Pathways of Amino Acid Degradation:- Phenylalanine Catabolism Is Genetically Defective in Some People
Given that many amino acids are either neuro transmitters or precursors or antagonists of neutrotransmitters, genetic defects of amino acid metabolism can cause defective neural development and mental retardation. In most such diseases specific inter mediates accumulate. For example, a genetic defect in phenylalanine hydroxylase, the first enzyme in the catabolic pathway for phenylalanine (Fig. 18–23), is re sponsible for the disease phenylketonuria (PKU), the most common cause of elevated levels of phenylalanine (hyperphenylalaninemia). Phenylalanine hydroxylase (also called phenylalanine-4-monooxygenase) is one of a general class of en zymes called mixed-function oxidases, all of which catalyze simultaneous hydroxylation of a substrate by an oxygen atom of O2 and reduction of the other oxygen atom to H2O. Phenylalanine hydroxylase 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 reductasein a reaction that requires NADH.
FIGURE 18–23 Catabolic pathways for phenylalanine and tyrosine. In humans these amino acids are normally con verted to acetoacetyl-CoA and fumarate. Genetic defects in many of these enzymes cause inheritable human diseases (shaded yellow).
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.
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 retar dation. 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 ad dressed to individuals on phenylalanine-controlled diets. Phenylketonuria can also be caused by a defect in the enzyme that catalyzes the regeneration of tetrahydrobiopterin (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 neurotransmitter's norepinephrine and serotonin, respectively—and in phenylketonuria of this type, these pre cursors 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.
FIGURE 18–25 Alternative pathways for catabolism of phenylalanine in phenylketonuria. In PKU, phenylpyruvate accumulates in the tissues, blood, and urine. The urine may also contain phenylacetate and phenyllactate.
Screening newborns for genetic diseases can be highly cost-effective, especially in the case of PKU. The tests (no longer relying on urine odor) are relatively in expensive, and the detection and early treatment of PKU in infants (eight to ten cases per 100,000 newborns) saves millions of dollars in later health care costs each year. More importantly, the emotional trauma avoided by early detection with these simple tests is inestimable. Another inheritable disease of phenylalanine catabolism is alkaptonuria, in which the defective enzyme is homogentisate dioxygenase (Fig. 18–23). Less serious than PKU, this condition produces few ill effects, although large amounts of homogentisate are excreted and its oxidation turns the urine black. Individuals with alkaptonuria are also prone to develop a form of arthritis. Alkaptonuria is of considerable historical interest. Archibald Garrod discovered in the early 1900s that this condition is inherited, and he traced the cause to the absence of a single enzyme. Garrod was the first to make a connection between an inheritable trait and an en zyme, a great advance on the path that ultimately led to our current understanding of genes and the infor mation pathways described in Part III.
