Showing papers on "Aldose published in 1999"

Peroxo-Bridged Dinuclear Cobalt(III) Complexes Containing N-Glycoside Ligands from Tris(2-aminoethyl)amine and d-Glucose or Maltose

Abstract: Peroxo-bridged dinuclear cobalt(III) complexes, [{Co((d-Glc)2-tren)}2(μ-O2)]X3·5H2O (X = Cl (2·5H2O), Br (3·5H2O)) and [{Co((Mal)2-tren)}2(μ-O2)]Cl3·6H2O (4·6H2O), were prepared from CoX2·6H2O, tris(2-aminoethyl)amine, and d-glucose (d-Glc) or maltose (α-d-glucopyranosyl-(1→4)-d-glucose; Mal), and were characterized by elemental analysis, UV−vis absorption, circular dichroism, 1H and 13C NMR spectroscopic techniques, and X-ray absorption and crystallographic analyses, where (aldose)2-tren is bis(N-aldosyl-2-aminoethyl)(2-aminoethyl)amine (aldose = d-Glc, Mal). The structure of 2 and 4 were determined by X-ray crystallography to consist of two Co(III) ions bridged by a peroxo unit: 2·4H2O·CH3OH, orthorhombic, P212121 (No. 19), a = 19.384(8) A, b = 23.468(5) A, c = 13.195(5) A, V = 6002(2) A3, Z = 4, Dcalcd = 1.440 g cm-3, T = −99 °C, R = 0.078, Rw = 0.085 for 4961 reflections with I > 3σ(I); 4·2.25H2O·3.75CH3OH, monoclinic, P21 (No. 4), a = 12.819(7) A, b = 49.168(18) A, c = 14.973(6) A, β = 104.59(4)°, V...

Cloning, Overexpression, and Mutagenesis of the Sporobolomyces salmonicolor AKU4429 Gene Encoding a New Aldehyde Reductase, Which Catalyzes the Stereoselective Reduction of Ethyl 4-Chloro-3-Oxobutanoate to Ethyl (S)-4-Chloro-3-Hydroxybutanoate

Abstract: Aldehyde reductase (EC 1.1.1.2), aldose reductase (EC 1.1.1.21), and carbonyl reductase (EC 1.1.1.184) catalyze NADPH-dependent reduction of a variety of carbonyl compounds and are widely distributed in mammalian and plant tissues. These enzymes are members of the aldo-keto reductase superfamily (4, 8); however, their physiological functions are not well understood. The amino acid sequences of aldose reductases and aldehyde reductases exhibit significant levels of similarity, but the amino acid sequences of carbonyl reductases do not (32). In previous papers, we described purification and characterization of three NADPH-dependent aldehyde reductases (ARI, ARII, and ARIII) of the red yeast Sporobolomyces salmonicolor AKU4429 (9, 14, 34). ARI is the most abundant aldehyde reductase in this yeast and catalyzes asymmetric reduction of ethyl 4-chloro-3-oxobutanoate (4-COBE) to ethyl (R)-4-chloro-3-hydroxybutanoate (4-CHBE) {enantiomeric excess for (R) = [(R − S)/(R + S] × 100 and vice versa}, a promising chiral building block for organic synthesis. In contrast, ARII is produced in considerably smaller amounts but reduces 4-COBE to the (S) enantiomer (92.7% enantiomeric excess), which is also a useful chiral building block for chemical synthesis of pharmaceuticals. In addition to the stereoselectivity of activity against 4-COBE, the N-terminal amino acid sequences of these two aldehyde reductases are quite different. Based on the amino acid sequence deduced from the cDNA sequence, ARI belongs to the aldo-keto reductase superfamily (13). Recently, an NADPH-dependent aldehyde reductase (S1), which reduces 4-COBE to the (S) enantiomer (100% enantiomeric excess), was purified from Candida magnoliae AKU4643 (31). The substrate specificities, subunit structures, and N-terminal amino acid sequences of ARII and S1 are not similar. This indicates that the two enzymes belong to the different groups. In this study, we cloned and analyzed a cDNA clone of the aldehyde reductase gene (ARII) in order to compare the catalytic mechanisms of ARI and ARII and to understand the molecular basis of the stereospecific reduction of 4-COBE.

Aldose and aldehyde reductases: structure-function studies on the coenzyme and inhibitor-binding sites.

Abstract: PURPOSE: To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases. METHODS: The crystal structure of porcine aldehyde reductase in complex with NADPH and the aldose reductase inhibitor sorbinil was determined. The contribution of each amino acid lining the coenzyme-binding site to the binding of NADPH was calculated using the Discover package. In human aldose reductase, the role of the non-conserved Pro 216 (Ser in aldehyde reductase) in the binding of coenzyme was examined by site-directed mutagenesis. RESULTS: Sorbinil binds to the active site of aldehyde reductase and is hydrogen-bonded to Trp 22, Tyr 50, His 113, and the non-conserved Arg 312. Unlike tolrestat, the binding of sorbinil does not induce a change in the side chain conformation of Arg 312. Mutation of Pro 216 to Ser in aldose reductase makes the binding of coenzyme more similar to that of aldehyde reductase. CONCLUSIONS: The participation of non-conserved active site residues in the binding of inhibitors and the differences in the structural changes required for the binding to occur are responsible for the differences in the potency of inhibition of aldose and aldehyde reductases. We report that the non-conserved Pro 216 inmore » aldose reductase contributes to the tight binding of NADPH.« less

Binding energy and specificity in the catalytic mechanism of yeast aldose reductases

Abstract: Derivatives of d-xylose and d-glucose, in which the hydroxy groups at C-5, and C-5 and C-6 were replaced by fluorine, hydrogen and azide, were synthesized and used as substrates of the NAD(P)H-dependent aldehyde reduction catalysed by aldose reductases isolated from the yeasts Candida tenuis, C. intermedia and Cryptococcus flavus. Steady-state kinetic analysis showed that, in comparison with the parent aldoses, the derivatives were reduced with up to 3000-fold increased catalytic efficiencies (k(cat)/K(m)), reflecting apparent substrate binding constants (K(m)) decreased to as little as 1/250 and, for d-glucose derivatives, up to 5.5-fold increased maximum initial rates (k(cat)). The effects on K(m) mirror the relative proportion of free aldehyde that is available in aqueous solution for binding to the binary complex enzyme-NAD(P)H. The effects on k(cat) reflect non-productive binding of the pyranose ring of sugars; this occurs preferentially with the NADPH-dependent enzymes. No transition-state stabilization energy seems to be derived from hydrogen-bonding interactions between enzyme-NAD(P)H and positions C-5 and C-6 of the aldose. In contrast, unfavourable interactions with the C-6 group are used together with non-productive binding to bring about specificity (6-10 kJ/mol) in a series of d-aldoses and to prevent the reaction with poor substrates such as d-glucose. Azide introduced at C-5 or C-6 destabilizes the transition state of reduction of the corresponding hydrogen-substituted aldoses by approx. 4-9 kJ/mol. The total transition state stabilization energy derived from hydrogen bonds between hydroxy groups of the substrate and enzyme-NAD(P)H is similar for all yeast aldose reductases (yALRs), at approx. 12-17 kJ/mol. Three out of four yALRs manage on only hydrophobic enzyme-substrate interactions to achieve optimal k(cat), whereas the NAD(P)H-dependent enzyme from C. intermedia requires additional, probably hydrogen-bonding, interactions with the substrate for efficient turnover.

Structure-Function Studies of FR-1

Abstract: The aldo-keto reductase (AKR) gene superfamily represents a collection of proteins expressed in a wide variety of plants, animals, yeast, and procaryotic organisms. Most AKRs were originally identified as enzymes capable of catalyzing the NADPH-dependent reduction of carbonyl groups contained in a broad range of substrates (Bachur, 1976). However, recent genetic studies mediated by genome and expression sequencing approaches have identified several new members of the AKR superfamily. Many of these new proteins are characterized by high sequence homology to AKR enzymes although little or no information is available about their potential catalytic activities. One such new protein, designated FR-1* was identified as the product of a gene upregulated in serum-starved mouse fibroblasts following treatment with fibroblast growth factor I (FGF-I) (Donohue et al., 1994). High amino acid sequence identity (~70%) was observed between FR-1 and aldose reductase as well as other AKRs. Many amino acid residues known to contribute to the catalytic mechanism in other AKR enzymes including aldose reductase (AKRlB I), aldehyde reductase (AKRIAI) and 3a.-hydroxysteroid dehydrogenase (AKR1C9) are conserved in FR-l. These residues include Tyr-48, His-ll 0, Lys-77 and Asp-43 (numbering is that of aldose reductase) (Barski et al. , 1995; Pawlowski & Penning, 1994; Schlegel et al., 1998; Tarle et al. , 1993). The present study was undertaken to evaluate whether FR -1 is a catalyst of carbonyl reduction and to measure the affinity of FR-1 for various ligands such as nucleotide cofactors, carbonyl substrates and aldose reductase inhibitors. Our studies show that FR-1 catalyzes the NADPH-dependent reduction of substrates representative of diverse structural classes of aliphatic and aromatic aldehydes. Both saturated and unsaturated aldehydes were excellent substrates. Unlike aldose reductase and aldehyde reductase, FR-1 catalyzed the reduction of simple ketones such as acetone and butanone; however virtually no catalytic activity could be detected using steroid and aldose substrates. FR-1 was inhibited by various aldose reductase inhibitors in a manner similar to human aldose reductase. Besides being an excellent substrate, 4-hydroxy-2-nonenal (HNE) inactivated the enzyme through a mechanism involving Michael addition to Cys-298.

Method of preparing an aldose or an aldose derivative by decarboxylation

Abstract: The subject matter of the present invention is a method of manufacturing an aldose or an aldose derivative containing n carbon atoms on the hydrocarbonic chain, characterized by the fact that, in an aqueous phase, at least one acid derivative of saccharide with n+1 carbon atoms containing at least one α-hydroxy acid unit, and/or at least one salt of such an acid derivative of saccharide, is brought into contact with hydrogen peroxide in the presence of a quantity of at least one tungsten or molybdenum salt, said quantity being less than 4 equivalents, preferably less than 2 equivalents, expressed as the total number of moles of tungsten and molybdenum divided by the total number of moles of acid derivative(s) of saccharide and of salt(s) of acid derivative(s) of saccharide.

Substituted indole alkanol acid

Abstract: PROBLEM TO BE SOLVED: To provide a new effective and safe medicine for treating a diabetic composition. SOLUTION: The pharmaceutical composition includes a new substituted indole alkanol acid (represented by the general formula I) interacting with an aldose reductase and suppressing the aldose reactase. (Wherein, A is a 1-4C alkylene substituted with a 1-2C alkyl or a mono- or di-substituted with a halogen; z is a bond; R1 is H, a 1-6C alkyl or a halogen; R2 , R3 , R4 and R5 are each independently H, a halogen, nitro, a 1-6C alkyl, (substituted) benzyl or the like; R6 is H or a 1-6C alkyl).

Nitromethyl ketone compounds having aldose reduction inhibiting properties and methods for their use

Abstract: The present invention relates to the compounds of formula: in which R 1 , R 2 , R 3 , E, A, X, Z, p and n are as defined herein. These compounds are aldose reductase inhibitors.

Copper-mediated decarboxylaion

Abstract: Process for producing an aldose or aldose derivative containing n carbon atoms comprises: (a) contacting an aqueous solution of a sugar acid having n+1 carbon atoms and containing at least one alpha -hydroxy acid unit, or a salt thereof, with hydrogen peroxide in the presence of a copper salt; (b) separating precipitated copper; (c) regenerating the copper salt with the corresponding acid; and (d) recycling the regenerated salt. The aqueous solution contains 1-60 wt.% of the sugar acid. The Cu salt is used in an amount of 0.01-50% based on the sugar acid. The H2O2 has a concentration of 35-70% and is used in an amount of 1-500 mole% based on the sugar acid. The reaction is effected at 0-100[deg]C, especially 15-40[deg]C, and pH 5-9, especially 6-8. The sugar acid is arabinonic acid, optionally in Na or Ca salt form. The copper salt is CuSO4 and is regenerated with H2SO4.