Model of the catalytic mechanism of human aldose reductase based on quantum chemical calculations

Aldose Reductase is an enzyme involved in diabetic complications, thoroughl y studied for the purpose of inhibitor development. The structure of an enz yme-inhibitor complex solved at sub-atomic resolution has been used to deve lop a model for the catalytic mechanism. This model has been refined using a combination of Molecular Dynamics and Quantum calculations. It shows that the proton donation, the subject of previous controversies, is the combine d effect of three residues: Lys 77, Tyr 48 and His 110. Lys 77 polarises th e Tyr 48 OH group, which donates the proton to His 110, which becomes doubl y protonated. His 110 then moves and donates the proton to the substrate. T he key information from the sub-atomic resolution structure is the orientat ion of the ring and the single protonation of the His 110 in the enzyme-inh ibitor complex. This model is in full agreement with all available experime ntal data.