L- PHE-TREATMENT OF ENU1/2 MICE LEADS TO STIMULATION  OF TETRAHYDROBIOPTERIN SYNTHESIS, PROBABLY  THROUGH GTPCH-GFRP MEDIATED ACTION, WITH  CONCOMITANT REDUCTION IN UBIQUITINATION  OF MUTANT PAH, AND INCREASE IN PAH Phenylketonuria is caused by a deficient activity of human phenylalanine hydroxylase (hPAH). This protein has been regarded as a highly unstable enzyme, fact postulated to be responsible for the lack of the full-length hPAH 3D structure. We aimed to obtain hPAH mutant chimerical forms presenting a higher activity and stability. Firstly, the hPAH mutants C29D, C29S, C284S, C445S, D145K, D151K, E181K and E360K, were produced in a prokaryotic expression system. Due to their higher expression level the C29S and E360K proteins were selected for further characterization regarding the oligomeric profile, enzyme kinetics, substrate activation and thermal inactivation. When compared to the hPAHwt, the E360K presented a higher degree of aggregates. The C29S showed an increase in catalytic activity (1.3-fold) Results: GLM analyses of variance showed that PKU patients with lifetime Phe<=240 μmol/l outperformed patients with Phe >240 μmol/l. When patients with Phe<=360 μmol/l were compared to those with Phe >360 μmol/l, fewer and less pronounced differences were observed. Compared to controls, patients with Phe<=240 μmol/l performed comparable on all tests, which was not true for patients with Phe<=360 μmol/l. Discussion: When inhibitory control and working memory were required simultaneously, average Phe concentrations of<=240 μmol/l were advantageous compared to<=360 μmol/l, urging consideration of lowering the upper target Phe to 240 μmol/l during the first 12 years of life.