Phenylketonuria (PKU): In classical PKU due to phenylalanine hydroxylase deficiency, which aberrant metabolite is formed from phenylalanine?

Introduction / Context:
Phenylketonuria (PKU) is a classic inborn error of metabolism characterized by deficient phenylalanine hydroxylase (or its cofactor tetrahydrobiopterin in some variants). Without conversion of phenylalanine to tyrosine, excess phenylalanine is shunted into alternative pathways, producing phenylketones that can be detected in urine and contribute to neurotoxicity if untreated.

Given Data / Assumptions:

• Phenylalanine hydroxylase normally converts phenylalanine to tyrosine.
• In PKU, this primary route is blocked.
• Alternate transamination of phenylalanine generates phenylpyruvate, which can be further reduced or decarboxylated to phenyllactate and phenylacetate.

Concept / Approach:
Identify the metabolic detour that occurs when the primary hydroxylation step is impaired. The amino group of phenylalanine is transferred to alpha-ketoglutarate, forming phenylpyruvate and glutamate via an aminotransferase. Elevated phenylalanine and its keto-acid derivatives are typical laboratory findings in untreated PKU, explaining the term phenylketonuria (phenyl ketones in urine).

Step-by-Step Solution:

Verification / Alternative check:
Newborn screening measures elevated phenylalanine; urinary analysis may reveal phenylketones. Dietary restriction of phenylalanine and tyrosine supplementation improve outcomes, confirming pathway logic.

Why Other Options Are Wrong:

• Isoleucine formation from phenylalanine does not occur.
• Reverse reactions listed are not physiologic.
• Phenylalanine → tyrosine is the normal (defective) step, not the aberrant product in PKU.

Common Pitfalls:
Confusing classical PAH deficiency with BH4 deficiency; both elevate phenylalanine, but the core detour to phenylpyruvate remains a defining biochemical feature.

Final Answer:
Phenylalanine to phenylpyruvate