Therapeutic targets for phenylketonuria (PKU)

Phenylketonuria (PKU) is a rare, loss-of-function, inborn error of metabolism. It is a chronic amino acid transport disorder caused by a heritable mutation that results in decreased metabolism of the essential amino acid phenylalanine (Phe). It is a common genetic disorder that arises from deficient activity of phenylalanine-4-hydroxylase (phenylalanine hydroxylase; PAH), the rate-limiting enzyme of the metabolic pathway that degrades Phe to tyrosine. The disorder is caused by mutations in the PAH gene, which encodes for the enzyme PAH. The majority of PKU-causing mutations in PAH are missense mutations. The current mainstay of treatment is lifelong dietary modification, including restriction of Phe and tyrosine supplementation. However, because the diet is so restrictive, adherence is extremely difficult. Further investigation is needed to find agents that may activate or act as a chaperone for PAH. This article presents those drug targets that are currently under active investigation for the treatment of PKU.