Sapropterin dihydrochloride, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, in the treatment of phenylketonuria.

Sapropterin dihydrochloride, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is being introduced in the US for treatment of phenylketonuria (PKU). This compound has been in use in Europe to treat mild forms of PKU. Tetrahydrobiopterin is the cofactor in the hydroxylation reaction of the three aromatic amino acids phenylalanine, tyrosine and tryptophan. It is also involved in other reactions, which are not the focus of this review. The cofactor BH4 is synthesized in many tissues in the body. The pathway of BH4 biosynthesis is complex, and begins with guanosine triphosphate (GTP). The first reaction that commits GTP to form pterins is GTP cyclohydrolase. Several reactions follow resulting in the active cofactor BH4. During the hydroxylation reaction BH4 is oxidized to quinonoid-BH2, which is recycled by dihydropteridine reductase, resulting in the active cofactor. It was discovered that some patients with PKU had a decline in blood phenylalanine after oral intake of BH4. This response to BH4 is not the result of change in the synthesis or regeneration of the cofactor, but rather an effect on the mutant enzyme phenylalanine hydroxylase either by accommodating the higher K(m) of the mutant enzyme or by acting as a chaperone for the mutant enzyme. This response has become of intense interest in the treatment of PKU.