G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
aldo-keto reductase family 1, member A1 (aldehyde reductase)
G00001242 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000007740 (Vega human gene)
ENSG00000117448 (Ensembl human gene)
10327 (Entrez Gene)
717 (G2Cdb plasticity & disease)
AKR1A1 (GeneCards)
103830 (OMIM)
Marker Symbol
Protein Sequence
P14550 (UniProt)

Synonyms (2)

  • ALR
  • DD3

Literature (28)

Pubmed - other

  • Genetic susceptibility to distinct bladder cancer subphenotypes.

    Guey LT, García-Closas M, Murta-Nascimento C, Lloreta J, Palencia L, Kogevinas M, Rothman N, Vellalta G, Calle ML, Marenne G, Tardón A, Carrato A, García-Closas R, Serra C, Silverman DT, Chanock S, Real FX, Malats N and EPICURO/Spanish Bladder Cancer Study investigators

    Spanish National Cancer Research Centre, Madrid, Spain.

    Background: Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes.

    Objective: To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity.

    The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n=1149).

    Measurements: A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n=586), high-grade nonmuscle invasive (n=219), and muscle invasive (n=246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested.

    Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate.

    Conclusions: These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.

    Funded by: Intramural NIH HHS: ZIA CP010136-16

    European urology 2010;57;2;283-92

  • PTEN identified as important risk factor of chronic obstructive pulmonary disease.

    Hosgood HD, Menashe I, He X, Chanock S and Lan Q

    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.

    Common genetic variation may play an important role in altering chronic obstructive pulmonary disease (COPD) risk. In Xuanwei, China, the COPD rate is more than twice the Chinese national average, and COPD is strongly associated with in-home coal use. To identify genetic variation that may be associated with COPD in a population with substantial in-home coal smoke exposures, we evaluated 1261 single nucleotide polymorphisms (SNPs) in 380 candidate genes potentially relevant for cancer and other human diseases in a population-based case-control study in Xuanwei (53 cases; 107 controls). PTEN was the most significantly associated gene with COPD in a minP analysis using 20,000 permutations (P=0.00005). SNP-based analyses found that homozygote variant carriers of PTEN rs701848 (OR(TT)=0.12, 95% CI=0.03-0.47) had a significant decreased risk of COPD. PTEN, or phosphatase and tensin homolog, is an important regulator of cell cycle progression and cellular survival via the AKT signaling pathway. Our exploratory analysis suggests that genetic variation in PTEN may be an important risk factor of COPD in Xuanwei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuanwei and other populations with coal smoke exposures.

    Funded by: Intramural NIH HHS: Z99 CA999999

    Respiratory medicine 2009;103;12;1866-70

  • Genetic polymorphisms in nitric oxide synthase genes modify the relationship between vegetable and fruit intake and risk of non-Hodgkin lymphoma.

    Han X, Zheng T, Lan Q, Zhang Y, Kilfoy BA, Qin Q, Rothman N, Zahm SH, Holford TR, Leaderer B and Zhang Y

    Yale University School of Public Health, New Haven, CT 06520-8034, USA.

    Oxidative damage caused by reactive oxygen species and other free radicals is involved in carcinogenesis. It has been suggested that high vegetable and fruit intake may reduce the risk of non-Hodgkin lymphoma (NHL) as vegetables and fruit are rich in antioxidants. The aim of this study is to evaluate the interaction of vegetable and fruit intake with genetic polymorphisms in oxidative stress pathway genes and NHL risk. This hypothesis was investigated in a population-based case-control study of NHL and NHL histologic subtypes in women from Connecticut, including 513 histologically confirmed incident cases and 591 randomly selected controls. Gene-vegetable/fruit joint effects were estimated using unconditional logistic regression model. The false discovery rate method was applied to adjust for multiple comparisons. Significant interactions with vegetable and fruit intake were mainly found for genetic polymorphisms on nitric oxide synthase (NOS) genes among those with diffuse large B-cell lymphoma and follicular lymphoma. Two single nucleotide polymorphisms in the NOS1 gene were found to significantly modify the association between total vegetable and fruit intake and risk of NHL overall, as well as the risk of follicular lymphoma. When vegetables, bean vegetables, cruciferous vegetables, green leafy vegetables, red vegetables, yellow/orange vegetables, fruit, and citrus fruits were examined separately, strong interaction effects were narrowed to vegetable intake among patients with diffuse large B-cell lymphoma. Our results suggest that genetic polymorphisms in oxidative stress pathway genes, especially in the NOS genes, modify the association between vegetable and fruit intake and risk of NHL.

    Funded by: FIC NIH HHS: 1D43TW007864-01, D43 TW007864; Intramural NIH HHS: Z01 CP010123-12; NCI NIH HHS: R01 CA062006; NCRR NIH HHS: UL1 RR024139

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2009;18;5;1429-38

  • Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway.

    Hosgood HD, Menashe I, Shen M, Yeager M, Yuenger J, Rajaraman P, He X, Chatterjee N, Caporaso NE, Zhu Y, Chanock SJ, Zheng T and Lan Q

    Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. hosgoodd@mail.nih.gov

    Common genetic variation may play an important role in altering lung cancer risk. We conducted a pathway-based candidate gene evaluation to identify genetic variations that may be associated with lung cancer in a population-based case-control study in Xuan Wei, China (122 cases and 111 controls). A total of 1260 single-nucleotide polymorphisms (SNPs) in 380 candidate genes for lung cancer were successfully genotyped and assigned to one of 10 pathways based on gene ontology. Logistic regression was used to assess the marginal effect of each SNP on lung cancer susceptibility. The minP test was used to identify statistically significant associations at the gene level. Important pathways were identified using a test of proportions and the rank truncated product methods. The cell cycle pathway was found as the most important pathway (P = 0.044) with four genes significantly associated with lung cancer (PLA2G6 minP = 0.001, CCNA2 minP = 0.006, GSK3 beta minP = 0.007 and EGF minP = 0.013), after adjusting for multiple comparisons. Interestingly, most cell cycle genes that were associated with lung cancer in this analysis were concentrated in the AKT signaling pathway, which is essential for regulation of cell cycle progression and cellular survival, and may be important in lung cancer etiology in Xuan Wei. These results should be viewed as exploratory until they are replicated in a larger study.

    Funded by: Intramural NIH HHS; NCI NIH HHS: TU2 CA105666

    Carcinogenesis 2008;29;10;1938-43

  • Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.

    Steuber H, Heine A, Podjarny A and Klebe G

    Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany.

    Inhibition of human aldose reductase (ALR2) evolved as a promising therapeutic concept to prevent late complications of diabetes. As well as appropriate affinity and bioavailability, putative inhibitors should possess a high level of selectivity for ALR2 over the related aldehyde reductase (ALR1). We investigated the selectivity-determining features by gradually mapping the residues deviating between the binding pockets of ALR1 and ALR2 into the ALR2 binding pocket. The resulting mutational constructs of ALR2 (eight point mutations and one double mutant) were probed for their influence towards ligand selectivity by X-ray structure analysis of the corresponding complexes and isothermal titration calorimetry (ITC). The binding properties of these mutants were evaluated using a ligand set of zopolrestat, a related uracil derivative, IDD388, IDD393, sorbinil, fidarestat and tolrestat. Our study revealed induced-fit adaptations within the mutated binding site as an essential prerequisite for ligand accommodation related to the selectivity discrimination of the ligands. However, our study also highlights the limits of the present understanding of protein-ligand interactions. Interestingly, binding site mutations not involved in any direct interaction to the ligands in various cases show significant effects towards their binding thermodynamics. Furthermore, our results suggest the binding site residues deviating between ALR1 and ALR2 influence ligand affinity in a complex interplay, presumably involving changes of dynamic properties and differences of the solvation/desolvation balance upon ligand binding.

    Journal of molecular biology 2008;379;5;991-1016

  • Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma.

    Lan Q, Zheng T, Shen M, Zhang Y, Wang SS, Zahm SH, Holford TR, Leaderer B, Boyle P and Chanock S

    Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, EPS 8109, Bethesda, MD 20892-7240, USA. qingl@mail.nih.gov

    Oxidative damage caused by reactive oxygen species (ROS) and other free radicals is involved in a number of pathological conditions including cancer. In a population-based case-control study of non-Hodgkin lymphoma (NHL) (n = 518 cases, 597 controls) among women in Connecticut, we analyzed one or more single nucleotide polymorphisms (SNPs) in ten candidate genes (AKR1A1, AKR1C1, AKR1C3, CYBA, GPX1, MPO, NOS2A, NOS3, OGG1, and SOD2) that mediate oxidative stress directly or indirectly in the NADPH oxidase-dependent respiratory burst. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and race. Polymorphisms in AKR1A1 and CYBA were significantly associated with increased risk of NHL. There was a 1.7-fold (95% CI = 1.2-2.4, P = 0.0047) increased risk of NHL for individuals who were variant homozygous for the AKR1A1 (IVS5 + 282T > C) SNP. The effect was most pronounced for risk of diffuse large B-cell lymphoma, but risk estimates were non-significantly elevated for other common B-cell histologies and T-cell lymphomas as well. In addition, individuals variant homozygous for the CYBA (Ex4 + 11C > T) SNP had a 1.6-fold (95% CI = 1.1-2.4, P = 0.019) increased risk of NHL that was particularly pronounced for T-cell lymphoma (OR = 3.5, 95% CI = 1.3-9.6, P = 0.013), but was also associated with non-significant increased risks for each of the common B-cell histologies. These results suggest that SNPs in genes related to the oxidative stress pathway may be associated with increased risk of NHL.

    Funded by: Intramural NIH HHS; NCI NIH HHS: CA62006

    Human genetics 2007;121;2;161-8

  • Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma.

    Wang SS, Davis S, Cerhan JR, Hartge P, Severson RK, Cozen W, Lan Q, Welch R, Chanock SJ and Rothman N

    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA. wangso@mail.nih.gov

    Evidence supporting the contribution of oxidative stress to key pathways in cancer, such as inflammation and DNA damage, continues to mount. We investigated variations within genes mediating oxidative stress to determine whether they alter risk for non-Hodgkin lymphoma (NHL). Thirteen single nucleotide polymorphisms (SNPs) from 10 oxidative stress genes (AKR1A1, AKR1C1, CYBA, GPX, MPO, NOS2A, NOS3, OGG1, PPARG and SOD2) were genotyped in 1172 NHL cases and 982 population-based controls from a USA multicenter case-control study. For NHL and five subtypes (diffuse large B-cell, follicular, marginal zone, small lymphocytic and T-cell), SNP associations were calculated. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for sex, age (<45, 45-64, 65+ years), race (white, black, other) and study site. Overall, the oxidative stress pathway was associated significantly with the B-cell NHL subtype, diffuse large B-cell lymphoma (DLBCL) (global P-value=0.003). Specifically, for nitric oxide synthase (NOS2A Ser608Leu, rs2297518) Leu/Leu homozygotes, there was a 2-fold risk increase for NHL (OR=2.2, 95% CI=1.1-4.4) (referent=Ser/Ser and Ser/Leu). This risk increase was consistent by cell lineage (B- and T-cell NHL) and pronounced for the two most common subtypes, diffuse large B-cell (OR=3.4, 95% CI=1.5-7.8) and follicular lymphoma (OR=2.6, 95% CI=1.0-6.8). In an analysis of manganese superoxide dismutase (SOD2 Val16Ala, rs1799725) Ala/Ala homozygotes, we observed moderately increased risks for B-cell lymphomas (OR=1.3, 95% CI=1.0-1.6; referent=Val/Val and Val/Ala) that was consistent across the B-cell subtypes. Genetic variations that result in an increased generation of reactive oxygen species appear to increase risk for NHL and its major subtypes, particularly DLBCL. Independent replication of our findings are warranted and further evaluation of oxidative stress in the context of inflammation, DNA repair and the induction of the NF-kappaB pathway may further reveal important clues for lymphomagenesis.

    Funded by: Intramural NIH HHS

    Carcinogenesis 2006;27;9;1828-34

  • Towards a proteome-scale map of the human protein-protein interaction network.

    Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP and Vidal M

    Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.

    Systematic mapping of protein-protein interactions, or 'interactome' mapping, was initiated in model organisms, starting with defined biological processes and then expanding to the scale of the proteome. Although far from complete, such maps have revealed global topological and dynamic features of interactome networks that relate to known biological properties, suggesting that a human interactome map will provide insight into development and disease mechanisms at a systems level. Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions. Using a stringent, high-throughput yeast two-hybrid system, we tested pairwise interactions among the products of approximately 8,100 currently available Gateway-cloned open reading frames and detected approximately 2,800 interactions. This data set, called CCSB-HI1, has a verification rate of approximately 78% as revealed by an independent co-affinity purification assay, and correlates significantly with other biological attributes. The CCSB-HI1 data set increases by approximately 70% the set of available binary interactions within the tested space and reveals more than 300 new connections to over 100 disease-associated proteins. This work represents an important step towards a systematic and comprehensive human interactome project.

    Funded by: NCI NIH HHS: R33 CA132073; NHGRI NIH HHS: P50 HG004233, R01 HG001715, RC4 HG006066, U01 HG001715; NHLBI NIH HHS: U01 HL098166

    Nature 2005;437;7062;1173-8

  • The structure of Apo R268A human aldose reductase: hinges and latches that control the kinetic mechanism.

    Bohren KM, Brownlee JM, Milne AC, Gabbay KH and Harrison DH

    The Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

    Aldose reductase (AR) catalyzes the NADPH-dependent reduction of glucose and other sugars to their respective sugar alcohols. The NADP+/NADPH exchange is the rate-limiting step for this enzyme and contributes in varying degrees to the catalytic rates of other aldo-keto reductase superfamily enzymes. The mutation of Arg268 to alanine in human recombinant AR removes one of the ligands of the C2-phosphate of NADP+ and markedly reduces the interaction of the apoenzyme with the nucleotide. The crystal structure of human R268A apo-aldose reductase determined to a resolution of 2.1 A is described. The R268A mutant enzyme has similar kinetic parameters to the wild-type enzyme for aldehyde substrates, yet has greatly reduced affinity for the nucleotide substrate which greatly facilitates its crystallization in the apoenzyme form. The apo-structure shows that a high temperature factor loop (between residues 214 and 226) is displaced by as much as 17 A in a rigid body fashion about Gly213 and Ser226 in the absence of the nucleotide cofactor as compared to the wild-type holoenzyme structure. Several factors act to stabilize the NADPH-holding loop in either the 'open' or 'closed' conformations: (1) the presence and interactions of the nucleotide cofactor, (2) the residues surrounding the Gly213 and Ser226 hinges which form unique hydrogen bonds in the 'open' or 'closed' structure, and (3) the Trp219 "latch" residue which interacts with an arginine residue, Arg293, in the 'open' conformation or with a cysteine residue, Cys298, in the 'closed' conformation. Several mutations in and around the high temperature factor loop are examined to elucidate the role of the loop in the mechanism by which aldose reductase binds and releases its nucleotide substrate.

    Funded by: NEI NIH HHS: EY-11018; NIDDK NIH HHS: DK-51697

    Biochimica et biophysica acta 2005;1748;2;201-12

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • A protein interaction framework for human mRNA degradation.

    Lehner B and Sanderson CM

    MRC Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge CB10 1SB, United Kingdom.

    The degradation of mRNA is an important regulatory step in the control of gene expression. However, mammalian RNA decay pathways remain poorly characterized. To provide a framework for studying mammalian RNA decay, a two-hybrid protein interaction map was generated using 54 constructs from 38 human proteins predicted to function in mRNA decay. The results provide evidence for interactions between many different proteins required for mRNA decay. Of particular interest are interactions between the poly(A) ribonuclease and the exosome and between the Lsm complex, decapping factors, and 5'-->3' exonucleases. Moreover, multiple interactions connect 5'-->3' and 3'-->5' decay proteins to each other and to nonsense-mediated decay factors, providing the opportunity for coordination between decay pathways. The interaction network also predicts the internal organization of the exosome and Lsm complexes. Additional interactions connect mRNA decay factors to many novel proteins and to proteins required for other steps in gene expression. These results provide an experimental insight into the organization of proteins required for mRNA decay and their coupling to other cellular processes, and the physiological relevance of many of these interactions are supported by their evolutionary conservation. The interactions also provide a wealth of hypotheses to guide future research on mRNA degradation and demonstrate the power of exhaustive protein interaction mapping in aiding understanding of uncharacterized protein complexes and pathways.

    Genome research 2004;14;7;1315-23

  • Enzymes in pancreatic islets that use NADP(H) as a cofactor including evidence for a plasma membrane aldehyde reductase.

    Laclau M, Lu F and MacDonald MJ

    University of Wisconsin Childrens Diabetes Center, Madison, USA.

    Recent evidence of a pyruvate malate shuttle capable of transporting a large amount of NADPH equivalents out of mitochondria in pancreatic islets suggests that cytosolic NADP(H) plays a role in beta cell metabolism. To obtain clues about these processes the activities of several NADPH-utilizing enzymes were estimated in pancreatic islets. Low levels of pyrroquinolone quinone (PQQ) and low levels of enzyme activity that reduce PQQ were found in islets. Low activities of palmitoyl-CoA and stearoyl-CoA desaturases were also detected. Significant activities of glutathione reductase, aldose reductase (EC. and aldehyde reductase (EC. were present in islets. Potent inhibitors of aldehyde and aldose reductases inhibited neither glucose-induced insulin release nor glucose metabolism in islets indicating that these reductases are not directly involved in glucose-induced insulin reaction. Over 90% of aldose reductase plus aldehyde reductase enzyme activity was present in the cytosol. Kinetic and chromatographic studies indicated that 60-70% of this activity in cytosol was due to aldehyde reductase and the remainder due to aldose reductase. Aldehyde reductase-like enzyme activity, as well as aldose reductase immunoreactivity, was detected in rat islet plasma membrane fractions purified by a polyethylene glycol-Dextran gradient or by a sucrose gradient. This is interesting in view of the fact that voltage-gated potassium channel beta subunits that contain aldehyde and aldose reductase-like NADPH-binding motifs have been detected in plasma membrane fractions of islets [Receptors and Channels 7: 237-243, 2000] and suggests that NADPH might have a yet unknown function in regulating activity of these potassium channels. Reductases may be present in cytosol to protect the insulin cell from molecules that cause oxidative injury.

    Funded by: NIDDK NIH HHS: DK 28348

    Molecular and cellular biochemistry 2001;225;1-;151-60

  • Expression and activities of aldo-keto oxidoreductases in Alzheimer disease.

    Picklo MJ, Olson SJ, Markesbery WR and Montine TJ

    Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    A reactive intermediate generated by lipid peroxidation, 4-hydroxy-2-nonenal (HNE), has received considerable attention as a potential effector of oxidative damage and Abeta peptide-mediated neurotoxicity in Alzheimer disease (AD). However, little is known about aldo-keto oxidoreductases, a group of enzymes that constitute a major detoxifying pathway for HNE and related reactive aldehydes in human brain. We have determined the regional, cellular, and class distribution in human brain of the 4 major aldo-keto oxidoreductases that detoxify HNE: aldehyde dehydrogenase (ALDH): aldose reductase; aldehyde reductase: and alcohol dehydrogenase (ADH). Of these 4 enzymes, only ALDH and aldose reductase were expressed in cerebral cortex. hippocampus, basal ganglia, and midbrain: all 4 enzymes were present in cerebellum. In cerebrum and hippocampus, aldose reductase was localized to pyramidal neurons and mitochondrial class 2 ALDH was localized to glia and senile plaques. ALDH, but not aldose reductase, activity was significantly increased in temporal cortex from patients with AD compared to age-matched controls. These results suggest that in brain regions involved in AD, neurons and glia utilize different mechanisms to detoxify HNE, and that increased ALDH activity is a protective response of cerebral cortex to AD.

    Funded by: NIA NIH HHS: AG00774, AG05144, AG16835; NIEHS NIH HHS: ES05826, ES10196

    Journal of neuropathology and experimental neurology 2001;60;7;686-95

  • Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members.

    O'connor T, Ireland LS, Harrison DJ and Hayes JD

    Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.

    Complementary DNA clones encoding human aflatoxin B(1) aldehyde reductase (AKR7A2), aldehyde reductase (AKR1A1), aldose reductase (AKR1B1), dihydrodiol dehydrogenase 1 (AKR1C1) and chlordecone reductase (AKR1C4) have been expressed in Escherichia coli. These members of the aldo-keto reductase (AKR) superfamily have been purified from E. coli as recombinant proteins. The recently identified AKR7A2 was shown to differ from the AKR1 isoenzymes in being able to catalyse the reduction of 2-carboxybenzaldehyde. Also, AKR7A2 was found to exhibit a narrow substrate specificity, with activity being restricted to succinic semialdehyde (SSA), 2-nitrobenzaldehyde, pyridine-2-aldehyde, isatin, 1,2-naphthoquinone (1,2-NQ) and 9,10-phenanthrenequinone. In contrast, AKR1A1 reduces a broad spectrum of carbonyl-containing compounds, displaying highest specific activity for SSA, 4-carboxybenzaldehyde, 4-nitrobenzaldehyde, pyridine-3-aldehyde, pyridine-4-aldehyde, 4-hydroxynonenal, phenylglyoxal, methylglyoxal, 2,3-hexanedione, 1, 2-NQ, 16-ketoestrone and d-glucuronic acid. Comparison between the kinetic properties of AKR7A2 and AKR1A1 showed that both recombinant enzymes exhibited roughly similar k(cat)/K(m) values for SSA, 1,2-NQ and 16-ketoestrone. Many of the compounds which are substrates for AKR1A1 also serve as substrates for AKR1B1, though the latter enzyme was shown to display a specific activity significantly less than that of AKR1A1 for most of the aromatic and aliphatic aldehydes studied. Neither AKR1C1 nor AKR1C4 was found to possess high reductase activity towards aliphatic aldehydes, aromatic aldehydes, aldoses or dicarbonyls. However, unlike AKR1A1 and AKR1B1, both AKR1C1 and AKR1C4 were able to catalyse the oxidation of 1-acenaphthenol and, in addition, AKR1C4 could oxidize di- and tri-hydroxylated bile acids. Specific antibodies raised against AKR7A2, AKR1A1, AKR1B1, AKR1C1 and AKR1C4 have been used to show the presence of all of the reductases in human hepatic cytosol; the levels of AKR1B1 and AKR1C1 were markedly elevated in livers with alcohol-associated injury, and indeed AKR1B1 was only detectable in livers with evidence of alcoholic liver disease. Western blotting of extracts from brain, heart, kidney, liver, lung, prostate, skeletal muscle, small intestine, spleen and testis showed that AKR7A2 is present in all of the organs examined, and AKR1B1 is similarly widely distributed in human tissues. These experiments revealed however, that the expression of AKR1A1 is restricted primarily to brain, kidney, liver and small intestine. The AKR1C family members proved not to be as widely expressed as the other reductases, with AKR1C1 being observed in only kidney, liver and testis, and AKR1C4 being found in liver alone. As human kidney is a rich source of AKR, the isoenzymes in this organ have been studied further. Anion-exchange chromatography of human renal cytosol on Q-Sepharose allowed resolution of AKR1A1, AKR1B1, AKR1C1 and AKR7A2, as identified by substrate specificity and Western blotting. Immunohistochemistry of human kidney demonstrated that AKR7A2 is expressed in a similar fashion to the AKR1 family members in proximal and distal convoluted renal tubules. Furthermore, both AKR7A2 and AKR1 members were expressed in renal carcinoma cells, suggesting that these groups of isoenzymes may be engaged in related physiological functions.

    Funded by: Wellcome Trust

    The Biochemical journal 1999;343 Pt 2;487-504

  • Characterization of the human aldehyde reductase gene and promoter.

    Barski OA, Gabbay KH and Bohren KM

    Molecular Diabetes and Metabolism Section, Baylor College of Medicine, Houston, Texas 77030, USA.

    Aldehyde reductase (EC; AKR1A1) is involved in the reduction of biogenic and xenobiotic aldehydes and is present in virtually every tissue. To study the regulation of its expression, the human aldehyde reductase gene and promoter were cloned and characterized. The protein coding region consists of eight exons, with two additional upstream exons, separated by a large intron of 9.4 kb, that code for the 5' untranslated region of the mRNA. Two mRNA transcripts that encode the same protein and that originate from alternative splicing were identified. The shorter transcript is the major form as shown by Northern blots and reverse transcription-PCR experiments. Northern blots of multiple tissues indicate that aldehyde reductase mRNA is present in all tissues examined and is most abundant in kidney, liver, and thyroid, which is consistent with the tissue enzyme distribution. The two mRNA transcripts do not exhibit differential tissue distribution. A construct containing a promoter region insert in a pGL3 vector drives transcription of a luciferase reporter gene and is 290-fold more active than a control vector without insert in transfected HepG2 cells. The activity of the full promoter construct is comparable to that of a pGL3 vector containing the SV40 promoter with an enhancer. The promoter does not contain a TATA box, but contains multiple GC-rich islands and exhibits bidirectional activity in transfection studies. The major active promoter element was localized by nested deletions and mutations to a DNA element (TGCAAT, -59 to -54) that presumptively binds the transcription factor CHOP [CAAT enhancer binding protein (C/EBP) homologous protein]. Comparison of the aldehyde reductase gene structure to all other characterized human genes of the aldo-keto reductase superfamily (aldose reductase, bile acid binder, and type I and type II 3alpha-hydroxysteroid dehydrogenases) indicates that it is more distantly related to these genes than they are among themselves.

    Funded by: NEI NIH HHS: EY11018; NICHD NIH HHS: 2T32HD07445

    Genomics 1999;60;2;188-98

  • The structural organization of the human aldehyde reductase gene, AKR1A1, and mapping to chromosome 1p33-->p32.

    Fujii J, Hamaoka R, Matsumoto A, Fujii T, Yamaguchi Y, Egashira M, Miyoshi O, Niikawa N and Taniguchi N

    Department of Biochemistry, Osaka University Medical School, Osaka, Japan. jfujii@biochem.med.osaka-u.ac.jp

    Genomic DNA encoding for human aldehyde reductase (AKR1A1), a member of the aldo-keto reductase superfamily, was isolated and characterized. The genomic DNA is approximately 16 kb in length and contains eight exons which encode the entire coding region and the 3'-untranslated sequences. AKR1A1 was localized on chromosome 1p33-->p32 by fluorescence in situ hybridization.

    Cytogenetics and cell genetics 1999;84;3-4;230-2

  • Mitochondrial aldehyde reductase: identification and characterization in rat liver and kidney cortex.

    Udovikova EA and Wojtczak L

    Nencki Institute of Experimental Biology, Warsaw, Poland.

    Aldehyde reductase (EC has been regarded so far as an exclusively cytosolic enzyme. The present investigation shows that mitochondria of rat liver, kidney cortex and, tentatively, heart also contain an enzyme catalyzing oxidation of NADPH by aldehydes, p-nitrobenzaldehyde, methylglyoxal and glyceraldehyde. Activity of the mitochondrial enzyme can only be measured after the organelles are disrupted by sonication or solubilized with nonionic detergents. Mitochondrial aldehyde reductase activity contributed to about 4.6% and 2.5% of the total cellular activity in liver and kidney cortex, respectively. However, the specific activity in liver mitochondria was about one third and in kidney cortex mitochondria one tenth of that in the cytosol of the corresponding organ. The mitochondrial enzyme resembled the cytosolic one by its absolute specificity towards NADPH as the electron donor, a similar profile of aldehydic electron acceptors and identical Km values. Mitochondrial aldehyde reductase differed from the cytosolic enzyme by low sensitivity to known inhibitors of cytosolic aldehyde reductase, AL-1576, AL-4114 and ONO-2235. In liver, about 60% of the mitochondrial activity was tightly bound to the membranes whereas about 40% was present in the mitochondrial matrix. The membrane-bound activity was inactivated by digestion of mitoplasts with trypsin, alpha-chymotrypsin or papain, thus pointing to exposition of the substrate-binding site at the external surface of the inner membrane. On the other hand, latency of the enzyme in intact mitochondria indicates that the NADPH-binding site is located at the inner surface. These data provide the first direct evidence for the existence of aldehyde reductase in mitochondria of some rat tissues.

    The international journal of biochemistry & cell biology 1998;30;5;597-608

  • Mechanism of human aldehyde reductase: characterization of the active site pocket.

    Barski OA, Gabbay KH, Grimshaw CE and Bohren KM

    Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.

    Human aldehyde reductase is a NADPH-dependent aldo-keto reductase that is closely related (65% identity) to aldose reductase, an enzyme involved in the pathogenesis of some diabetic and galactosemic complications. In aldose reductase, the active site residue Tyr48 is the proton donor in a hydrogen-bonding network involving residues Asp43/Lys77, while His110 directs the orientation of substrates in the active site pocket. Mutation of the homologous Tyr49 to phenylalamine or histidine (Y49F or Y49H) and of Lys79 to methionine (K79M) in aldehyde reductase yields inactive enzymes, indicating similar roles for these residues in the catalytic mechanism of aldehyde reductase. A H112Q mutant aldehyde reductase exhibited a substantial decrease in catalytic efficiency (kcat/Km) for hydrophilic (average 150-fold) and aromatic substrates (average 4200-fold) and 50-fold higher IC50 values for a variety of inhibitors than that of the wild-type enzyme. The data suggest that His112 plays a major role in determining the substrate specificity of aldehyde reductase, similar to that shown earlier for the homologous His110 in aldose reductase [Bohren, K. M., et. al. (1994) Biochemistry 33, 2021-2032]. Mutation of Ile298 or Val299 affected the kinetic parameters to a much lesser degree. Unlike native aldose reductase, which contains a thiol-sensitive Cys298, neither the I298C or V299C mutant exhibited any thiol sensitivity, suggesting a geometry of the active site pocket different from that in aldose reductase. Also different from aldose reductase, the detection of a significant primary deuterium isotope effect on kcat (1.48 +/- 0.02) shows that nucleotide exchange is only partially rate-limiting. Primary substrate and solvent deuterium isotope effects on the H112Q mutant suggest that hydride and proton transfers occur in two discrete steps with hydride transfer taking place first. Dissociation constants and spectroscopic and fluorimetric properties of nucleotide complexes with various mutants suggest that, in addition to Tyr49 and His112, Lys79 plays a hitherto unappreciated role in nucleotide binding. The mode of inhibition of aldehyde reductase by aldose reductase inhibitors (ARIs) is generally similar to that of aldose reductase and involves binding to the E:NADP+ complex, as shown by kinetic and direct inhibitor-binding experiments. The order of ARI potency was AL1576 (Ki = 60 nM) > tolrestat > ponalrestat > sorbinil > FK366 > zopolrestat > alrestatin (Ki = 148 microM). Our data on aldehyde reductase suggest that the active site pocket significantly differs from that of aldose reductase, possibly due to the participation of the C-terminal loop in its formation.

    Funded by: NIDDK NIH HHS: DK43595

    Biochemistry 1995;34;35;11264-75

  • In vivo glycation of aldehyde reductase, a major 3-deoxyglucosone reducing enzyme: identification of glycation sites.

    Takahashi M, Lu YB, Myint T, Fujii J, Wada Y and Taniguchi N

    Department of Biochemistry, Osaka University Medical School, Japan.

    We have reported that the enzyme which reduces 3-deoxyglucosone (3-DG), a major intermediate and a potent cross-linker in the Maillard reaction, is identical with aldehyde reductase [Takahashi, M., Fujii, J., Teshima, T., Suzuki, K., Shiba, T., & Taniguchi, N. (1993) Gene 127, 249-253]. The enzyme purified from normal rat liver was found to be partially glycated as judged by binding to a boronate column and reactivity to anti-epsilon-hexitol lysine IgG. Sites of in vivo glycation of rat liver aldehyde reductase were identified by sequencing of digested peptides labeled with NaB[3H]4 and by mass spectrometry. The major glycated sites were lysines 67, 84, and 140. The glycated enzyme had low catalytic efficiency (kcat/Km) as compared to the nonglycated form. In streptozotocin-induced diabetic rats, the glycated form was significantly increased in kidneys. Because the enzyme plays a role in detoxifying 3-DG formed through the Maillard reaction in vivo, glycation of aldehyde reductase and reduction of its activity may result in the metabolic imbalance under diabetic conditions.

    Biochemistry 1995;34;4;1433-8

  • Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications.

    El-Kabbani O, Green NC, Lin G, Carson M, Narayana SV, Moore KM, Flynn TG and DeLucas LJ

    The University of Alabama at Birmingham, Center for Macromolecular Crystallography, 35294-0005, USA.

    The crystal structures of porcine and human aldehyde reductase, an enzyme implicated in complications of diabetes, have been determined by X-ray diffraction methods. The crystallographic R factor for the refined porcine aldehyde reductase model is 0.19 at 2.8 A resolution. There are two molecules in the asymmetric unit related by a local non-crystallographic twofold axis. The human aldehyde reductase model has been refined to an R factor of 0.21 at 2.48 A resolution. The amino-acid sequence of porcine aldehyde reductase revealed a remarkable homology with human aldehyde reductase. The coenzyme-binding site residues are conserved and adopt similar conformations in human and porcine aldehyde reductase apo-enzymes. The tertiary structures of aldhyde reductase and aldose reductase are similar and consist of a beta/alpha-barrel, with the coenzyme-binding site located at the carboxy-terminus end of the strands of the barrel. The crystal structure of porcine and human aldehyde reductase should allow in vitro mutagenesis to elucidate the mechanism of action for this enzyme and facilitate the effective design of specific inhibitors.

    Acta crystallographica. Section D, Biological crystallography 1994;50;Pt 6;859-68

  • Aldose and aldehyde reductases from human kidney cortex and medulla.

    Robinson B, Hunsaker LA, Stangebye LA and Vander Jagt DL

    Department of Biochemstry, University of New Mexico School of Medicine, Albuquerque 87131.

    Aldose reductase and aldehyde reductase were purified to homogeneity from multiple samples of human kidney cortex and medulla. A single form of aldose reductase is expressed in kidney that is kinetically and immunochemically indistinguishable from aldose reductase expressed in other human tissues. The results support the conclusion that there is a single human aldose reductase, and that aldose reductase is expressed in a reduced form, characterized by high sensitivity to aldose reductase inhibitors and ability to catalyze the reduction of glucose. Aldose reductase is easily oxidized to a form that is insensitive to aldose reductase inhibitors and unable to catalyze the reduction of glucose. This form does not appear to exist in vivo, even in kidney from diabetics. There is wide variation in the level of expression of aldose reductase in kidney, especially in cortex. The immunochemically separate but similar aldehyde reductase is also expressed in kidney as a single enzyme indistinguishable from aldehyde reductase from other human tissues. Aldehyde reductase levels exceed those of aldose reductase, both in cortex and medulla.

    Funded by: NIDDK NIH HHS: DK43238

    Biochimica et biophysica acta 1993;1203;2;260-6

  • Aldose reductase in human retinal pigment epithelial cells.

    Sato S, Lin LR, Reddy VN and Kador PF

    Laboratory of Ocular Therapeutics, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.

    Sugar alcohols have been reported to accumulate in retinal pigment epithelium (RPE) of diabetic animals. This finding has raised interest in the role of RPE in diabetes-associated retinal changes such as cystoid macular edema. To confirm the presence of aldose reductase in this tissue, the NADPH-dependent enzyme was purified to an apparent homogeneity from cultured human RPE cells, characterized, and its biochemical properties investigated. The induction of aldose reductase by hypertonic stress was also examined. The purification of aldose reductase was performed by a series of chromatographic steps which include gel filtration, affinity chromatography and chromatofocusing. Final purity achieved was monitored by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The kinetic properties and susceptibility to inhibition of the purified aldose reductase were essentially identical to aldose reductase purified from human placenta and kidney. In addition to aldose reductase, chromatofocusing demonstrated the presence of aldehyde reductase, another NADPH-dependent reductase. However, the amounts of aldehyde reductase present were much smaller than those of aldose reductase and the levels of aldehyde reductase appeared too small to contribute to the polyol production in the RPE cells. Culture of RPE cells in hypertonic medium containing 150 mM sodium chloride (600 mosmol total) increased both reductase activity, monitored with DL-glyceraldehyde as substrate, and immunoblot staining for aldose reductase. Chromatofocusing of RPE cells cultured in hypertonic media resulted in a prominent increase in the peak corresponding to aldose reductase compared to the peak height of cells grown in control medium. No increase in aldehyde reductase from RPE cells cultured in hypertonic medium was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

    Funded by: NEI NIH HHS: NEI EY00484, NEI EY05025

    Experimental eye research 1993;57;2;235-41

  • Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin.

    Dawson SJ and White LA

    Department of Microbiology, Southampton General Hospital, U.K.

    A patient with Haemophilus aphrophilus endocarditis was successfully treated with ciprofloxacin. The response to treatment with cefotaxime and netilmicin for 12 days was poor but was satisfactory to a 6 weeks' course of ciprofloxacin.

    The Journal of infection 1992;24;3;317-20

  • Purification and characterization of human testis aldose and aldehyde reductase.

    Tanimoto T, Ohta M, Tanaka A, Ikemoto I and Machida T

    Division of Biological Chemistry, National Institute of Hygienic Sciences, Tokyo, Japan.

    1. Aldose reductase and aldehyde reductase were purified to homogeneity from human testis. 2. The molecular weight of aldose reductase and aldehyde reductase were estimated to be 36,000 and 38,000 by SDS-PAGE, and the pI values of these enzymes were found to be 5.9 and 5.1 by chromatofocusing, respectively. 3. Aldose reductase had activity for aldo-sugars, whereas aldehyde reductase was virtually inactive for aldo-sugars. The Km values of aldose reductase for D-glucose, D-galactose and D-xylose were 57, 49 and 6.2 mM, respectively. Aldose reductase utilized both NADPH and NADH as coenzymes, whereas aldehyde reductase only NADPH. 4. Sulfate ion caused 3-fold activation of aldose reductase, but little for that of aldehyde reductase. 5. Sodium valproate inhibited significantly aldehyde reductase, but not aldose reductase. Aldose reductase was inhibited strongly by aldose reductase inhibitors being in clinical trials at concentrations of the order of 10(-7)-10(-9) M. Aldehyde reductase was also inhibited by these inhibitors, but its susceptibility was less than aldose reductase. 6. Reaction of aldose reductase with pyridoxal 5'-phosphate (PLP) resulted ca 2.5-fold activation, but aldehyde reductase did not cause the activation. PLP-treated aldose reductase has lost the susceptibility to aldose reductase inhibitor.

    The International journal of biochemistry 1991;23;4;421-8

  • Aldehyde and aldose reductases from human placenta. Heterogeneous expression of multiple enzyme forms.

    Vander Jagt DL, Hunsaker LA, Robinson B, Stangebye LA and Deck LM

    Department of Biochemistry, University of New Mexico School of Medicine, Albuquerque 87131.

    Aldehyde reductase (ALR1) and aldose reductase (ALR2) were purified from human placenta by a rapid and efficient scheme that included rapid extraction of both reductases from 100,000 x g supernatant material with Red Sepharose followed by purification by chromatofocusing on Pharmacia PBE 94 and then chromatography on a hydroxylapatite high performance liquid chromatography column. Expression of ALR1 and ALR2 in placenta is variable with ALR1/ALR2 ratios ranging from 1:4 to 4:1. ALR1 and ALR2 are immunochemically distinct. ALR1 shows broad specificity for aldehydes but does not efficiently catalyze the reduction of glucose due to poor binding (Km = 2.5 M). ALR1 exhibits substrate inhibition with many substrates. ALR2 also shows broad specificity for aldehydes. Although glucose is a poor substrate for ALR2 compared with other substrates, the affinity of ALR2 for glucose (Km = 70 mM) suggests that glucose can be a substrate under hyperglycemic conditions. ALR2 shows normal hyperbolic kinetics with most substrates except with glyceraldehyde, which exhibits substrate activation. Treatment of ALR2 with dithiothreitol converted it into a form that exhibited hyperbolic kinetics with glyceraldehyde. Dithiothreitol treatment of ALR2 did not alter its properties toward other substrates or affect its inhibition by aldose reductase inhibitors such as sorbinil (2,4-dihydro-6-fluorospiro-[4H-1-benzopyran-4,4'-imidazolidine]-2' ,5'- dione), tolrestat (N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]thioxomethyl]-N- methylglycine), or statil (3-[(4-bromo-2-fluorophenyl)methyl]-3,4-dihydro-4-oxo-1-phthalazineac etic acid).

    Funded by: NCRR NIH HHS: S07 RR-05583-25

    The Journal of biological chemistry 1990;265;19;10912-8

  • The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases.

    Bohren KM, Bullock B, Wermuth B and Gabbay KH

    Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.

    Aldehyde reductase [EC] and aldose reductase [EC] are monomeric NADPH-dependent oxidoreductases having wide substrate specificities for carbonyl compounds. These enzymes are implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Enzyme inhibition as a direct pharmacokinetic approach to the prevention of diabetic complications resulting from the hyperglycemia of diabetes has not been effective because of nonspecificity of the inhibitors and some appreciable side effects. To understand the structural and evolutionary relationship of these enzymes, we cloned and sequenced cDNAs coding for aldose and aldehyde reductases from human liver and placental cDNA libraries. Human placental aldose reductase (open reading frame of 316 amino acids) has a 65% identity (identical plus conservative substitutions) to human liver and placental aldehyde reductase (open reading frame of 325 amino acids). The two sequences have significant identity to 2,5-diketogluconic acid reductase from corynebacterium, frog rho-crystallin, and bovine lung prostaglandin F synthase (reductase). Southern hybridization analysis of human genomic DNA indicates a multigene system for aldose reductase, suggesting the existence of additional proteins. Thus, the aldo-keto reductase superfamily of proteins may have a more significant and hitherto not fully appreciated role in general cellular metabolism.

    Funded by: NHLBI NIH HHS: HL-34999; NIDDK NIH HHS: DK-39044

    The Journal of biological chemistry 1989;264;16;9547-51

  • Primary structure of aldehyde reductase from human liver.

    Wermuth B, Omar A, Forster A, di Francesco C, Wolf M, von Wartburg JP, Bullock B and Gabbay KH

    Progress in clinical and biological research 1987;232;297-307

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000011 G2C Homo sapiens Human clathrin Human orthologues of mouse clathrin coated vesicle genes adapted from Collins et al (2006) 150
L00000012 G2C Homo sapiens Human Synaptosome Human orthologues of mouse synaptosome adapted from Collins et al (2006) 152
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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