Phenylalanine 4-monooxygenase (PAH)

Phenylalanine 4-monooxygenase (PAH) is a rate-limiting hepatic enzyme responsible for the conversion of the essential amino acid L-phenylalanine to L-tyrosine using tetrahydrobiopterin (BH4) as a cofactor (UniProt P00439). This metabolic pathway is the primary route for phenylalanine disposal, and its impairment leads to the accumulation of phenylalanine in the blood and brain, a condition known as Phenylketonuria (PKU) (StatPearls, NBK535378). If untreated, the resulting hyperphenylalaninemia causes severe intellectual disability, seizures, and behavioral problems (NIH Genetics Home Reference). Therapeutic strategies targeting PAH include the use of Sapropterin dihydrochloride, a synthetic form of the BH4 cofactor that acts as a pharmacological chaperone to stabilize misfolded PAH variants and enhance residual enzymatic activity (FDA, Kuvan Label). For patients with complete enzyme deficiency, enzyme substitution therapies like Pegvaliase utilize a non-mammalian phenylalanine ammonia-lyase to reduce phenylalanine levels, bypassing the defective PAH enzyme entirely (PubMed, 29753764).

Other names

Phenylalanine hydroxylasePheHPH

Pharmacological chaperone that stabilizes the enzyme and enhances residual activity; or enzyme substitution therapy to degrade phenylalanine independently of the native enzyme.