Partial Inhibition of Aldose Reductase by Nitazoxanide and Its Molecular Basis

Zheng, Xuehua; Zhang, Liping; Chen, Weijia; Chen, Yunyun; Xie, Wei; Hu, Xiaopeng

doi:10.1002/cmdc.201200333

Cited by 22 publications

(25 citation statements)

References 14 publications

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“…The shape of the open substrate‐binding pocket in AKRs is defined by loop 2, loop 4, and the C‐terminal loop. To the best of our knowledge, the structures of hAR·NADP + with d ‐glyceraldehyde and glucose‐6‐phosphate represent the only examples of substrate bound ternary complexes of an AKR superfamily member . Although Zheng et al .…”

Section: Resultsmentioning

confidence: 99%

“…The specific transfer of the 4‐pro‐ R hydride to the carbonyl carbon atom of the substrate is known to be highly conserved in this superfamily. However, despite extensive structural studies (69 inhibitor bound AKR1 structures in the PDB), it is intriguing that only two structures of a substrate bound ternary complex of an AKR superfamily member have been reported, namely, hAR bound to d ‐glyceraldehyde (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=3V36) and to glucose‐6‐phosphate (PDB: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=2ACQ) .…”

Section: Introductionmentioning

confidence: 99%

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Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

2018

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Aldose reductases (ARs) belonging to the aldo‐keto reductase (AKR) superfamily catalyze the conversion of carbonyl substrates into their respective alcohols. Here we report the crystal structures of the yeast Debaryomyces nepalensis xylose reductase (DnXR, AKR2B10) in the apo form and as a ternary complex with a novel NADP‐DTT adduct. Xylose reductase, a key enzyme in the conversion of xylose to xylitol, has several industrial applications. The enzyme displayed the highest catalytic efficiency for l‐threose (138 ± 7 mm−1·s−1) followed by d‐erythrose (30 ± 3 mm−1·s−1). The crystal structure of the complex reveals a covalent linkage between the C4N atom of the nicotinamide ring of the cosubstrate and the S1 sulfur atom of DTT and provides the first structural evidence for a protein mediated NADP–low‐molecular‐mass thiol adduct. We hypothesize that the formation of the adduct is facilitated by an in‐crystallo Michael addition of the DTT thiolate to the specific conformation of bound NADPH in the active site of DnXR. The interactions between DTT, a four‐carbon sugar alcohol analog, and the enzyme are representative of a near‐cognate product ternary complex and provide significant insights into the structural basis of aldose binding and specificity and the catalytic mechanism of ARs. Database Structural data are available in the PDB under the accession numbers http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZCI and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZCM.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

2018

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“…The X-ray structure of human AKR1B1 in complex with D-glyceraldehyde and the NADP cofactor (PDB code 3V36) [54], as well as the co-crystal structure of human AKR1B1 in complex with a nitrofuryl-oxadiazol inhibitor (PDB code 2IKH) [55], were downloaded from the Protein Data Bank [56]. Molecular docking calculations were performed with GOLD 5.1 (CCDC Software Ltd., Cambridge, UK) [57] using the piecewise linear potential (PLP) fitness function.…”

Section: Molecular Dockingmentioning

confidence: 99%

Aldose Reductase Differential Inhibitors in Green Tea

et al. 2020

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Aldose reductase (AKR1B1), the first enzyme in the polyol pathway, is likely involved in the onset of diabetic complications. Differential inhibition of AKR1B1 has been proposed to counteract the damaging effects linked to the activity of the enzyme while preserving its detoxifying ability. Here, we show that epigallocatechin gallate (EGCG), one of the most representative catechins present in green tea, acts as a differential inhibitor of human recombinant AKR1B1. A kinetic analysis of EGCG, and of its components, gallic acid (GA) and epigallocatechin (EGC) as inhibitors of the reduction of L-idose, 4-hydroxy2,3-nonenal (HNE), and 3-glutathionyl l-4-dihydroxynonanal (GSHNE) revealed for the compounds a different model of inhibition toward the different substrates. While EGCG preferentially inhibited L-idose and GSHNE reduction with respect to HNE, gallic acid, which was still active in inhibiting the reduction of the sugar, was less active in inhibiting HNE and GSHNE reduction. EGC was found to be less efficient as an inhibitor of AKR1B1 and devoid of any differential inhibitory action. A computational study defined different interactive modes for the three substrates on the AKR1B1 active site and suggested a rationale for the observed differential inhibition. A chromatographic fractionation of an alcoholic green tea extract revealed that, besides EGCG and GA, other components may exhibit the differential inhibition of AKR1B1.

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“…The beneficial effect of ALR-inhibitors in preventing diabetic complications provides strong support to the hypothesis that ALR1 and ALR2 inhibition could be an effective strategy in the prevention or delay of diabetic cataract. However, several ALR inhibitor studies are inconsistent with observations found in experimental animals and also in clinical trials to assess efficacy against various diabetic complications 22,79,80 . Interestingly, our in silico docking analysis shows that vitamin K1 competitively binds in both ALR1 and ALR2 and this binding site overlaps ~50% of the NADPH binding site.…”

Section: Discussionmentioning

confidence: 97%

Vitamin K1 prevents diabetic cataract by inhibiting lens aldose reductase 2 (ALR2) activity

Raman

Varsha

Srinivasan

et al. 2019

Sci Rep

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This study investigated the potential of vitamin K1 as a novel lens aldose reductase inhibitor in a streptozotocin-induced diabetic cataract model. A single, intraperitoneal injection of streptozotocin (STZ) (35 mg/kg) resulted in hyperglycemia, activation of lens aldose reductase 2 (ALR2) and accumulation of sorbitol in eye lens which could have contributed to diabetic cataract formation. However, when diabetic rats were treated with vitamin K1 (5 mg/kg, sc, twice a week) it resulted in lowering of blood glucose and inhibition of lens aldose reductase activity because of which there was a corresponding decrease in lens sorbitol accumulation. These results suggest that vitamin K1 is a potent inhibitor of lens aldose reductase enzyme and we made an attempt to understand the nature of this inhibition using crude lens homogenate as well as recombinant human aldose reductase enzyme. Our results from protein docking and spectrofluorimetric analyses clearly show that vitamin K1 is a potent inhibitor of ALR2 and this inhibition is primarily mediated by the blockage of DL-glyceraldehyde binding to ALR2. At the same time docking also suggests that vitamin K1 overlaps at the NADPH binding site of ALR2, which probably shows that vitamin K1 could possibly bind both these sites in the enzyme. Another deduction that we can derive from the experiments performed with pure protein is that ALR2 has three levels of affinity, first for NADPH, second for vitamin K1 and third for the substrate DL-glyceraldehyde. This was evident based on the dose-dependency experiments performed with both NADPH and DL-glyceraldehyde. Overall, our study shows the potential of vitamin K1 as an ALR2 inhibitor which primarily blocks enzyme activity by inhibiting substrate interaction of the enzyme. Further structural studies are needed to fully comprehend the exact nature of binding and inhibition of ALR2 by vitamin K1 that could open up possibilities of its therapeutic application.

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Partial Inhibition of Aldose Reductase by Nitazoxanide and Its Molecular Basis

Cited by 22 publications

References 14 publications

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

Aldose Reductase Differential Inhibitors in Green Tea

Vitamin K1 prevents diabetic cataract by inhibiting lens aldose reductase 2 (ALR2) activity

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