ao7b00815_si_001.pdf (554.73 kB)
New Insights into the Catalytic Mechanism of Aldose Reductase: A QM/MM Study
journal contribution
posted on 2017-09-13, 17:39 authored by Marie-Pierre Dréanic, Colin M. Edge, Tell TuttleAldose reductase is the first enzyme
of the polyol pathway in which
glucose is converted to fructose via sorbitol. The understanding of
this key enzyme is important as it has been linked to some diabetes
mellitus complications. The mechanism of the enzyme was investigated
using a hybrid quantum mechanics/molecular mechanics (QM/MM) method.
It was found that depending on the protonation state of His110 the
mechanism can be concerted or stepwise and the proton donor can be
either Tyr48 or His110. These findings are different from the previous
theoretical studies based on QM/MM calculations using either AM1 or
HF/4-31G, in which the reduction is, respectively, a stepwise or one-step
process. The QM/MM energy barriers for the reduction of d-glyceraldehyde were evaluated at a B3LYP/6-31G* level for both HIP
and HIE protonation states of His110. These were, respectively, 6.5
± 2.2 and 16.7 ± 1.0 kcal/mol, which makes only the HIE
protonation state consistent with the experimental value of 14.8 kcal/mol
derived from kinetics experiments and makes Tyr48 the most probable
proton donor.