Enzyme kinetics: Phenylalanine hydroxylase and phenylketonuria

Phenylalanine hydroxylase (PAH) is the rate-limiting enzyme of the phenylalanine metabolic pathway. Phenylalanine hydroxylase catalyzes the hydroxylation of the aromatic ring of phenylalanine, converting it to tyrosine, as shown in Figure 1. The PAH enzyme requires two cofactors - tetrahydrobiopterin (BH${}_4$‍) and iron - to function.

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

Phenylketonuria (PKU) is an autosomal recessive genetic disorder that results from an inactivating mutation in the gene coding for PAH - the most common of which replaces cytosine (C) with adenine (A) at position 742 in the gene sequence. An alternate form of PKU results from a deficiency in the cofactor tetrahydrobiopterin. Those with PKU are unable to metabolize phenylalanine and convert it to 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, behavior 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.