In Vitro and In Vivo Chaperone Effect of (R)-2-amino-6-(1R,...

Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme of serotonin (5-HT) synthesis in the mammalian brain. The 1473G mutation in the Tph2 gene decreases TPH2 activity in the mouse brain by twofold. (R)-2-amino-6-(1R, 2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydropterin-4(3H)-one (BH₄) is a pharmacological chaperone for aromatic amino acid hydroxylases. In the present study, chaperone effects of BH₄ on the mutant C1473G TPH2 were investigated in vitro and in vivo. In vitro BH₄ increased the thermal stability (T₅₀ value) of mutant and wild-type TPH2 molecules. At the same time, neither chronic (twice per day for 7 days) intraperitoneal injection of 48.3 mg/kg of BH₄ nor a single intraventricular administration of 60 μg of the drug altered the mutant TPH2 activity in the brain of Balb/c mice. This result indicates that although BH₄ shows a chaperone effect in vitro, it is unable to increase the activity of mutant TPH2 in vivo.