Aldose and aldehyde reductases: Correlation of molecular modeling and mass spectrometric studies on the binding of inhibitors to the active site

El‐Kabbani, Ossama; Rogniaux, Hélène; Barth, Patrick; Chung, Roland Poh-Tuck; Fletcher, Elisabeth V.; Dorsselaer, Alain Van; Podjarny, A.

doi:10.1002/1097-0134(20001115)41:3<407::aid-prot120>3.0.co;2-9

Cited by 26 publications

(20 citation statements)

References 37 publications

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“…Docking with all-trans-and 9-cis-retinal resulted in severe contacts against amino acid side chains from the substrate-binding pocket. Similarly to what has been observed with other substrates and inhibitors [27,31,32], the larger loop C could be the determinant for the absence of activity of pig aldehyde reductase with retinoids. Figure 4A).…”

Section: Docking With Retinoidssupporting

confidence: 66%

See 1 more Smart Citation

Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism

Crosas

Hyndman

Gallego

et al. 2003

Biochemical Journal

154

138

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Aldo-keto reductases (AKRs) are NAD(P)H-dependent oxidoreductases that catalyse the reduction of a variety of carbonyl compounds, such as carbohydrates, aliphatic and aromatic aldehydes and steroids. We have studied the retinal reductase activity of human aldose reductase (AR), human small-intestine (HSI) AR and pig aldehyde reductase. Human AR and HSI AR were very efficient in the reduction of all- trans -, 9- cis - and 13- cis -retinal ( k (cat)/ K (m)=1100-10300 mM(-1).min(-1)), constituting the first cytosolic NADP(H)-dependent retinal reductases described in humans. Aldehyde reductase showed no activity with these retinal isomers. Glucose was a poor inhibitor ( K (i)=80 mM) of retinal reductase activity of human AR, whereas tolrestat, a classical AKR inhibitor used pharmacologically to treat diabetes, inhibited retinal reduction by human AR and HSI AR. All- trans -retinoic acid failed to inhibit both enzymes. In this paper we present the AKRs as an emergent superfamily of retinal-active enzymes, putatively involved in the regulation of retinoid biological activity through the assimilation of retinoids from beta-carotene and the control of retinal bioavailability.

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Section: Docking With Retinoidssupporting

confidence: 66%

“…Recent studies on AR and aldehyde reductase suggest that the C-terminal loop (loop C) is critical for substrate specificity, catalytic efficiency and inhibitor sensitivity [27,31,32]. The most significant structural difference between ARs and aldehyde reductases is the size of loop C, which is nine residues longer in aldehyde reductases.…”

Section: Discussionmentioning

confidence: 99%

Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism

Crosas

Hyndman

Gallego

et al. 2003

Biochemical Journal

154

138

View full text Add to dashboard Cite

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“…Sorbinil only binds to the anionic pocket and has been shown to inhibit ALR1 and ALR2 equally. However, other inhibitors that bind to both the “anionic” and “specificity” pockets show specificity for ALR2 [31], [33]. β-glucogallin occupies both the “anionic” and “specificity” pockets resulting in more active site interactions (Figure 4C–D).…”

Section: Resultsmentioning

confidence: 99%

The Isolation and Characterization of β-Glucogallin as a Novel Aldose Reductase Inhibitor from Emblica officinalis

et al. 2012

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Diabetes mellitus is recognized as a leading cause of new cases of blindness. The prevalence of diabetic eye disease is expected to continue to increase worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. The plant Emblica officinalis (gooseberry) has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans. Extracts from this plant have been shown to be efficacious against the progression of cataract in a diabetic rat model. Aldose reductase (ALR2) is implicated in the development of secondary complications of diabetes including cataract and, therefore, has been a major drug target for the development of therapies to treat diabetic disease. Herein, we present the bioassay-guided isolation and structure elucidation of 1-O-galloyl-β-D-glucose (β-glucogallin), a major component from the fruit of the gooseberry that displays selective as well as relatively potent inhibition (IC50 = 17 µM) of AKR1B1 in vitro. Molecular modeling demonstrates that this inhibitor is able to favorably bind in the active site. Further, we show that β-glucogallin effectively inhibits sorbitol accumulation by 73% at 30 µM under hyperglycemic conditions in an ex-vivo organ culture model of lenses excised from transgenic mice overexpressing human ALR2 in the lens. This study supports the continued development of natural products such as β-glucogallin as therapeutic leads in the development of novel therapies to treat diabetic complications such as cataract.

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“…[α] 25 D −3.4 ( c = 0.22, CH 3 OH); IR (neat) ν max 3410, 1637, 1604, 1532, 1448, 1333 cm −1 ; 1 H NMR (500 MHz, CD 3 OD) δ 6.28 (s, 2H), 4.85 (d, J = 9.0 Hz, 1H), 3.79–3.76 (dd, J = 2.0, 12.0 Hz, 1H), 3.61–3.58 (dd, J = 5.0, 12.0 Hz, 1H), 3.37–3.20 (m, 6H); 13 C NMR (125.7 MHz, CD 3 OD) δ 175.5, 147.0, 133.2, 127.0, 109.4, 81.2, 79.6, 79.0, 73.9, 71.3, 62.6, 43.5; ESI-HRMS calcd. for C 14 H 15 NO 9 Na [M + Na] + , 368.0952; found, 368.0958.…”

Section: Resultsmentioning

confidence: 99%

Design of an Amide N-Glycoside Derivative of β-Glucogallin: A Stable, Potent, and Specific Inhibitor of Aldose Reductase

Chang

Zhou

et al. 2013

J. Med. Chem.

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β-glucogallin (BGG), a major component of the Emblica officinalis medicinal plant, is a potent and selective inhibitor of aldose-reductase (AKR1B1). New linkages (ether/triazole/amide) were introduced via high yielding, efficient syntheses to replace the labile ester, and an original 2-step (90%) preparation of BGG was developed. Inhibition of AKR1B1was assessed in vitro and using transgenic lens organ cultures, which identified the amide linked glucoside (BGA) as a stable, potent and selective lead therapeutic toward the treatment of diabetic eye disease.

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Aldose and aldehyde reductases: Correlation of molecular modeling and mass spectrometric studies on the binding of inhibitors to the active site

Cited by 26 publications

References 37 publications

Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism

Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism

The Isolation and Characterization of β-Glucogallin as a Novel Aldose Reductase Inhibitor from Emblica officinalis

Design of an Amide N-Glycoside Derivative of β-Glucogallin: A Stable, Potent, and Specific Inhibitor of Aldose Reductase

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