Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.1.1.1 (alcohol dehydrogenase)
9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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)
...
PMID:Glucose metabolism in Giardia intestinalis. 205 39

Many of the complications of diabetes appear to be closely linked to increased conversion of tissue glucose to sorbitol which is catalysed by aldose reductase (aldehyde reductase 2, ALR2). Inhibition of ALR2 could, therefore, lead to a reduction in the development of diabetic complications. Ponalrestat ["Statil" (a trademark, the property of Imperical Chemical Industries PLC), "Prodiax" (a trademark, the property of Merck, Sharp and Dohme), ICI 128436, MK538] inhibits ALR2 from a number of sources. Until now, the mechanism of this inhibition has not been fully elucidated. In this paper, we present a detailed mechanism for inhibition of bovine lens ALR2 by ponalrestat. Treatment of humans with some ALR2 inhibitors leads to side-effects, some of which may result from interactions with other enzymes. Aldehyde reductase (ALR1) is probably the most closely related enzyme to ALR2. Inhibition of ALR1 from bovine kidney was, therefore, investigated in order to assess the specificity of ponalrestat. The values of Ki and Kies (apparent dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for the interactions of ponalrestat with ALR1 and ALR2 has been calculated by non-linear fitting of kinetic data. These values indicate that ponalrestat does not compete with binding of glucose of NADPH to ALR2, nor with binding of glucuronate or NADPH to ALR1. Lack of competition and the structural dissimilarity of substrates and inhibitor make it unlikely that ponalrestat will utilize substrate binding sites on other enzymes, and so produce undesirable side-effects via such a mechanism. Ponalrestat is a potent inhibitor (Ki = Kies = 7.7 nM) of ALR2 and follows a pure noncompetitive mechanism with respect to glucose. Efficacy, therefore, will not be decreased by development of hyperglycaemia. The compound is a mixed noncompetitive inhibitor of ALR1 when glucuronate is varied. The values of Ki and Kies are 60 microM and 3 microM, respectively, so that inhibition tends towards uncompetitive. The selectivity of ponalrestat in favour of ALR2, therefore, lies in the range 390 to 7,800-fold, being higher at lower concentrations of glucuronate. The high selectivity of ponalrestat in favour of ALR2 rather than ALR1 suggests that the compound is unlikely to inhibit other enzymes which have less homology with ALR2.
...
PMID:Ponalrestat: a potent and specific inhibitor of aldose reductase. 210 33

Engelbreth-Holm-Swarm (EHS) tumor cells were utilized as a model for investigating the production of basement membrane components. These cells contain two immunologically distinct NADPH-dependent reductases, aldose reductase (EC 1.1.1.21) and aldehyde reductase (EC 1.1.1.2), which were purified to apparent homogeneity by a combination of procedures which included ammonium sulfate fractionation, Sephadex G-75 gel filtration, Matrex Gel Orange A affinity chromatography, and chromatofocusing on Pharmacia Mono P. The molecular weights of aldose and aldehyde reductases were estimated to be 38K and 40K, respectively, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Substrate specificity studies showed that both enzymes were capable of reducing a variety of aldehydes to their respective alcohols; however, only aldehyde reductase oxidized L-gulonic acid. Surprisingly, both enzymes showed similar reactivities with D-glucose and D-galactose, suggesting that both aldose and aldehyde reductases may contribute to sorbitol production in the EHS tumor cell. The activities of both enzymes were increased by the presence of sulfate ion, but chloride ion decreased the activity of aldose reductase. Both aldose and aldehyde reductases were inhibited by a series of structurally diverse aldose reductase inhibitors.
...
PMID:Purification and properties of aldose reductase and aldehyde reductase from EHS tumor cells. 210 20

The presence of several NADPH-dependent reductases has been observed in the dog lens. Applying the purification procedures of gel filtration, affinity chromatography and chromatofocusing to dog lens homogenates resulted in the purification of aldose reductase. This enzyme appeared similar to dog kidney aldose reductase in molecular weight, isoelectric point, kinetic properties, and susceptibility to inhibition by aldose reductase inhibitors. Evidence for the presence of trace amounts of aldehyde reductase in the dog lens was also observed, although this enzyme is not present in sufficient quantities for isolation and characterization. The presence of a labile third enzyme that is immunologically distinct from either aldose reductase or aldehyde reductase was also detected. This enzyme utilizes only glyceraldehyde as substrate and is not inhibited by aldose reductase inhibitors.
...
PMID:NADPH-dependent reductases of the dog lens. 211 52

A broad group of structurally diverse aldose reductase inhibitors including flavonoids, carboxylic acids and hydantoins, have been examined for their ability to inhibit rat kidney aldehyde reductase (EC 1.1.1.19, EC 1.1.1.20) versus rat lens aldose reductase (EC 1.1.1.21). All aldose reductase inhibitors examined inhibited aldehyde reductase to some extent both in the reductive reaction as determined with glyceraldehyde as substrate and NADPH as coenzyme, and in the oxidative reaction where L-gulonic acid was oxidized to D-glucuronic acid in the presence of NADP+. Of the inhibitors examined, 2,7-difluorospirofluorene-9,5'-imidazolidine-2',4'-dion e (Al1576) was the most potent inhibitor requiring only concentrations in the 10(-8) M range to inhibit 50% of the in vitro activity of rat kidney aldehyde reductase (IC50 value), whereas 3-dioxo-1-H-benz[de]isoquinoline-2(3H)-acetic acid (alrestatin) was the least potent inhibitor requiring concentrations in the 10(-5) M range. Both the reductive and oxidative steps appeared equally inhibited by these aldose reductases inhibitors. Moreover, all compounds appeared to inhibit either crude or highly purified rat kidney aldehyde reductase to essentially the same extent. Marked differences in the selectivity of these inhibitors, expressed as the ratio of IC50 values for rat kidney aldehyde reductase versus rat lens aldose reductase with glyceraldehyde as substrate, were observed with selectivity for aldose reductase ranging from ca. 2-fold for Al1576 to 119-fold for 3-(4-bromo-2-fluorobenzyl-4-oxo-3-phthalazine-1-ylacetic acid (Ponalrestat). Kinetic and competition studies suggest that these inhibitors interact with aldehyde reductase at a common site that is not identical to either the substrate or nucleotide binding site. These results suggest that the inhibitor binding sites of rat kidney aldehyde reductase and aldose reductase contain several common characteristics.
...
PMID:Inhibition of aldehyde reductase by aldose reductase inhibitors. 211 25

Aldose reductase and aldehyde reductase from the medulla of the rat kidney have been purified to homogeneity by using affinity chromatography, gel filtration and chromatofocusing. The molecular weights of aldose reductase and aldehyde reductase by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis were found to be 37000 and 39000, respectively. The isoelectric points of aldose reductase and aldehyde reductase were found to be 5.4 and 6.2 by chromatofocusing, respectively. The major differences of amino acid compositions between both enzymes were found in serine, alanine and aspartic acid. Substrate specificity studies showed that aldose reductase utilized aldo-sugars such as D-glucose and D-galactose, but aldehyde reductase did not use them. The Km values of aldose reductase for various substrates were lower than those of aldehyde reductase. Aldose reductase utilized both reduced nicotinamide adenine dinucleotide phosphate (NADPH) and reduced nicotinamide adenine dinucleotide (NADH) as coenzymes, whereas aldehyde reductase utilized only NADPH. The presence of the sulfate ion resulted in a dramatic activation of aldose reductase whereas it did not affect aldehyde reductase activity. These enzymes were strongly inhibited by the known aldose reductase inhibitors. However, aldose reductase was more susceptible than aldehyde reductase to inhibition by the aldose reductase inhibitors.
...
PMID:Characterization of aldose reductase and aldehyde reductase from the medulla of rat kidney. 211 95

Two acidic and three basic forms of monomeric dihydrodiol dehydrogenase with molecular weights in the range of 36,000-39,000 were purified from human liver. One acidic enzyme (pI 5.2), which was specific for NADP- and dihydrodiols of benzene and naphthalene, was immunologically identified as aldehyde reductase. The other four enzymes oxidized alicyclic alcohols as well as the dihydrodiols using both NADP+ and NAD+ as cofactors, but showed differences in specificity for hydroxysteroids and inhibitor sensitivity. Two of the basic enzymes (pI 9.7 and 9.1) exhibited a 20 alpha-hydroxysteroid dehydrogenase activity and sensitivity to 1,10-phenanthroline, whereas the third basic enzyme (pI 7.6) oxidized some 3 alpha-hydroxysteroids at low rates and was inhibited by cyclopentane-1,1-diacetic acid. Another acidic enzyme, which accounted for the largest amount of enzyme activity in the tissue and appeared in two heterogenous forms with pI values of 5.9 and 5.4, showed a high 3 alpha-hydroxysteroid dehydrogenase activity and was the most sensitive to inhibition by medroxyprogesterone acetate. The Km values of the enzymes, except the pI 5.2 enzyme, for hydroxysteroids (10(-6) to 10(-7) M) were lower than those for xenobiotic alcohols.
...
PMID:Purification and properties of multiple forms of dihydrodiol dehydrogenase from human liver. 212 26

A series of substituted N-[[(4-benzoylamino)phenyl]sulfonyl]amino acids (BAPS-amino acids) were synthesized by established methods, and the stereochemistry of the products was confirmed by HPLC analysis after chiral derivatization. When tested against aldose reductase (alditol:NADP+ oxidoreductase; EC 1.1.1.21; ALR2) isolated from rat lens, all of the BAPS-amino acids were determined to be significantly more inhibitory than the corresponding N-(phenylsulfonyl)amino acids. Structure-inhibition and enzyme kinetic analyses suggest that the BAPS-amino acids inhibit ALR2 by a mechanism similar to the N-(phenylsulfonyl)amino acids. However, multiple inhibition analyses indicate that the increased inhibitory activity of the BAPS-amino acids is a result of interaction with multiple sites present on ALR2. Enzyme specificity studies with several of the BAPS-amino acids demonstrated that these compounds do not produce significant inhibition of other nucleotide-requiring enzymes including aldehyde reductase (alcohol: NADP+ oxidoreductase; EC 1.1.1.2; ALR1).
...
PMID:Inhibitory activity and mechanism of inhibition of the N-[[(4-benzoylamino)phenyl]sulfonyl]amino acid aldose reductase inhibitors. 212 5

Adriamycin was internalized in canine red blood cells (RBC) by two procedures involving (a) simple diffusion of the drug into cells and (b) hypotonic dialysis followed by isotonic resealing. The two procedures yielded comparable amounts of encapsulated adriamycin, around 35 micrograms/10(9) RBC. Exposure of adriamycin-loaded RBC to 0.16% glutaraldehyde consistently slowed down the rate of efflux of the drug as compared with non-glutaraldehyde-treated cells: after 1 h of incubation at 37 degrees C, greater than 80% of adriamycin was still present inside the glutaraldehyde-treated RBC, while at 24 h it was 66%, compared to 10% and 1%, respectively, in the adriamycin-loaded, non-glutaraldehyde-treated cells. Canine RBC showed a higher rate of transformation of adriamycin than the human cells, the only intracellular metabolite being adriamycinol, which is apparently formed by the NADPH-dependent enzyme aldehyde reductase. Production of adriamycinol was remarkably lower in the glutaraldehyde-treated RBC, as a result of progressive and extensive inactivation of hexose monophosphate shunt activity responsible for NADPH formation. These results, coupled with the known selective targeting of glutaraldehyde-treated RBC to liver, hold promise as to in vivo applications of this drug delivery system in antineoplastic therapy.
...
PMID:Construction and characterization of adriamycin-loaded canine red blood cells as a potential slow delivery system. 212 36

Aldose reductase was purified from human skeletal and heart muscle by a rapid and efficient scheme involving Red Sepharose chromatography, chromatofocusing on Pharmacia PBE 94, and hydroxylapatite high pressure liquid chromatography. The scheme afforded homogeneous enzyme, 65% recovery, in 2 days. All muscle samples express aldose reductase but not the closely related aldehyde reductase. Aldose reductase is isolated in one of two forms that are distinguishable by their kinetic patterns with glyceraldehyde as substrate and which are interconvertible by treatment with dithiothreitol. Both forms are capable of catalyzing the reduction of glucose (Km = 68 mM), and both are highly sensitive to inhibition by aldose reductase inhibitors. The reduction of glucose was shown to be nearly stoichiometric with production of sorbitol (92 +/- 2%). Dialysis of aldose reductase in the absence of thiols or NADP converts it into a form that shows markedly different kinetic properties, including very weak catalytic activity toward glucose and insensitivity to aldose reductase inhibitors. This modified form can be converted back into the native form by dithiothreitol. Thiol titration of the two forms of aldose reductase with Ellman's reagent indicated that two thiol groups were lost when the enzyme was dialyzed in the absence of dithiothreitol or NADP.
...
PMID:Aldose reductase from human skeletal and heart muscle. Interconvertible forms related by thiol-disulfide exchange. 217 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---