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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to elucidate the key atoms and/or stereostructures necessary for the inhibitory emergence of aldose reductase, crystal structure determinations were carried out for 11 oxazolecarbamate analogues, which have similar chemical and physicochemical properties but different inhibitory activities. The molecular conformations, revealed by X-ray analyses, were also ascertained to be energetically stable from theoretical conformational energy calculations. A surprising degree of conformational similarity was observed for the potent inhibitors. The analyses of the quantitative structure--activity relationships showed that the molecular conformation and the dipole moment, as well as the hydrophobicity at the oxazole C5-site, were important for high activity.
Mol Pharmacol 1988 Sep
PMID:Structure-activity relationship of aldose reductase inhibitors based on X-ray crystal structures of oxazolecarbamate derivatives. 313 30

The computer-automated structure evaluation program has been used to study 482 compounds relevant to the inhibition of the aldose reductase enzyme. Major activating/inactivating fragments were generated automatically. The significance of these molecular descriptors with respect to the activity of the compounds is discussed.
Mol Pharmacol 1988 Dec
PMID:An artificial intelligence approach to the study of the structural moieties relevant to drug-receptor interactions in aldose reductase inhibitors. 314 9

The effect of glucose concentrations and hormones on glucose consumption, lactate, pyruvate, sorbitol and fructose formation of porcine aortic endothelial cells and human umbilical vein endothelial cells has been investigated. Endothelial cells have a high glycolytic activity which is saturated far below physiologic blood glucose levels (KM apparent less than 1 mmol/l). Glucocorticoids reduce glucose catabolism as a function of their concentration. Insulin, adrenaline, triiodothyronine and glucagon do not influence glucose consumption. Studies with the non-metabolizable analogue 3-O-methyl-D-glucose revealed that glucocorticoids slow down glucose transport into the endothelial cell. The passage of glucose through the cell membrane is the rate-limiting step of glucose utilization. Consequently, the intracellular glucose level is independent of the ambient glucose concentration and endothelial cells do not accumulate sorbitol under hyperglycaemic conditions since the affinity of aldose reductase for glucose is low.
Mol Cell Endocrinol 1985 Dec
PMID:Endothelial plasma membrane is a glucocorticoid-regulated barrier for the uptake of glucose into the cell. 390 87

Recent experimental results suggesting that diabetic pathology can at least in part be directly controlled through inhibition of the enzyme aldose reductase (alditol:NADPH oxidoreductase, EC 1.1.1.21) have spurred great interest in the development of specific inhibitors of this enzyme. Specific structural and electronic similarities of apparently diverse aldose reductase inhibitors have been observed through basic studies which utilize computer molecular modeling, molecular orbital calculations, known structure-activity relationships, and protein-modification reagents such as 2-bromo-4'-nitroacetophenone. From these similarities, a model of the aldose reductase inhibitor site has been postulated along with the pharmacophor requirements for the inhibitors--guidelines which should aid in the rational design of new inhibitors.
Mol Pharmacol 1983 Nov
PMID:Pharmacophor requirements of the aldose reductase inhibitor site. 641 1

The inhibition of aldose reductase from a human source by alrestatin was studied. The enzyme from placenta was purified to apparent homogeneity by (NH4)2SO4 precipitation, DEAE-cellulose chromatography, electrofocusing, and affinity chromatography. This enzyme from human or rat placenta at the (NH4)2SO4 state of purification was relatively insensitive to alrestatin (IC50 greater than 50 microM). On purification by electrofocusing, however, human or rat placenta aldose reductase exhibited a marked increase in its sensitivity to alrestatin (IC50 = 1.0 microM). In contrast to human or rat placenta aldose reductase, rat lens aldose reductase was equally sensitive to alrestatin at the corresponding stages of purification (IC50 = 1.0 microM). Experiments in which the sensitive and insensitive forms of placenta aldose reductase were mixed revealed that the difference in susceptibility to alrestatin could not be attributed to nonspecific binding of alrestatin by proteins present in the (NH4)2SO4 fraction. A heat-inactivated (NH4)2SO4 fraction of human placenta aldose reductase added to the sensitive placenta enzyme from human or rats caused a time-dependent conversion to the insensitive form of aldose reductase. This suggested that a heat-stable dissociable factor, associated with placenta aldose reductase at the crude stage, may be responsible for the insensitivity to alrestatin. This insensitivity could be of pharmacological significance if it is relevant in vivo and it exists in tissues where aldose reductase plays a physiological role.
Mol Pharmacol 1984 May
PMID:Human placenta aldose reductase. Forms sensitive and insensitive to inhibition by alrestatin. 642 99

Acrolein, a highly cytotoxic aldehyde, is a metabolic by-product of the antineoplastic agent cyclophosphamide and is responsible for the development of hemorrhagic cystitis, a serious side effect of cyclophosphamide therapy. Aldose reductase (EC 1.1.1.21), a member of the aldo-keto reductase superfamily, catalyzes the NADPH-dependent reduction of acrolein to allyl alcohol (Km = 80 microM, kcat = 87 min-1). Aldose reductase is expressed at different levels in individuals. This suggests that individual differences in the reductive metabolism of acrolein may be a determinant of acrolein toxicity. In addition to being a substrate, acrolein also produces a time-dependent 7-20-fold increase in the activity of aldose reductase toward a variety of substrates. This involves initial binding of acrolein to a second site (Ks = 58 microM). Acrolein activation of aldose reductase results not only in higher kcat values for all substrates but also in higher Km values and decreased catalytic efficiencies. Acrolein activation of aldose reductase reduces its affinity for aldose reductase inhibitors.
Mol Pharmacol 1994 Apr
PMID:Aldose reductase-catalyzed reduction of acrolein: implications in cyclophosphamide toxicity. 818 57

Human and Bovine kidney aldose and aldehyde reductases from cortex, medulla and papilla have been purified by DE-52 column chromatography or chromatofocusing and have been biochemically characterized. In both human and bovine kidney, cortex contains only aldehyde reductase and papilla aldose reductase. Medulla however, contains aldose as well as aldehyde reductase.
Biochem Mol Biol Int 1993 May
PMID:The distribution of aldose and aldehyde reductases in different regions of human and bovine kidney. 835 34

An abundant 37-kDa protein, which comprises up to 30% of the soluble proteins of the ovary, has been found to have 20 alpha-hydroxysteroid dehydrogenase (20 alpha HSD) activity. The steroidogenic enzyme 20 alpha HSD regulates the conversion of progesterone to 20 alpha-hydroxyprogesterone in many mammalian species. Complimentary DNA clones encoding a unique and abundant 20 alpha HSD were isolated from a mature rabbit ovary library using guinea pig antisera generated to the purified 37-kDa protein and from a 5' EcoRI fragment from the initial positive clone. A full-length cDNA clone of 1217 basepairs encoding a 323-amino acid protein with an estimated mol wt of 37 kilodaltons was obtained. Amino acid sequence data indicate a similarity to human chlordecone reductase, bovine lung prostaglandin F synthase, human aldose reductase, human aldehyde reductase, and frog lens rho-crystallin, placing rabbit ovarian 20 alpha HSD in the aldo-keto reductase family of proteins. Northern blot analysis demonstrated a 1.2-kilobase mRNA in the interstitial tissue of mature rabbit ovaries and, to a lesser extent, in corpora luteal tissue. 20 alpha HSD was expressed in bacteria as a recombinant protein and was shown to possess enzymatic activity, preferring NADP as a cofactor. These studies demonstrate that an abundant ovarian protein belonging to the superfamily of NADP-dependent aldo-keto reductases has 20 alpha HSD activity. This is the first example of an abundant crystallin-related protein with known enzymatic activity in a tissue other than the lens.
Mol Endocrinol 1993 Jan
PMID:Molecular cloning and expression of an abundant rabbit ovarian protein with 20 alpha-hydroxysteroid dehydrogenase activity. 824 25

To analyze the patterns of gene expression associated with seed dormancy in wild oat (Avena fatua), we have isolated cDNA clones corresponding to genes that are differentially expressed in dormant and afterripened line M73 embryos. Gene transcripts of these clones were maintained in embryos of imbibed dormant caryopses, but declined rapidly in afterripened embryos after imbibition. GA3 treatment of dormant caryopses, which breaks dormancy, could lower the transcript levels in dormant embryos. When the germination of afterripened caryopses was inhibited by high temperature (35 degrees C), the decline in abundance of the transcripts in afterripened embryos was arrested. These genes were expressed to various degrees in water-stressed, but not in unstressed, 7-day-old seedlings. The expression of the genes was also ABA-inducible in afterripened embryos. The expression patterns in non-dormant line SH430 wild oat were similar to those of afterripened M73. DNA sequence analyses indicated that some of the cDNA clones encode LEA (late embryogenesis-abundant) proteins and aldose reductase. The significance of the expression of these genes in maintaining seed dormancy or longevity is discussed.
Plant Mol Biol 1995 Nov
PMID:Cloning and characterization of differentially expressed genes in imbibed dormant and afterripened Avena fatua embryos. 854 7

The high sensitivity of reverse transcriptase-polymerase chain reaction for detecting low copy number mRNA transcripts has been standardized to analyze the mRNA profiles of catalase, glutathione peroxidase, CuZn-superoxide dismutase and aldose reductase, with respect to the housekeeping gene cyclophilin, in rat lenses cultured in hyperglycemic (50mM glucose) or oxidative (100 microM H2O2) media for 24, 40 and 60 hr. In response to hyperglycemia mRNA expression of catalase appeared to be inhibited at 24 hr but attained normal levels by 40 hr. On the other hand, mRNA levels of catalase were higher than normal between 40 and 60 hr in the presence of H2O2. Glutathione peroxidase mRNA abundance although enhanced in response to both hyperglycemia as well as H2O2-induced stress, displayed opposite trends with time-an increase from 24-60 hr due to hyperglycemia and a decrease to normal by 60 hr in the presence of H2O2. In contrast, CuZn-superoxide dismutase was inhibited at 50 mM glucose achieving baseline levels by 60 hr, while H2O2 elicited an induction at 24 hr which waned to basal levels by 60 hr. Interestingly, aldose reductase was unaffected by hyperglycemia but showed an appreciable increase with time upon exposure of the lens to H2O2. The role of these enzymes in cataractogenesis with regard to their respective mRNA levels is discussed.
Res Commun Mol Pathol Pharmacol 1996 Apr
PMID:Semi-quantitation of mRNA by polymerase chain reaction. Levels of oxidative defense enzymes and aldose reductase in rat lenses cultured in hyperglycemic or oxidative medium. 873 24


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