Which enzyme is deficient in phenylketonuria (PKU), leading to accumulation of phenylalanine and its metabolites?

Explanation

## Enzyme Deficiency in Phenylketonuria **Key Point:** Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of the enzyme **phenylalanine hydroxylase (PAH)**, which catalyzes the conversion of phenylalanine to tyrosine. ### Biochemical Consequence Phenylalanine hydroxylase requires the cofactor **tetrahydrofolate (BH₄)** for its catalytic activity. When this enzyme is deficient or absent: 1. Phenylalanine accumulates in blood and urine (hyperphenylalaninemia) 2. Phenylalanine is metabolized via alternative pathways to form: - Phenylpyruvate (transamination) - Phenyllactate (reduction) - Phenylacetate (oxidation) 3. These metabolites impart a characteristic "musty" or "mousy" odor to urine ### Clinical Significance **High-Yield:** PKU is screened at birth in most developed countries (Guthrie test or tandem mass spectrometry). Early diagnosis and dietary restriction of phenylalanine prevents intellectual disability, light skin pigmentation, and eczema. **Clinical Pearl:** Tyrosine becomes a conditionally essential amino acid in PKU patients because it cannot be synthesized from phenylalanine; dietary supplementation is required. ### Pathophysiology of Neurological Damage Accumulated phenylalanine and its metabolites: - Inhibit transport of other large neutral amino acids across the blood-brain barrier - Interfere with myelin formation - Reduce dopamine and serotonin synthesis (tyrosine is the precursor) - Cause seizures, behavioral problems, and developmental delay if untreated