The genetic basis of Phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive genetic disorder that results from an inactivating mutation in the gene coding for the phenylalanine hydroxylase enzyme. As a result of this mutation, those with PKU are unable to metabolize phenylalanine and convert it into tyrosine, resulting in a build-up of phenylalanine. Excess phenylalanine is then metabolized to form phenylpyruvate via the action of the enzyme phenylalanine transaminase. Without enzymes to remove phenylalanine, this amino acid can build up to dangerous levels, especially when food is consumed that is high in protein such as meat, milk, nuts, and cheese.

Left untreated, PKU can lead to serious medical problems including brain damage, behaviour problems, and seizures. Treatments include a low-protein diet supplemented with a formula containing amino acids and other essential nutrients. There have been over $300$‍ identified mutants that result in PKU, most of which are in the phenylalanine hydroxylase catalytic domain.

Phenylalanine hydroxylase is the rate-limiting enzyme of the phenylalanine metabolic pathway. Phenylalanine hydroxylase catalyzes the aromatic ring of phenylalanine, converting it to tyrosine. This enzyme requires two-cofactors, tetrahydrobiopterin (BH${}_4$‍) and iron to function (Figure 1). Another form of PKU can exist when there is a deficiency in the cofactor tetrahydrobiopterin.

Figure 1. Phenylalanine is converted to tyrosine by phenylalanine hydroxylase. Attribution: Phenylalanine hydroxylase, Overallreaction, Wikipedia.