Since, many amino acids are either neurotransmitters or precursors or antagonists of neurotransmitters, genetic defects of amino acid metabolism can cause defective neural development and mental retardation. Phenylalanine hydroxylase, the first enzyme in the catabolic pathway for phenylalanine, is responsible for the disease phenylketonuria (PKU), the most common cause of elevated levels of phenylalanine (hyperphenylalaninemia).
In individuals with PKU, a secondary, normally little used pathway of phenylalanine metabolism comes into play. In this pathway phenylalanine undergoes transamination with pyruvate to yield phenylpyruvate. Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name “phenylketonuria.” Much of the phenylpyruvate, rather than being excreted as such, is either decarboxylated to phenylacetate or reduced to phenyllactate. Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe intellectual deficits. This may be caused by excess phenylalanine competing with other amino acids for transport across the blood-brain barrier, resulting in a deficit of required metabolites.
(Nelson L. D. and Cox M. M. (2013). Lehninger Principles of Biochemistry, 6th edition. W.H. Freeman and Company. pp 719-720)
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