A ‘specificity’ pocket inferred from the crystal structures of the complexes of aldose reductase with the pharmaceutically important inhibitors tolrestat and sorbinil

Urzhumtsev, Alexandre; Favier, F.; Mitschler, A.; Barbanton, J.; Barth, Patrick; Urzhumtseva, Ludmila; Biellmann, Jean‐François; Podjarny, A.; Moras, Dino

doi:10.1016/s0969-2126(97)00216-5

Cited by 240 publications

(344 citation statements)

References 37 publications

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“…In the present study we have further characterized the nature of the interactions between AR inhibitors and the enzyme active site by modeling Tolrestat, Sorbinil and Zopolrestat in the active site of the human holoenzyme. In agreement with crystallographic studies of the human and porcine enzymes [12,16] we have identified a number of apolar residues in the active site that appear to interact with the inhibitors and stabilize them in the active site. To confirm these observations we have quantified the activity of Tolrestat, Sorbinil and Zopolrestat with AR enzymes containing single mutations to these apolar residues.…”

supporting

confidence: 84%

“…Results from several of these studies have indicated that AR inhibitors occupy the active site of the enzyme [12,13,15,16]. Consistent with these findings, site-directed mutagenesis studies have shown that replacing the active-site residue Tyr48 with Phe or His prevented the binding of the AR inhibitor alrestatin.…”

mentioning

confidence: 66%

“…The inhibitors Tolrestat, Sorbinil and Zopolrestat were modeled in the active site of the human AR holoenzyme (Brookhaven Protein Data Bank entry 1ADS) [17] using a previously described procedure [18]. Briefly, each inhibitor molecule was manually docked in the active site of the holoenzyme in an orientation similar to that present in the crystal structure of the corresponding ternary complex [12,16]. Water molecules in the active site of the holoenzyme coinciding with the inhibitor-binding position were removed.…”

Section: Methodsmentioning

confidence: 99%

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Probing the inhibitor‐binding site of aldose reductase with site‐directed mutagenesis

Hohman

El‐Kabbani

Malamas

et al. 1998

European Journal of Biochemistry

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Aldose reductase (AR) has been implicated in the etiology of the secondary complications of diabetes, and enzyme inhibitors have been proposed as therapeutic agents. While effectively preventing the development of diabetic complications in animals, results from clinical studies of AR inhibitors have been disappointing, possibly due to poor potency in man. To assist in the design of more potent and specific inhibitors, crystallographic studies have attempted to identify enzyme-inhibitor interactions. Resolution of crystal complexes has suggested that the inhibitors bind to the enzyme active site and are held in place through hydrogen bonding and van der Waals interactions formed within two hydrophobic pockets. To confirm and extend these findings we quantified inhibitor activity with single, site-directed, mutant, human AR enzymes in which the apolar active-site residues tryptophan 20, Ϫ79, Ϫ111 and phenylalanine 115 were replaced with alanine or tyrosine, decreasing the potential for van der Waals interactions.Consistent with molecular models, the inhibitory activity of Tolrestat, Sorbinil and Zopolrestat decreased 800Ϫ2000-fold when tested with the mutant enzyme in which Trp20 was replaced with alanine. Further, alanine substitution for Trp111 decreased Zopolrestat's activity 400-fold, while mutations to Trp79 and Phe115 had little effect on the activity of any of the inhibitors. The alanine mutation at Trp111 had no effect on Tolrestat's activity but decreased the activity of Sorbinil by about 1000-fold. These latter effects were unanticipated based on the number of non-bonded interactions between the inhibitors, Tolrestat and Sorbinil, and Trp20 and Trp111 that have been identified in the crystal structures. In spite of these unexpected findings, our results are consistent with the hypothesis that AR inhibitors occupy the enzyme active site and that hydrophobic interactions between the enzyme and inhibitor contribute to inhibitor binding stability.Keywords : site-directed mutagenesis ; human aldose reductase; enzyme inhibition; polyol pathway ; diabetes.The polyol pathway has been implicated in the etiology of the secondary complications of diabetes. There are two enzymes in this pathway. The first, aldose reductase (AR), catalyzes the reduction of glucose to sorbitol and the second, sorbitol dehydrogenase, catalyzes the oxidation of sorbitol to fructose. AR has a relatively low affinity for glucose and during conditions of normal glycemia (80Ϫ110 mg/dl), where cellular glucose rapidly becomes phosphorylated via hexokinase, little substrate enters the pathway. During hyperglycemia, however, the cellular level of glucose greatly increases in tissues where glucose entry is independent of insulin. In these tissues which include the lens, retina, kidney and peripheral nerves, all sites of diabetes-induced

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supporting

confidence: 84%

mentioning

confidence: 66%

Section: Methodsmentioning

confidence: 99%

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Probing the inhibitor‐binding site of aldose reductase with site‐directed mutagenesis

Hohman

El‐Kabbani

Malamas

et al. 1998

European Journal of Biochemistry

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“…Although the inhibition assays on our compounds were conducted on rat ALR2, the use of the crystal structure of the human ALR2 for docking study seems reasonable according to the following facts: (i) the crystal structure of rat ALR2 is unknown; (ii) the human and rat sequences of this enzyme are characterized by 85 % identity [16]; (iii) all active-site residues are largely conserved across the ALR2 isoforms sequenced so far [17]. The energy-minimized structure of IDD594 was preliminarily docked into ALR2 to examine how closely the FlexX algorithm can reproduce the binding modes observed in the crystallographic structure.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…The hydrogen bonds predicted by FlexX were virtually identical to those found in the crystal structure. It is known from the crystal structures of complexes of ALR2 with carboxylic acid inhibitors that these bind ALR2 with the carboxylate moiety interacting with Tyr48, His110, and Trp111, which are the three key residues involved in binding [17]. Accordingly, compound 3k was expected to bind ALR2 with its carboxylate moiety in a similar position.…”

Section: Molecular Modelingmentioning

confidence: 99%

Synthesis and Activity of a New Series of(Z)-3-Phenyl-2-benzoylpropenoic Acid Derivatives as Aldose Reductase Inhibitors

Wang

Yan²,

Hao

et al. 2007

Molecules

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During the course of studies directed towards the discovery of novel aldose reductase inhibitors for the treatment of diabetic complications, we synthesized a series of new (Z)-3-phenyl-2-benzoylpropenoic acid derivatives and tested their in vitro inhibitory activities on rat lens aldose reductase. Of these compounds, (Z)-3-(3,4-dihydroxyphenyl)-2-(4-methylbenzoyl)propenoic acid (3k) was identified as the most potent inhibitor, with an IC 50 of 0.49µM. The theoretical binding mode of 3k was obtained by simulation of its docking into the active site of the human aldose reductase crystal structure.

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Review: The structure and function of yeast xylose (aldose) reductases

Lee

1998

Yeast

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Yeast xylose (aldose) reductases are members of the aldo‐keto reductase family of enzymes which are widely distributed in a variety of other organisms. In yeasts, these enzymes catalyse the first step of xylose metabolism where xylose is converted to xylitol. In the past 16 years, xylose reductases from yeasts able to ferment or utilize xylose have been isolated and studied mainly because of their importance in xylose bioconversions. In recent years, genes encoding xylose reductases from several yeasts have been cloned and sequenced. A comparison of the primary sequences of yeast xylose reductases with the much better characterized human aldose reductase and human aldehyde reductase reveals that the yeast enzymes are hybrids between aldo‐keto reductases and the short chain dehydrogenases/reductases families of enzymes. Why this is so and its evolutionary significance is presently not known. This short review will critically examine the structure and function information that can be gleaned from the sequence comparison. Several interesting questions arise from the sequence comparison and these can provide fruitful areas for further investigations. © 1998 John Wiley & Sons, Ltd.

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A ‘specificity’ pocket inferred from the crystal structures of the complexes of aldose reductase with the pharmaceutically important inhibitors tolrestat and sorbinil

Cited by 240 publications

References 37 publications

Probing the inhibitor‐binding site of aldose reductase with site‐directed mutagenesis

Probing the inhibitor‐binding site of aldose reductase with site‐directed mutagenesis

Synthesis and Activity of a New Series of(Z)-3-Phenyl-2-benzoylpropenoic Acid Derivatives as Aldose Reductase Inhibitors

Review: The structure and function of yeast xylose (aldose) reductases

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