7-Substituted pterins: formation during phenylalanine hydroxylation in the absence of dehydratase

Previously we described a new form of human hyperphenylalaninemia characterized by the formation of 7-substituted pterins. We present evidence strongly suggesting that the 7-substituted pterins are formed by rearrangement of 6-substituted pterins. This rearrangement occurs during the phenylalanine hydroxylase reaction cycle which normally involves the enzymes phenylalanine hydroxylase, pterin-4a-OH-dehydratase, and q-dihydropterin reductase, specifically in the absence of dehydratase activity. We conclude that formation of 7-substituted pterins in humans is a consequence of an absence of dehydratase activity, which might result from a genetic defect. A chemical mechanism for this rearrangement is presented. Our results also suggest that tetrahydroneopterin can be a cofactor for the phenylalanine hydroxylase system in vivo.