Rh3

Tyrosine

FIGURE 18-24 Role of tetrahydrobiopterin in the phenylalanine hydroxylase reaction. The H atom shaded pink is transferred directly from C-4 to C-3 in the reaction. This feature, discovered at the NIH, is called the NIH Shift.

requires the cofactor tetrahydrobiopterin, which carries electrons from NADH to O2 and becomes oxidized to dihydrobiopterin in the process (Fig. 18-24). It is subsequently reduced by the enzyme dihydrobiopterin reductase in a reaction that requires NADH.

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 (Fig. 18-25). 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 phenyl-alanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. 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.

Phenylketonuria was among the first inheritable metabolic defects discovered in humans. When this condition is recognized early in infancy, mental retardation can largely be prevented by rigid dietary control. The diet must supply only enough phenylalanine and tyro-sine to meet the needs for protein synthesis. Consumption of protein-rich foods must be curtailed. Natural proteins, such as casein of milk, must first be hydrolyzed and much of the phenylalanine removed to provide an appropriate diet, at least through childhood. Because the artificial sweetener aspartame is a dipeptide of aspartate and the methyl ester of phenylalanine (see Fig. 1-23b), foods sweetened with aspartame bear warnings addressed to individuals on phenylalanine-controlled diets.

Phenylketonuria can also be caused by a defect in the enzyme that catalyzes the regeneration of tetrahy-drobiopterin (Fig. 18-24). The treatment in this case is more complex than restricting the intake of phenylalanine and tyrosine. Tetrahydrobiopterin is also required for the formation of l-3,4-dihydroxyphenylalanine (l-dopa) and 5-hydroxytryptophan—precursors of the neurotransmitters norepinephrine and serotonin, respectively—and in phenylketonuria of this type, these precursors must be supplied in the diet. Supplementing the diet with tetrahydrobiopterin itself is ineffective because it is unstable and does not cross the blood-brain barrier.

-CH2 —CH—COO" Phenylalanine aminotransferase

Pyruvate

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