Structure of Aldehyde Reductase Holoenzyme in Complex with the Potent Aldose Reductase Inhibitor Fidarestat:  Implications for Inhibitor Binding and Selectivity

Aldose reductase and aldehyde reductase belong to the aldo-keto reductase superfamily of enzymes whose members are responsible for a wide variety of biological functions. Aldose reductase has been identified as the first enzyme involved in the polyol pathway of glucose metabolism which converts glucose into sorbitol. Glucose over-utilization through the polyol pathway has been linked to tissue-based pathologies associated with diabetes complications, which make the development of a potent aldose reductase inhibitor an obvious and attractive strategy to prevent or delay the onset and progression of the complications. Structural studies of aldose reductase and the homologous aldehyde reductase in complex with inhibitor were carried out to explain the difference in the potency of enzyme inhibition. The aim of this review is to provide a comprehensive summary of previous studies to aid the development of aldose reductase inhibitors that may have less toxicity problems than the currently available ones.

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“…Fidarestat binds to the active site of ALR1 with its cyclic imide moiety anchored in the anion-binding site [43] (Fig. 3).…”

Section: Structure Of the Alr1/fidarestat Complexmentioning

confidence: 99%

Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites

El‐Kabbani

Podjarny

2007

Cell. Mol. Life Sci.

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“…A full geometry optimization was carried out at the Hartree-Fock/6-31G* level using GAMESS [43]. Optimization was started from standard CHARMM [39][40][41] values for the internal coordinates and the crystal structure geometry for each of the isomers of fidarestat [29][30][31][32][33]. Geometrical convergence was obtained after 43 cycles of optimization with a final gradient of 0.214×10 -3 Hartree/Bohr.…”

Section: Partial Charge and Force Constant Calculation For Fidarestatmentioning

confidence: 99%

“…Fidarestat {(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide}, which shows higher activity and selectivity than other inhibitors, contains a carbamoyl-substituted cyclic imide-chroman system ring ( Figure 1) [29][30][31]. The structures of the respective complexes with ALR2 suggest that alteration of the interactions between the cyclic imide rings and carbamoyl groups of the substrate with residues Trp20, Val47, Tyr48, Trp79, His110, Trp111, Phe122, Trp219, Cys298, Ala299 and Leu300 could account for differences in their inhibitory potencies (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Binding of Fidarestat Stereoisomers with Aldose Reductase

Kim

Hong

Lee

2006

IJMS

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Abstract:The stereospecificity in binding to aldose reductase (ALR2) of two fidarestat {6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide} stereoisomers [(2S,4S) and (2R,4S)] has been investigated by means of molecular dynamics simulations using free energy integration techniques. The difference in the free energy of binding was found to be 2.0 ± 1.7 kJ/mol in favour of the (2S,4S)-form, in agreement with the experimental inhibition data. The relative mobilities of the fidarestats complexed with ALR2 indicate a larger entropic penalty for hydrophobic binding of (2R,4S)-fidarestat compared to (2S,4S)-fidarestat, partially explaining its lower binding affinity. The two stereoisomers differ mainly in the orientation of the carbamoyl moiety with respect to the active site and rotation of the bond joining the carbamoyl substituent to the ring. The detailed structural and energetic insights obtained from out simulations allow for a better understanding of the factors determining stereospecific inhibitor-ALR2 binding in the EPF charges model.

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“…Aldehyde reductase (ALR1; EC: 1.1.1.2) is another member of aldo-ketoreductase (AKR) family and is very similar to ALR2 in sequence, structure and reaction. ALR1 plays a role in reactive aldehyde detoxification (23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Aldose Reductase and Sorbitol Accumulation by Hydroalcoholic Extract of Propolis

Aberomand

Parvank

Mohammadzadeh

et al. 2016

Jundishapur J Nat Pharm Prod

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Background: Increased polyol pathway activity and subsequent occurrences, and particular sorbitol accumulation are noticed in the development of various secondary complications of diabetes. Aldose reductase (ALR2) or aldo-ketoreductase (AKR1B1) as the first and rate limiting enzyme of this pathway is a good target for new drugs for diabetes complications. A good inhibitor should inhibit aldehyde reductase (ALR1), the other member of this family lesser than ALR2. Bee propolis is a known substance in ancient medicine, but its effect on polyol pathway is unknown. Objectives: The current study aimed to investigate the effect of hydroalcoholic extract of propolis (HAEP) on partial purified bovine lens ALR2, also the effect of HAEP on sorbitol accumulation in human erythrocytes in high-glucose condition (ex vivo). Materials and Methods: Total protein was determined by lowery method. Bovine lens ALR2 was partially purified by gel filtration chromatography on sephadexTM G25. Bovine cortex kidney ALR1 was partially purified by diethylaminoethyl (DEAE) precipitation. The hydroalcoholic extract was obtained from frozen propolis. The enzyme activity and sorbitol accumulation in erythrocytes were determined spectroflourimetrically. Results: It was found that ethyl acetate (EthAc) fraction (the more potent fraction) of HAEP inhibited ALR2 by IC50 value of 1.12 mg/mL up to 50% and this fraction can inhibit ALR2 8.25-fold greater than ALR1. In addition, it was found that this fraction could decrease sorbitol accumulation in human erythrocytes under high-glucose condition. Conclusions:The obtained results indicated that propolis may be a good candidate for more studies to find new drugs for the treatment of secondary complications of diabetes.

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Structure of Aldehyde Reductase Holoenzyme in Complex with the Potent Aldose Reductase Inhibitor Fidarestat: Implications for Inhibitor Binding and Selectivity

Cited by 76 publications

References 63 publications

Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites

Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites

Binding of Fidarestat Stereoisomers with Aldose Reductase

Inhibition of Aldose Reductase and Sorbitol Accumulation by Hydroalcoholic Extract of Propolis

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