payet, N.; Hyndman, D.; Veyssiere, G.; Bertagna, X.; Jean,
C.; Martinez, A.: Decreased expression of cyclic adenosine monophosphate-regulated
aldose reductase (AKR1B1) is associated with malignancy in human sporadic
adrenocortical tumors. J. Clin. Endocr. Metab. 89: 3010-3019, 2004.
8. Nishimura, C.; Matsuura, Y.; Kokai, Y.; Akera, T.; Carper, D.;
Morjana, N.; Lyons, C.; Flynn, T. G.: Cloning and expression of human
aldose reductase. J. Biol. Chem. 265: 9788-9792, 1990.
9. Shah, V. O.; Dorin, R. I.; Sun, Y.; Braun, M.; Zager, P. G.: Aldose
reductase gene expression is increased in diabetic nephropathy. J.
Clin. Endocr. Metab. 82: 2294-2298, 1997.
*FIELD* CN
John A. Phillips, III - updated: 10/26/2005
Rebekah S. Rasooly - updated: 7/20/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 07/09/2009
carol: 2/13/2009
alopez: 10/26/2005
carol: 4/30/2001
alopez: 11/15/1999
mgross: 7/20/1999
carol: 5/18/1999
alopez: 10/20/1997
alopez: 9/5/1997
mark: 11/27/1996
mark: 2/26/1996
carol: 4/6/1994
carol: 9/21/1993
carol: 12/21/1992
carol: 6/3/1992
supermim: 3/16/1992
carol: 8/19/1991
*RECORD*
*FIELD* NO
103880
*FIELD* TI
*103880 ALDO-KETO REDUCTASE FAMILY 1, MEMBER B1; AKR1B1
;;ALDOSE REDUCTASE; AR;;
ALDEHYDE REDUCTASE 1; ALDR1
read more*FIELD* TX
DESCRIPTION
See aldehyde reductase (103830). Aldose reductase (EC 1.1.1.21) is a
member of the monomeric, NADPH-dependent aldo-keto reductase family and
participates in glucose metabolism and osmoregulation. It is believed to
play a protective role against toxic aldehydes derived from lipid
peroxidation and steroidogenesis that could affect cell
growth/differentiation when accumulated (Lefrancois-Martinez et al.,
2004). It is the first enzyme of the polyol pathway of sugar metabolism,
is most abundantly expressed in adrenal gland, and has been implicated
in diabetic complications (Shah et al., 1997).
CLONING
Chung and LaMendola (1989) cloned and sequenced the aldose reductase
gene from a human placental cDNA library using antibodies against the
bovine lens aldose reductase. The deduced amino acid sequence indicated
that maturation of aldose reductase involves removal of the N-terminal
methionine. Nishimura et al. (1990) also cloned the aldose reductase
gene using synthetic oligonucleotide probes based on partial amino acid
sequences of purified human psoas muscle aldose reductase. Bohren et al.
(1989) isolated aldose reductase and aldehyde reductase cDNAs. They
reported that the 2 proteins are 51% identical. Northern blot analysis
revealed that aldose reductase was expressed as an approximately 1.4-kb
mRNA in placenta.
Graham et al. (1991) determined the sequence of the ALDR1 gene by
analysis of cDNA and genomic clones. The gene codes for a 316-amino acid
protein with a molecular mass of 35,858 Da. A major site of
transcription initiation in liver was mapped to an adenine residue 31
nucleotides upstream from the A of the ATG initiation codon.
GENE STRUCTURE
Graham et al. (1991) determined that the ALDR1 gene extends over
approximately 18 kb and consists of 10 exons, giving rise to a 1,384
nucleotide mRNA, excluding the poly(A) tail. The exons range in size
from 82 to 168 bp, whereas the introns range from 325 to about 7,160 bp.
The promoter region of the gene contains a TATA (TATTTA) box and a CCAAT
box, located 37 and 104 nucleotides upstream, respectively, from the
transcription initiation site. Graham et al. (1991) found 4 Alu elements
in the ALDR1 gene: 2 in intron 1 and 1 each in introns 4 and 9.
GENE FUNCTION
Using specific antibodies, Northern blot analysis, and enzymatic assays,
Lefrancois-Martinez et al. (2004) presented evidence that AKR1B1
detectable in 15-week-old fetal glands is regulated by cAMP in human
adrenocortical cells and thus that AKR1B1 is functionally related to the
ACTH-responsive murine akr1b7/mvdp (mouse vas deferens protein) gene
rather than to its direct ortholog, the mouse aldose reductase akr1b3
gene.
BIOCHEMICAL FEATURES
Aldose reductase catalyzes the reduction of a number of aldehydes,
including the aldehyde form of glucose, which is reduced to the
corresponding sugar alcohol, sorbitol (Chung and LaMendola, 1989).
Sorbitol is subsequently metabolized to fructose by sorbitol
dehydrogenase. Under normal conditions, this pathway plays a minor role
in glucose metabolism in most tissues. In diabetic hyperglycemia,
however, cells undergoing insulin-independent uptake of glucose produce
significant quantities of sorbitol. The sorbitol accumulates in cells
because of its poor penetration across cellular membranes and its slow
metabolism by sorbitol dehydrogenase. The resulting hyperosmotic stress
to cells may be a cause of diabetic complications such as neuropathy,
retinopathy, and cataracts.
Epidemiology studies in patients with insulin-dependent diabetes (IDDM;
222100) and noninsulin-dependent diabetes mellitus (NIDDM; 125853) are
consistent with the hypothesis that a genetic factor influences the risk
for kidney disease of diabetes mellitus (see 603933). Aldose reductase,
the rate-limiting enzyme in the polyol pathway, catalyzes the
NADPH-dependent reduction of sugar aldehydes to their corresponding
sugar polyols. Shah et al. (1997) explored the hypothesis that increased
AR gene expression is a risk factor for nephropathy associated with
IDDM. They studied the following 4 groups: normal subjects, those with
IDDM and no evidence of nephropathy, those with IDDM and nephropathy,
and nondiabetics with nephropathy. They quantitated AR mRNA from
peripheral blood mononuclear cells by RNase protection assay. The
AR/beta-actin mRNA ratio was higher in the group with diabetic
nephropathy (603933) (0.088; CI, 0.06-80.108) than in the group of
normal subjects (0.045; CI, 0.033-0.057; P less than 0.01), the group
with IDDM without nephropathy (0.045; CI, 0.030-0.060; P less than
0.01), or the group of nondiabetics with kidney disease (0.019; CI,
0.011-0.027; P less than 0.001). In contrast, among nondiabetics, the
AR/beta-actin mRNA ratios were 2-fold lower in those with kidney disease
than in the group of normal subjects (P less than 0.01). The authors
concluded that the degree of AR gene expression modulates the risk for
nephropathy in IDDM subjects.
Lefrancois-Martinez et al. (2004) studied if changes in AKR1B1
expression could be associated with adrenal disorders. Relative
abundance of AKR1B1 mRNA was decreased in adrenocortical carcinomas when
compared with adenomas. Most (7 of 8) adrenocortical carcinomas had very
low relative AKR1B1 protein levels when compared with benign tumors
(cortisol-producing adenomas, nonfunctional adenomas,
aldosterone-producing adenomas), Cushing hyperplasia (see 219080), or
normal adrenals.
MAPPING
Using PCR to amplify specifically the human AR sequence in hamster/human
hybrid DNA and also in mouse/human monochromosome hybrids, Graham et al.
(1991) assigned the gene to chromosome 7. The assignment was confirmed
and regionalized to 7q35 by in situ hybridization to human metaphase
chromosomes using a novel, rapid method.
Using a cDNA clone encoding human aldose reductase, Bateman et al.
(1993) mapped gene sequences to human chromosomes 1, 3, 7, 9, 11, 13,
14, and 18 by analysis of somatic cell hybrids. By in situ
hybridization, sequences were localized to 1q32-q42, 3p12, 7q31-q35,
9q22, 11p14-p15, and 13q14-q21. As a putative functional ALDR1 gene had
been mapped to chromosome 7 and a putative pseudogene (ALDRP1) to
chromosome 3, the sequences on the other 7 chromosomes were thought to
represent other active genes, non-aldose reductase homologous sequences,
or pseudogenes.
- PSEUDOGENES
Brown et al. (1992) identified a putative pseudogene (ALDRP1) that
contained no intronic sequences; the functional aldose reductase has 9
introns. In addition, the homology was absent in the region 5-prime to
the transcription start site for the cDNA, implying that regulatory
elements such as the promoter were missing from the pseudogene. They
mapped the pseudogene to chromosome 3 by PCR, using amplimers specific
for it to amplify DNA from somatic cell hybrids.
*FIELD* RF
1. Bateman, J. B.; Kojis, T.; Heinzmann, C.; Klisak, I.; Diep, A.;
Carper, D.; Nishimura, C.; Mohandas, T.; Sparkes, R. S.: Mapping
of aldose reductase gene sequences to human chromosomes 1, 3, 7, 9,
11, and 13. Genomics 17: 560-565, 1993.
2. Bohren, K. M.; Bullock, B.; Wermuth, B.; Gabbay, K. H.: The aldo-keto
reductase superfamily: cDNAs and deduced amino acid sequences of human
aldehyde and aldose reductases. J. Biol. Chem. 264: 9547-9551, 1989.
3. Brown, L.; Hedge, P. J.; Markham, A. F.; Graham, A.: A human aldehyde
dehydrogenase (aldose reductase) pseudogene: nucleotide sequence analysis
and assignment to chromosome 3. Genomics 13: 465-468, 1992.
4. Chung, S.; LaMendola, J.: Cloning and sequence determination of
human placental aldose reductase gene. J. Biol. Chem. 264: 14775-14777,
1989.
5. Graham, A.; Brown, L.; Hedge, P. J.; Gammack, A. J.; Markham, A.
F.: Structure of the human aldose reductase gene. J. Biol. Chem. 266:
6872-6877, 1991.
6. Graham, A.; Heath, P.; Morten, J. E. N.; Markham, A. F.: The human
aldose reductase gene maps to chromosome region 7q35. Hum. Genet. 86:
509-514, 1991.
7. Lefrancois-Martinez, A.-M.; Bertherat, J.; Val, P.; Tournaire,
C.; Gallo-Payet, N.; Hyndman, D.; Veyssiere, G.; Bertagna, X.; Jean,
C.; Martinez, A.: Decreased expression of cyclic adenosine monophosphate-regulated
aldose reductase (AKR1B1) is associated with malignancy in human sporadic
adrenocortical tumors. J. Clin. Endocr. Metab. 89: 3010-3019, 2004.
8. Nishimura, C.; Matsuura, Y.; Kokai, Y.; Akera, T.; Carper, D.;
Morjana, N.; Lyons, C.; Flynn, T. G.: Cloning and expression of human
aldose reductase. J. Biol. Chem. 265: 9788-9792, 1990.
9. Shah, V. O.; Dorin, R. I.; Sun, Y.; Braun, M.; Zager, P. G.: Aldose
reductase gene expression is increased in diabetic nephropathy. J.
Clin. Endocr. Metab. 82: 2294-2298, 1997.
*FIELD* CN
John A. Phillips, III - updated: 10/26/2005
Rebekah S. Rasooly - updated: 7/20/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 07/09/2009
carol: 2/13/2009
alopez: 10/26/2005
carol: 4/30/2001
alopez: 11/15/1999
mgross: 7/20/1999
carol: 5/18/1999
alopez: 10/20/1997
alopez: 9/5/1997
mark: 11/27/1996
mark: 2/26/1996
carol: 4/6/1994
carol: 9/21/1993
carol: 12/21/1992
carol: 6/3/1992
supermim: 3/16/1992
carol: 8/19/1991