hydroxylasesphenylalanine

Hydroxylases that act on phenylalanine, commonly referred to as phenylalanine hydroxylases, are enzymes that catalyze the hydroxylation of phenylalanine to tyrosine. The best characterized member is phenylalanine hydroxylase (PAH), a liver enzyme that uses tetrahydrobiopterin (BH4) as a cofactor and molecular oxygen to convert phenylalanine into tyrosine.

In the reaction, phenylalanine combines with oxygen, and BH4 is oxidized to dihydrobiopterin (BH2). The regenerated BH4 is supplied by dihydropteridine reductase, allowing the cycle to continue. PAH is a cytosolic homotetramer and belongs to the aromatic amino acid hydroxylase family of nonheme iron enzymes, sharing a common mechanism and iron cofactor with related enzymes such as tyrosine hydroxylase and tryptophan hydroxylase.

Genetically, the PAH gene is located on chromosome 12 in humans. Pathogenic variants in PAH cause phenylketonuria (PKU), an inherited autosomal recessive disorder characterized by elevated phenylalanine levels, which can lead to neurodevelopmental impairment if untreated. Newborn screening programs detect high phenylalanine concentrations, enabling early intervention.

Treatment and management focus on controlling phenylalanine intake. Many patients benefit from a phenylalanine-restricted diet, and those with some residual PAH activity may respond to sapropterin dihydrochloride (a synthetic form of BH4) to enhance enzyme function. PAH serves as a central example of how a single enzyme coordinates amino acid metabolism with dietary and developmental outcomes. Related enzymes in the same family illustrate conserved catalytic strategies while acting on different substrates.