Functional studies drive treatment of phenylketonuria to become personalized

Background: Phenylketonuria(PKU) is the most common inborn error of amino acid metabolism. PKU is due to defects in enzyme phenylalanine hydroxylase (PAH) that converts phenylalanine (Phe) to tyrosine. When given as a treatment, PAH chaperone tetrahydrobiopterin (BH4) corrects the biochemical phenotype in patients with milder forms of the disease also known as BH4 responsive PAH-deficiency. A significant gap of knowledge concerns the enzymatic function associated with PAH genotypes, which are often found in compound heterozygous state. Methods: Improvedactivity landscapes method was used to
determine PAH function in a cell model as a result of 100 most common PAH genotypes. Results: Depicting enzyme activity of variant PAH proteins as activity landscapes allows for the determination of the optimal working range of the protein in the functional metabolic and therapeutic context. The binding of the pharmacological chaperone BH4 depends on the patient’s Phe concentration. Using improved PAH activity landscapes method, the most frequent PAH genotypes were performed as 3D images that visualize behavior
of misfolded protein in a gradient of BH4 and Phe concentrations. Discussion: Using only the standard protocol for BH4-loading test disregarding the patient’s PAH genotype may lead to false negative testing results. Therefore, there is a need for employing a holistic approach that would guide pediatricians to personalize BH4-loading tests and dietary treatment schemes.The information resulting from PAH activity landscapes will allow to avoid false negative test results and create individualized treatment regimens.