A Proposal for Mitochondrial Processing Peptidase Catalytic Mechanism

The reaction mechanism of the MitochondrialProcessing Peptidase enzyme (MPP) was investigated by usinghybrid density functional theory. This enzyme removes theNH2-terminal targeting signals of nuclear-encoded mitochondrialprotein precursors in the mitochondrial matrix. Thecatalytic process was studied using a model for the active siteconsisting of 161 atoms locating all the stationary points on the potential energy curve and determining the main energetic,structural, and electronic features that drive the catalysis. Despite the differences between the B3LYP and MPWB1K descriptions, itis possible hypothesize that the rate-limiting step of the reaction is most likely the nucleophilic attack of zinc-bound hydroxide to acarbonyl carbon of the substrate. The results allowed assignment of the proper roles to some active site residues in this mechanism