Phenylketonuria: an inborn error of phenylalanine metabolism

Abstract

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU and hyperphenylalaninaemia (HPA) are caused by mutations in the PAH gene on chromosome 12q23.2. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. A better understanding of the biochemistry, genetics and molecular basis of PKU, as well as the need for improved treatment options, has led to the development of new therapeutic strategies.

Figure 1

Phe metabolism in humans. Intake of l-Phe is via the diet and it is recycled through amino acid pools. Hydroxylation by PAH with its cofactor BH₄, in the presence of molecular O₂, produces L-Tyr. Alternative metabolism of L-Phe by decarboxylation or transamination produces various metabolites which are excreted in urine. Based on Scriver CR and Kaufman S (2001).

Figure 2

Conversion of Phe to Tyr is via a pathway involving the para-hydroxylation of the benzene by PAH, the cofactor BH₄ and molecular oxygen.

Figure 3

The domain structure of PAH. Each PAH subunit is classified into three functional domains which are involved with regulation, catalytic activity, and subunit binding. Reprinted from Molecular Genetics and Metabolism, 68, Erlandsen H and Stevens RC, The structural basis of phenylketonuria, 103–25, Copyright (1999), with permission from Elsevier.

Figure 4

Structural components of PAH. The catalytic domain of PAH contains a motif of 26 or 27 amino acids which are responsible for ferric iron and cofactor (BH₄) binding. Adapted from Huften IG et al (1995).

Figure 5

The basic structure of the human PAH gene. Found on the long arm of chromosome 12 (12q23.2), the human PAH gene contains 13 exons which encode a polypeptide of 452 amino acids.