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The International Journal of... Jan 2010Aldose reductase (AR), that catalyzes the rate limiting step of the polyol pathway of glucose metabolism, besides reducing glucose to sorbitol, reduces a number of lipid... (Review)
Review
Aldose reductase (AR), that catalyzes the rate limiting step of the polyol pathway of glucose metabolism, besides reducing glucose to sorbitol, reduces a number of lipid peroxidation - derived aldehydes and their glutathione conjugates. Recent studies suggest that apart from its involvement in diabetic complications, AR's catalytic activity plays a key role in a number of inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and colon cancer. Furthermore, AR is overexpressed in human cancers such as liver, colon, breast, cervical and ovarian. Since AR inhibitors have already undergone up to phase-iii clinical trials for diabetic complications, they could be safe anti-inflammatory drugs. Therefore the future use of AR inhibitors in down-regulating major inflammatory pathologies such as cancer and cardiovascular diseases could relieve some of the major health concerns of worldwide.
Topics: Aldehyde Reductase; Animals; Humans; Inflammation
PubMed: 19778627
DOI: 10.1016/j.biocel.2009.09.009 -
Biochemical Society Transactions Aug 1996
Review
Topics: Aldehyde Reductase; Animals; Binding Sites; Cloning, Molecular; Humans; Molecular Structure; Monosaccharides; NADP; Oxidation-Reduction
PubMed: 8878869
DOI: 10.1042/bst0240888 -
Metabolism: Clinical and Experimental Apr 1986The aldehyde reductases comprise a group of monomeric NADPH-dependent oxidoreductases with a broad and similar substrate specificity. Three major reductases, ALR1, ALR2,...
The aldehyde reductases comprise a group of monomeric NADPH-dependent oxidoreductases with a broad and similar substrate specificity. Three major reductases, ALR1, ALR2, and ALR3, occur in tissues. The predominant one, ALR1, is aldehyde reductase; ALR2 is aldose reductase, an enzyme implicated in the etiology of diabetic complications; and ALR3 is carbonyl reductase, the only reductase with any affinity for ketones. ALR1 and ALR2 are immunologically nonrelated, and little immunologic relatedness exists between aldehyde reductases, particularly ALR1, from different species. The evolutionary relatedness of ALR2, however, may be closer, particularly among the primates. ALR2 from human and monkey tissues are immunologically identical.
Topics: Alcohol Oxidoreductases; Aldehyde Reductase; Animals; Haplorhini; Humans; Imidazoles; Imidazolidines; Kidney; Kinetics; Muscles; Substrate Specificity; Sugar Alcohol Dehydrogenases; Swine
PubMed: 3083200
DOI: 10.1016/0026-0495(86)90197-6 -
Lens and Eye Toxicity Research 1989The distribution of aldose reductase and aldehyde reductase II in the epithelium, cortex and nuclear regions of the bovine lens has been studied. The levels of the two...
The distribution of aldose reductase and aldehyde reductase II in the epithelium, cortex and nuclear regions of the bovine lens has been studied. The levels of the two enzymes in different regions of the bovine lens were determined after partial purification by DEAE-cellulose (DE-52) column chromatography. Aldose reductase was present in all the three regions of the lens, whereas aldehyde reductase II was present mainly in the epithelium and cortex. The activity of the enzymes, expressed per mg protein, was 10-15 fold higher in lens epithelium as compared to cortex and when expressed per g tissue wet weight, was approximately 2 fold higher. Substrate specificity of aldose reductase purified from all three regions of the lens was comparable, but the susceptibility to inhibition by various aldose reductase inhibitors was significantly different. As compared to the enzyme of cortex and nucleus, the epithelial aldose reductase was less (30-40%) susceptible to inhibition by aldose reductase inhibitors such as sorbinil, tolrestat, statil and tetramethylene glutaric acid. The substrate specificity and characteristics of inhibition of aldehyde reductase II purified from epithelium and cortex were similar.
Topics: Alcohol Dehydrogenase; Aldehyde Reductase; Animals; Cattle; Chromatography, Ion Exchange; Epithelium; Fluorometry; Glutarates; Imidazoles; Imidazolidines; Kinetics; Lens Cortex, Crystalline; Lens Nucleus, Crystalline; Lens, Crystalline; Naphthalenes; Phenobarbital; Phthalazines; Spectrophotometry; Substrate Specificity
PubMed: 2518623
DOI: No ID Found -
Future Medicinal Chemistry Jul 2020Aldose Reductase 2 (ALR2), the rate-limiting enzyme of the polyol pathway, plays an important role in detoxification of some toxic aldehydes. Under hyperglycemia, this... (Review)
Review
Aldose Reductase 2 (ALR2), the rate-limiting enzyme of the polyol pathway, plays an important role in detoxification of some toxic aldehydes. Under hyperglycemia, this enzyme overactivates and causes diabetic complications (DC). Therefore, ALR2 inhibition has been established as a potential approach to manage these complications. Several ALR2 inhibitors have been reported, but none of them could reach US FDA approval. One of the main reasons is their poor selectivity over ALR1, which leads to the toxicity. The current review underlines the molecular connectivity of ALR2 with DC and comparative analysis of the catalytic domains of ALR2 and ALR1, to better understand the selectivity issues. This report also discusses the key features required for ALR2 inhibition and to limit toxicity due to off-target activity.
Topics: Aldehyde Reductase; Diabetes Complications; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Molecular Structure
PubMed: 32602375
DOI: 10.4155/fmc-2020-0032 -
Biochemistry Nov 1996Human aldehyde reductase has a preference for carboxyl group-containing negatively charged substrates. It belongs to the NADPH-dependent aldo-keto reductase superfamily...
Human aldehyde reductase has a preference for carboxyl group-containing negatively charged substrates. It belongs to the NADPH-dependent aldo-keto reductase superfamily whose members are in part distinguished by unique C-terminal loops. To probe the role of the C-terminal loops in determining substrate specificities in these enzymes, two arginine residues, Arg308 and Arg311, located in the C-terminal loop of aldehyde reductase, and not found in any other C-terminal loop, were replaced with alanine residues. The catalytic efficiency of the R311A mutant for aldehydes containing a carboxyl group is reduced 150-250-fold in comparison to that of the wild-type enzyme, while substrates not containing a negative charge are unaffected. The R311A mutant is also significantly less sensitive to inhibition by dicarboxylic acids, indicating that Arg311 interacts with one of the carboxyl groups. The inhibition pattern indicates that the other carboxyl group binds to the anion binding site formed by Tyr49, His112, and the nicotinamide moiety of NADP+. The correlation between inhibitor potency and the length of the dicarboxylic acid molecules suggests a distance of approximately 10 A between the amino group of Arg311 and the anion binding site in the aldehyde reductase molecule. The sensitivity of inhibition of the R311A mutant by several commercially available aldose reductase inhibitors (ARIs) was variable, with tolrestat and zopolrestat becoming more potent inhibitors (30- and 5-fold, respectively), while others remained the same or became less potent. The catalytic properties, substrate specificity, and susceptibility to inhibition of the R308A mutant remained similar to that of the wild-type enzyme. The data provide direct evidence for C-terminal loop participation in determining substrate and inhibitor specificity of aldo-keto reductases and specifically identifies Arg311 as the basis for the carboxyl-containing substrate preference of aldehyde reductase.
Topics: Aldehyde Reductase; Arginine; Binding Sites; Dicarboxylic Acids; Enzyme Inhibitors; Humans; Isoelectric Point; Kinetics; Mutagenesis, Site-Directed; Solubility; Structure-Activity Relationship; Substrate Specificity
PubMed: 8916913
DOI: 10.1021/bi9619740 -
The Biochemical Journal Apr 1984Aldehyde reductase (aldose reductase) was purified to homogeneity (as judged by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis) from bovine lens by affinity...
Aldehyde reductase (aldose reductase) was purified to homogeneity (as judged by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis) from bovine lens by affinity chromatography on NADP+-Sepharose. The enzyme, a monomer of Mr about 40000, was active with a variety of alpha- hydroxyketones , including fructose. The minimum degree of the rate equation was 2:2 in the case of DL-glyceraldehyde, but linear kinetics were observed for glucose and NADPH over the concentration range studied. The enzyme largely followed a ternary-complex mechanism, with initial binding of NADPH before glucose and final release of NADP+.
Topics: Aldehyde Reductase; Amino Acids; Animals; Cattle; Chromatography, Affinity; Glucose; Glyceraldehyde; Kinetics; Lens, Crystalline; Molecular Weight; NADP; Osmolar Concentration; Substrate Specificity; Sugar Alcohol Dehydrogenases
PubMed: 6426471
DOI: 10.1042/bj2190033 -
Biochimica Et Biophysica Acta Aug 1984Immunochemical characterizations of aldose reductase and aldehyde reductases I and II, partially purified by DEAE-cellulose (DE-52) column chromatography from human...
Immunochemical characterizations of aldose reductase and aldehyde reductases I and II, partially purified by DEAE-cellulose (DE-52) column chromatography from human tissues, were carried out by immunotitration, using antisera raised against the homogenous preparations of human and bovine lens aldose reductase and human placenta aldehyde reductase I and aldehyde reductase II. Anti-aldose antiserum cross-reacted with aldehyde reductase I, anti-aldehyde reductase I antiserum cross-reacted with aldose reductase and anti-aldehyde reductase II antiserum precipitated aldehyde reductase II, but did not cross-react with aldose reductase or aldehyde reductase I from all the tissues examined. DE-52 elution profiles, substrate specificity and immunochemical characterization indicate that aldose reductase is present in human aorta, brain, erythrocyte and muscle; aldehyde reductase I is present in human kidney, liver and placenta; and aldehyde reductase II is present in human brain, erythrocyte, kidney, liver, lung and placenta. Monospecific anti-alpha and anti-beta antisera were purified from placenta anti-aldehyde reductase I antiserum, using immunoaffinity techniques. Anti-alpha antiserum precipitated both aldehyde reductase I and aldose reductase, whereas anti-beta antibodies cross-reacted with only aldehyde reductase I. Based on these studies, a three gene loci model is proposed to explain the genetic interrelationships among these enzymes. Aldose reductase is a monomer of alpha subunits, aldehyde reductase I is a dimer of alpha and beta subunits and aldehyde reductase II is a monomer of delta subunits.
Topics: Aldehyde Oxidoreductases; Aldehyde Reductase; Female; Humans; Sugar Alcohol Dehydrogenases; Tissue Distribution
PubMed: 6432055
DOI: 10.1016/0304-4165(84)90399-4 -
Recent Patents on Anti-cancer Drug... Nov 2009Aldo-keto reductase 1 member B1 (AKR1B1) is pathogenically involved in diabetic complications by driving glucose flux through polyol pathway; a variety of AKR1B1... (Review)
Review
Aldo-keto reductase 1 member B1 (AKR1B1) is pathogenically involved in diabetic complications by driving glucose flux through polyol pathway; a variety of AKR1B1 inhibitors has been developed for the treatment of diabetic complications and a body of invaluable preclinical and clinical data have been collected through decades' efforts. Recent studies have shown that some AKR1B1 inhibitors demonstrate strong inhibitory activity to aldo-keto reductase family 1 member B10 (AKR1B10), a protein identical to AKR1B1, in vitro and in cancer cells. AKR1B1 and AKR1B10 are overexpressed in human tumors, such as liver, breast, and lung cancer, and may play a critical role in the development and progression of cancer through carbonyl detoxification, retinoic acid homeostatic regulation, and lipid metabolic control, as well as the activation of tobacco smoke carcinogens. Therefore, AKR1B1 inhibitors may represent a novel class of antitumor agents; and the clinical data assembled in diabetic clinics would greatly assist the transition of these inhibitors to cancer clinics. This article summaries the current understanding of the expression and function of AKR1B1 and AKR1B10 in human cancers and reviews the patents and papers of AKR1B1 inhibitors. Authors' opinions concerning the current and future development of AKR1B1 and/or AKR1B10-specific inhibitors are discussed.
Topics: Aldehyde Reductase; Aldo-Keto Reductases; Diabetes Complications; Enzyme Inhibitors; Humans; Neoplasms
PubMed: 19522700
DOI: 10.2174/157489209789206931 -
Nihon Yakurigaku Zasshi. Folia... Jun 2012
Review
Topics: Aldehyde Reductase; Aldo-Keto Reductases; Biomarkers, Tumor; Cell Division; Drug Resistance, Neoplasm; Fatty Acids; Humans; Substrate Specificity
PubMed: 22997641
DOI: No ID Found