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How does a defect in phenylalanine hydroxylase cause phenylketonuria?
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Metabolomics
In anabolic reactions, a cell uses energy to combine small molecules into larger molecules. In catabolic reactions, molecules are broken down, and energy is released.
In phenylketonuria (PKU), a defect in the enzyme phenylalanine hydroxylase renders it inactive, preventing the normal metabolic conversion of the amino acid phenylalanine into tyrosine.12
This metabolic block leads to the following consequences:
- Accumulation: Abnormally high levels of phenylalanine build up in the blood, urine, and cerebrospinal fluid.1
- Metabolic Interference: The excess phenylalanine and its abnormal breakdown products, such as ketone compounds, interfere with central nervous system processes. This disrupts the production of essential neurotransmitters like dopamine, leading to nerve cell damage, cognitive dysfunction, and seizures.1
- Pigmentation Changes: Because tyrosine is a precursor to melanin, the inability to produce it often results in reduced pigmentation, typically manifesting as fair skin, blue eyes, and blond hair.1
In some cases, the disorder is caused by a deficiency in tetrahydrobiopterin, a cofactor required for the enzyme to function correctly.1