Mutations in the phenylalanine hydroxylase (PAH) gene cause PAH deficiency with various phenotypes. A new hyperphenylalaninemia phenotype showing responsiveness to pharmacological doses of tetrahydrobiopterin (BH4) was recently discovered. We investigated the specific consequences of mutations in the PAH gene on structure and function of recombinant variant PAH proteins derived from mutations identified in patients with BH4 responsiveness. The analysis of the oligomeric state of variant PAH revealed various patterns ranging from wildtype to a complete loss of functional tetramers. Kinetic studies showed that PAH mutations can exert an effect on all kinetic properties of the enzyme even if not mapping to the catalytic domain. In contrast to previous assumptions, affinity to the cofactor was only mildly affected. Moreover, some proteins showed reduced stability when degraded by a misfolding-sensitive protease and/or upon thermal inactivation. Taken together, this data indicates that single PAH mutations lead to specific patterns of altered protein structure and function. Our results are in line with the hypothesis of phenylketonuria being a model disease for protein folding defects.
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