%0 Journal Article %1 hlwoodcock:S.1998 %A Lee, Y. S. %A Hodoscek, M. %A Brooks, B. R. %A Kador, P. F. %D 1998 %J Biophysical Chemistry %K bernie inhibition mechanism nadph enzyme complications tyrosine-48 dynamics mutagenesis crystal-structure active-site diabetic catalytic qmmm mutant aldehyde reductase combined simulations proton site-directed aldose potentials donor binding %N 3 %P 203--216 %T Catalytic mechanism of aldose reductase studied by the combined potentials of quantum mechanics and molecular mechanics %V 70 %X The catalytic reduction of D-glyceraldehyde to glycerol by aldose reductase has been investigated with the combined potentials of quantum mechanics (QM) and molecular mechanics (MM) to resolve the question of whether Tyr48 or His110 serves as the proton donor during catalysis. Site directed mutagenesis studies favor Tyr48 as the proton donor while the presence of a water channel linking the N delta 1 of His110 to the bulk solvent suggests that His110 is the proton donor. Utilizing the combined potentials of QM and MM, the binding mode of substrate D-glyceraldehyde was investigated by optimizing the local geometry of Asp43, Lys77, Tyr48, His110 and NADPH at the active site of aldose reductase. Reaction pathways for the reduction of D-glyceraldehyde to glycerol were then constructed by treating both Tyr48 and His110 as proton donors. Comparison of energetics obtained from the reaction pathways suggests His110 to be the proton donor. Based on these findings, a reduction mechanism of D-glyceraldehyde to glycerol is described. (C) 1998 Elsevier Science B.V.

@article{hlwoodcock:S.1998, abstract = {The catalytic reduction of D-glyceraldehyde to glycerol by aldose reductase has been investigated with the combined potentials of quantum mechanics (QM) and molecular mechanics (MM) to resolve the question of whether Tyr48 or His110 serves as the proton donor during catalysis. Site directed mutagenesis studies favor Tyr48 as the proton donor while the presence of a water channel linking the N delta 1 of His110 to the bulk solvent suggests that His110 is the proton donor. Utilizing the combined potentials of QM and MM, the binding mode of substrate D-glyceraldehyde was investigated by optimizing the local geometry of Asp43, Lys77, Tyr48, His110 and NADPH at the active site of aldose reductase. Reaction pathways for the reduction of D-glyceraldehyde to glycerol were then constructed by treating both Tyr48 and His110 as proton donors. Comparison of energetics obtained from the reaction pathways suggests His110 to be the proton donor. Based on these findings, a reduction mechanism of D-glyceraldehyde to glycerol is described. (C) 1998 Elsevier Science B.V.}, added-at = {2006-06-16T05:03:46.000+0200}, author = {Lee, Y. S. and Hodoscek, M. and Brooks, B. R. and Kador, P. F.}, biburl = {https://www.bibsonomy.org/bibtex/24446f182d4c19ffd76168dbc8293b69b/hlwoodcock}, citeulike-article-id = {569335}, comment = {ZD310 BIOPHYS CHEM}, interhash = {ff3e21551815235a8bb3668256267594}, intrahash = {4446f182d4c19ffd76168dbc8293b69b}, journal = {Biophysical Chemistry}, keywords = {bernie inhibition mechanism nadph enzyme complications tyrosine-48 dynamics mutagenesis crystal-structure active-site diabetic catalytic qmmm mutant aldehyde reductase combined simulations proton site-directed aldose potentials donor binding}, number = 3, pages = {203--216}, priority = {2}, timestamp = {2006-06-16T05:03:46.000+0200}, title = {Catalytic mechanism of aldose reductase studied by the combined potentials of quantum mechanics and molecular mechanics}, volume = 70, year = 1998 }