Publication
Title
Aldose reductase as a target for drug design : molecular modeling calculations on the binding of acyclic sugar substrates to the enzyme
Author
Abstract
In an attempt to obtain a picture of the binding conformation of aldehyde substrates to human aldose reductase (hAR), modeling calculations have been performed on the binding of three substrate, D-xylose, L-xylose, and D-lyxose, to wild-type human aldose reductase and two of its site-directed mutants, It was found that the average geometry of D-xylose in the active site of wild-type aldose reductase is characterized by strong hydrogen bonds involving the reactive carbonyl oxygen of the substrate and both Tyr48 and His110. The calculations also suggest the importance of Trp111 in the binding of 2'-hydroxyl-containing aldehyde substrates. A good correlation between calculated interaction enthalpies and experimental log(K-m) or log(k(cat)/K-m) values was obtained when His110 was modeled with its N epsilon 2 atom protonated and N delta 1 unprotonated. No correlation was found for the other two configurations of His110. On the basis of comparisons of the calculated substrate binding conformations for the three possible His110 configurations, and on the correlations between measured log(K-m) or log(k(cat)/K-m) and calculated parameters, it is proposed that His110 is neutral and protonated at N epsilon 2 when an aldehyde substrate is bound to the hAR/NADPH complex. A chain of three hydrogen-bonded water molecules has been identified in all available crystal structures and is located in an enzyme channel which links the N delta 1 atom of His110 to the solvent-accessible surface of the enzyme. A possible role of this channel in the mechanism of catalysis of aldose reductase is suggested.
Language
English
Source (journal)
Biochemistry / American Chemical Society. - Washington, D.C., 1962, currens
Publication
Washington, D.C. : 1995
ISSN
0006-2960 [print]
1520-4995 [online]
Volume/pages
34:26(1995), p. 8299-8308
ISI
A1995RH03600011
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Publication type
Subject
External links
Web of Science
Record
Identification
Creation 11.12.2013
Last edited 11.10.2017