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Query: UNIPROT:P06889 (Mol)
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The amino acid compositions of several monomeric NADPH-dependent aldehyde reductases from a variety of species have been determined and analyzed by the difference index method of Metzger et al. (1968). The difference indexes among mammals range from 4.15 - 6.10 indicating considerable homology. Comparison of chicken aldehyde reductase with mammalian aldehyde reductases gave values in the range 6.8 - 9.9 suggesting a close relationship whereas the difference indexes for the enzymes from fruit fly and Baker's yeast versus vertebrate aldehyde reductases (10.9 - 14.4) indicate more distant relationships. The extent of sequence homology among aldehyde reductases from these species was estimated from a plot of difference index versus percent sequence difference for oxido-reductases of known sequence. From this plot, and using a mammal-chicken divergence time of 300 million years and a mammalian order split of 75 million years, the rate of evolution of aldehyde reductases was calculated to lie in the range 5.8 - 15.6% sequence difference per 100 million years. Comparison with rates of evolution of oligomeric dehydrogenases indicates that aldehyde reductases comprise the most rapidly evolving family of oxido-reductases. This is probably related to the monomericity of aldehyde reductases since there is a direct correlation between the number of subunits and the rate of evolution.
J Mol Evol 1979 Dec
PMID:Compositional relatedness of aldehyde reductases from several species. 4 5

The small intestine of 12-week-old streptozotocin-diabetic rats was examined by light and transmission electron microscopy in order to study the effects of alternative treatments on microvillous morphology. Four groups were examined: untreated diabetic rats, insulin-treated diabetics and rats treated with an aldose reductase inhibitor (ponalrestat) given with and without insulin. Numbers and dimensions of microvilli at the apex of columnar absorptive epithelial cells (enterocytes) were estimated using stereological principles. Values were obtained for the organ as a whole as well as for different sites along its length. In the untreated diabetic intestine, the mean (standard error of mean) number of microvilli was 4.5 (0.8) x 10(12) with a total surface area of 1.9 (0.50) m2. On average, the microvilli were 1.1 (0.08) microns long, 104 (3.8) nm in diameter and packed on the villous surface at a density of 3400 (50) per 100 microns 2. Their length at least varied with intestinal location. Significant effects of insulin therapy were detected. In contrast, the study failed to find any significant effect of aldose reductase inhibition on any variable except microvillous packing density.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Responses of enterocyte microvilli in experimental diabetes to insulin and an aldose reductase inhibitor (ponalrestat). 136 Jul 26

Incubation of human placental aldose reductase (EC 1.1.1.21) with menadione (0.5-3.0 mM) resulted in time-dependent loss of the catalytic activity of the enzyme. Kinetic analysis of the data suggests that the inactivation process follows a single apparent rate constant that displays hyperbolic dependence on menadione concentration, indicating that menadione forms a kinetically significant, dissociable complex with the enzyme before the formation of an inactive enzyme-menadione complex. The inactivation of the enzyme with menadione was reversed upon dialysis of the inactivated enzyme against buffer containing 10 mM dithiothreitol suggesting that menadione reacts with enzyme sulfhydryl residue(s). Inactivation of the enzyme was significantly prevented by dithiothreitol (5 mM), NADPH (0.1 mM), and DL-glyceraldehyde (10 mM). Correlation of the fractional remaining activity with the extent of modification indicates that loss of catalytic activity corresponds to the modification of a single amino acid residue of the enzyme protein. Recombinant human aldose reductase, obtained by overexpression in Escherichia coli, and aldose reductase in which Cys-80 or Cys-303 was replaced by serine were also inactivated by menadione. However, enzyme in which Cys-298 was replaced by serine was insensitive to menadione. On the basis of these observations, it is suggested that menadione forms a thiodione-like adduct with Cys-298, leading to inactivation of the enzyme.
Mol Pharmacol 1992 Nov
PMID:Mechanism of inhibition of aldose reductase by menadione (vitamin K3). 143 55

It is well established that normal patterns of epithelial cell proliferation and metabolism, and of fiber cell differentiation and maturation are essential for the maintenance of transparency in the ocular lens. Several factors, including exposure to high levels of sugars, have been known to result in the compromise of lens transparency. For example, initiation of lens cell damage by galactose induces lens epithelial cells to proliferate. Elevated levels of c-myc mRNA have usually been correlated with rapid cell growth and increased entry of cells into the S phase. Therefore, changes in c-myc mRNA levels may provide an early indication of the stimulation of lens epithelial cells to proliferate and differentiate, which has been postulated to be an early and important event in response to lens cell injury by galactose. By Northern blot hybridization analysis we quantitated c-myc mRNA levels in the lens capsule epithelia of rats (1) exposed to galactose, and (2) undergoing a partial recovery from the galactose-induced cell damage. At the onset of lens cell damage, we find c-myc mRNA to elevate to 6-fold by 24 hr, and by 48 hr decreases to about 3-fold the normal levels. During recovery, c-myc mRNA continues to be expressed at high levels approaching a 10-fold increase by day 12, then decreasing to levels of about 8-fold the control by day 30. The 24 h transitory elevation in c-myc mRNA in lens epithelial cells is in accord with our previous observations on the 24 h increase in MP26, gamma crystallin and aldose reductase mRNAs following a high influx of galactose. Therefore, the elevation in c-myc mRNA as well suggest that galactose appears to cause lens cells to undergo an early transitory period of gene induction following the exposure of lens cells to galactose.
Mol Cell Biochem 1992 May 13
PMID:Expression of c-myc protooncogene in rat lens cells during development, maturation and reversal of galactose cataracts. 151 36

Large crystals of porcine aldose reductase have been grown from polyethylene glycol solutions. The crystals are triclinic, space-group P1, with a = 81.3 A, b = 85.9 A, c = 56.6 A, alpha = 102.3 degrees, beta = 103.3 degrees and gamma = 79.0 degrees. The crystals grow within ten days to dimensions of 0.6 mm x 0.4 mm x 0.2 mm and diffract to at least 2.5 A. There are four molecules in the unit cell related by a set of three mutually perpendicular non-crystallographic 2-fold axes.
J Mol Biol 1991 Apr 20
PMID:Purification, crystallization and preliminary crystallographic analysis of porcine aldose reductase. 190 21

Complementary DNA clones encoding 3 alpha-hydroxysteroid dehydrogenase (3 alpha HSD) were isolated from a rat liver cDNA lambda gt11 expression library using monoclonal antibodies as probes. The sizes of the cDNA inserts ranged from 1.3-2.3 kilobases. Sequence analysis indicated that variation in the DNA size was due to heterogeneity in the length of 3' noncoding sequences. A full-length cDNA clone of 1286 basepairs contained an open reading frame encoding a protein of 322 amino acids with an estimated mol wt of 37 kDa. When expressed in E. coli, the encoded protein migrated to the same position on sodium dodecyl sulfate-polyacrylamide gels as the enzyme purified from rat liver cytosols. The protein expressed in bacteria was highly active in androsterone reduction in the presence of NAD as cofactor, and this activity was inhibited by indomethacin, a potent inhibitor of 3 alpha HSD. The predicted amino acid sequence of 3 alpha HSD was related to sequences of several other enzymes, including bovine prostaglandin F synthase, human chlordecone reductase, human aldose reductase, human aldehyde reductase, and frog lens epsilon-crystalline, suggesting that these proteins belong to the same gene family.
Mol Endocrinol 1991 Jun
PMID:Molecular cloning and expression of rat liver 3 alpha-hydroxysteroid dehydrogenase. 192 97

The effect of glucose and other monosaccharides on Giardia intestinalis was investigated by growing G. intestinalis trophozoites in Diamond's TYI-S-33 medium modified by changes in the monosaccharide component, and observing changes in the trophozoite growth and product formation (alanine, ethanol and acetate). Reducing the glucose concentration from 50 mM to 10 mM had little effect on trophozoite growth and product formation. Below 10 mM glucose, ethanol production was markedly reduced, there was a lesser effect on alanine, but acetate production was unaffected. In medium in which no glucose had been added, trophozoites grew at about half the rate of controls (50 mM glucose) and continued to form the same products. Growth in medium containing 10 mM ribose or 10 mM fructose substituted for glucose produced a metabolic profile similar to that of the no glucose added condition. The activity of a number of glycolytic and related enzymes was also determined, but the enzymic profile was not affected by the monosaccharide status of the medium. Ethanol production by trophozoites was specifically depressed by the aldehyde reductase inhibitor, valproate; 3 mM valproate reduced ethanol production by 90%. The alcohol dehydrogenase inhibitor pyrazole had no effect on ethanol production or any other parameter. This differential inhibition suggests that ethanol is produced by an aldehyde reductase or related enzyme. The observations that G. intestinalis trophozoites can continue to grow, replicate and produce the same metabolites in medium containing little or no glucose suggest that G. intestinalis is not solely dependent on glucose as a metabolic fuel.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Biochem Parasitol 1991 Mar
PMID:Glucose metabolism in Giardia intestinalis. 205 39

Purification and storage of aldose reductase isolated from human placenta or kidney in beta-mercaptoethanol-containing buffers causes a time-dependent decrease in its catalytic activity, as well as in its sensitivity to inhibition by aldose reductase inhibitors such as sorbinil. Dithiothreitol (DTT) slowly regenerated the enzyme activity, as well as reversed the alterations in the sensitivity of the enzyme to sorbinil. In contrast to sorbinil, the inhibition of aldose reductase by tolrestat was less affected by purification and/or storage in beta-mercaptoethanol-containing buffers. Kinetic analysis of the rate of increase in sensitivity of the enzyme to sorbinil on incubation with DTT reveals that the reaction follows two kinetically distinct rate constants. Also, sorbinil protected the enzyme from inactivation with sulfhydryl-modifying reagents 5,5'-dithiobis(2-nitrobenzoic acid) and glutathione disulfide. The enzyme stored in beta-mercaptoethanol migrates as two distinct bands, one corresponding to molecular weight 36,000 and the other to molecular weight 33,000, on nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whereas under reducing conditions the protein migrates as a single discrete band corresponding to molecular weight 36,000. Moreover, the molecular weight 33,000 form of the enzyme could be converted to the molecular weight 36,000 form on reduction with DTT, indicating that the molecular weight 33,000 form of the enzyme is due to intramolecular disulfide bond(s) formed, which presumably cause the protein to assume a more folded conformation and migrate faster through the gel, and not due to proteolysis. These studies indicate that oxidation of sulfhydryl residues, including disulfide bond formation, during purification and storage in beta-mercaptoethanol-containing buffers alters the sensitivity of the enzyme to some inhibitors.
Mol Pharmacol 1989 Dec
PMID:Involvement of sulfhydryl residues in aldose reductase-inhibitor interaction. 251 74

During the reductive process in the tissues, the aerobes generate a number of oxidants. Unless these oxidants are reduced, oxidative damage and cell death would occur. Oxidation of plasma membrane lipids leads to autocatalytic chain reactions which eventually alter the permeability of the cell. The role of oxidative damage in the pathophysiology of diabetic complications and ischemic reperfusion injury of myocardium, especially the changes in the channel activity which may lead to arrhythmia have been studied. Hyperglycemia activates aldose reductase which could efficiently reduce glucose to sorbitol in the presence of NADPH. Since NADPH is also aldose required by glutathione reductase for reducing oxidants, its diversion would lead to membrane lipid oxidation and permeability changes which are probably responsible for diabetic complications such as cataractogenesis, retinopathy, neuropathy etc. Antioxidants such as butylated hydroxy toluene (BHT) and also reductase inhibitors prevent or delay some of these complications. By using patch-clamp technique in isolated frog myocytes, we have shown that hydroxy radicals generated by ferrous sulfate and ascorbate as well as lipid peroxides such as t-butyl hydroperoxide facilitate the entry of Na+ by oxidizing Na+-channels. Increased intracellular Na+ leads to an increase in Na+/Ca2+ exchange. The increased Na+ concentration by itself may produce electrical disturbance which would result in arrhythmia. Increased Ca2+ may affect proteases and may help in the conversion of xanthine dehydrogenase to xanthine oxidase, consequently increased production of super oxide radicals. Increased membrane lipid peroxidation and other oxygen free-radical associated membrane damage in myocytes has been demonstrated.
Mol Cell Biochem
PMID:The effect of oxidants on biomembranes and cellular metabolism. 251 41

Crystals of pig lens aldose reductase have been grown from polyethylene glycol solutions at pH 6.2 and analysed by X-ray diffraction. Two crystal forms were obtained. The first belongs to space group P1 with unit cell dimensions a = 81.3 A, b = 85.9 A, c = 56.6 A, alpha = 102.3 degrees, beta = 103.3 degrees, gamma = 79.0 degrees, with four molecules in the unit cell related by a 222 non-crystallographic symmetry. The second crystal form is hexagonal. The space group is P6(2)22 with a = b = 101 A, c = 257 A and two molecules in the asymmetric unit. Both forms are suitable for X-ray structure analysis to better than 3 A resolution.
J Mol Biol 1987 Jun 20
PMID:Crystallization and preliminary X-ray study of pig lens aldose reductase. 311 67


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