Classic PKU (phenylalanine hydroxylase deficiency) causes intellectual disability when untreated. Sapropterin (BH4 — tetrahydrobiopterin) therapy benefits ~25% of PKU patients. What is the molecular basis for this selective BH4 responsiveness?

• A BH4 induces PAH gene transcription via a sterol-response element
• B BH4 is a direct substrate for the residual PAH enzyme; patients with partial-activity missense mutations have sufficient residual enzyme that is stabilized/activated by pharmacological BH4 doses ✓
• C BH4 acts as a cofactor for dihydrobiopterin reductase, the real deficient enzyme in these patients
• D BH4 competitively inhibits the phenylalanine transporter, reducing phenylalanine influx into neurons

Explanation

Phenylalanine hydroxylase requires BH4 as an obligate cofactor. In BH4-responsive PKU, patients carry missense mutations that produce PAH protein with significantly reduced affinity for BH4 (increased Km) but not absent activity. Pharmacological doses of oral sapropterin (synthetic BH4) saturate this kinetically impaired enzyme, restoring enough activity to metabolize phenylalanine. This is a pharmacological chaperone/cofactor supplementation strategy. Patients with null mutations (no protein) do not respond. BH4 deficiency itself (from DHPR or GTP cyclohydrolase defects) causes malignant PKU unresponsive to phenylalanine restriction alone.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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