Phenylalanine metabolism — identifying a more toxic metabolite In disorders of phenylalanine metabolism (e.g., phenylketonuria), accumulation of which compound is considered particularly toxic to the nervous system?

Introduction / Context:
Phenylketonuria (PKU) is characterized by deficient phenylalanine hydroxylase activity, leading to the accumulation of phenylalanine and its alternative transamination products. Among these, phenylpyruvate and related metabolites (phenyllactate, phenylacetate) contribute significantly to neurotoxicity and the classic “mousy” odor. Recognizing the most problematic metabolite aids in understanding pathophysiology and rationale for dietary therapy.

Given Data / Assumptions:

• PKU diverts phenylalanine toward transamination producing phenylpyruvate.
• Elevated phenylketones interfere with brain development and neurotransmitter balance.
• Tyrosine becomes conditionally essential in PKU management.

Concept / Approach:

Although high phenylalanine is harmful, the keto acid phenylpyruvate and its derivatives are particularly implicated in neurotoxicity. These compounds disrupt myelination and neurotransmitter synthesis and can be detected in urine (“phenylketones”). Therefore, phenylpyruvate is the best answer when asked to identify the most toxic compound among common choices.

Step-by-Step Solution:

Verification / Alternative check:

Clinical testing reveals elevated urinary phenylketones; dietary restriction of phenylalanine reduces phenylpyruvate levels and improves outcomes, corroborating its central role.

Why Other Options Are Wrong:

Tyrosine is a downstream product and therapeutic supplement in PKU; lysine is unrelated; phenylalanine is elevated but the question asks for the most toxic compound among listed, highlighting phenylpyruvate; acetoacetate is a ketone body not specific to PKU toxicity.

Common Pitfalls:

Equating the highest concentration (phenylalanine) with the principal toxin without considering metabolite potency.

Final Answer:

Phenylpyruvate