In silico analyses of the enzymatic activity decrease of mutant phenylalanine hydroxylase and the chaperone effect of its inhibitor

Abstract

Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to the reduction in enzymatic activity of phenylalanine hydroxylase (PAH) caused by mutations. In recent years, small compounds that recover the enzymatic activity of mutant PAHs, pharmacological chaperone (PhC), have been reported. These compounds are expected to have potential for novel therapeutic agent for PKU treatment. For the molecular design of more effective PhC drugs, it is important to understand the mechanisms of the reduction in enzymatic activity by mutation and its restoration by PhC binding. In the present study, these mechanisms were investigated using molecular dynamics simulation. As a results, it was shown that the thermal motion of the PAH active site is increased by the mutation. The results suggest that the reduction in the enzymatic activity is caused by the increment of the thermal motion of the active site due to mutation.　 In addition, it was shown that the enzymatic activity of mutant PAH is recovered by stabilization of the thermal motion of the active site by PhC binding.