phenylalanine hydroxylase

Phenylalanine hydroxylase catalyzes the irreversible hydroxylation of phenylalanine to tyrosine in the liver, a key step in amino acid catabolism. This reaction requires molecular oxygen and the cofactor tetrahydrobiopterin (BH4), which is regenerated by dihydropteridine reductase (DHPR). Deficiency of PAH (classic PKU) or, less commonly, deficiency of BH4 synthesis/regeneration enzymes (malignant PKU/hyperphenylalaninemia) results in elevated blood phenylalanine levels. Excess phenylalanine is toxic to the CNS, competitively inhibiting neutral amino acid transport across the blood-brain barrier and impairing myelin synthesis and neurotransmitter production (dopamine, serotonin, norepinephrine). Clinically, untreated PKU presents with severe intellectual disability, seizures, hypopigmentation (due to decreased melanin from tyrosine deficiency), eczema, and a characteristic musty/mousy body odor from phenylacetate excretion. Since tyrosine becomes an essential amino acid in PAH deficiency, and tyrosine is a precursor for melanin, catecholamines, and thyroid hormones, deficiencies in these pathways contribute to the phenotype. Diagnosis is made via newborn screening (elevated phenylalanine, normal/low tyrosine) and confirmed with genetic testing (PAH gene mutations on chromosome 12q). Management involves lifelong dietary restriction of phenylalanine (avoiding high-protein foods and artificial sweeteners containing aspartame) and tyrosine supplementation. Maternal PKU is a critical concept: women with PKU who are not on strict dietary control during pregnancy risk fetal effects including microcephaly, congenital heart defects, and intellectual disability due to teratogenic effects of high phenylalanine crossing the placenta, even if the fetus does not have PKU itself. This distinguishes it from other inborn errors of metabolism and is a classic board question. Sapropterin (synthetic BH4) can be used in some BH4-responsive PAH deficient patients to enhance residual enzyme activity.