Phenylalanine in phenylketonuria

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. 

Figure 6.1. Metabolism of phenylalanine in phenylketonuria. Square brackets enclose substances not excreted in the urine. (Courtesy Blackwell, Oxford.)...

Goldstein, F.B. (1963), Studies on phenylketonuria. II. Excretion of A/ -acetyl-L-phenylalanine in phenylketonuria. Biochim. Biophys. Acta, 71,204. 

Phenylpyruvic acid can cause mental retardation m infants who are deficient m the enzymes necessary to convert l phenylalanine to l tyrosine This disorder is called phenylketonuria, or PKU disease PKU disease can be detected by a simple test rou tmely administered to newborns It cannot be cured but is controlled by restricting the dietary intake of l phenylalanine In practice this means avoiding foods such as meat that are rich m l phenylalanine... 

FIGURE 2 The two phenylalanine peaks include the radioactive tracer (the right-hand peak) and the phenylalanine in the blood (the peak 5mu to the left). The presence of the latter peak shows that the babv from whom the blood was drawn has phenylketonuria. 

Figure 30-13. Alternative pathways of phenylalanine catabolism in phenylketonuria. The reactions also occur in normal liver tissue but are of minor significance.

A much more serious genetic disease, first described by Foiling in 1934, is phenylketonuria. Here the disturbance in phenylalanine metabolism is due to an autosomal recessive deficiency in liver phenylalanine hydroxylase (Jervis, 1954) which normally converts significant amounts of phenylalanine to tyrosine. Phenylalanine can therefore only be metabolized to phenylpyruvate and other derivatives, a route which is inadequate to dispose of all the phenylalanine in the diet. The amino acid and phenylpyruvate therefore accummulate. The condition is characterized by serious mental retardation, for reasons which are unknown. By the early 1950s it was found that if the condition is diagnosed at birth and amounts of phenylalanine in the diet immediately and permamently reduced, mental retardation can be minimized. The defect is shown only in liver and is not detectable in amniotic fluid cells nor in fibroblasts. A very sensitive bacterial assay has therefore been developed for routine screening of phenylalanine levels in body fluids in newborn babies. 

Phenylketonuria (PKU) is a group of inherited disorders caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that catalyses the conversion of phenylalanine to tyrosine, the first step in the pathway for catabolism of this amino acid. As a result, the concentration of phenylalanine in the liver and the blood increases. This high concentration in the liver increases the rate of a side reaction in which phenylalanine is converted to phe-nylpyruvic acid and phenylethylamine, which accumulate in the blood and are excreted in the urine. 

The phenylalanine hydroxylase gene showing thirteen exons, restriction sites, and some of the mutations resulting in phenylketonuria. 

For example, alkaponuria is characterized by homogentisic acid in urine phenylketonuria, which results in mental retardation, is characterized by quantities of phenylpyruvic acid in the urine. It is diagnosed in a suspected patient by determining the amount of this acid in the urine and the increased levels of phenylalanine in the plasma. Maple sugar disease is diagnosed the presence of large amounts of the branched chain amino acids, such as valine, leucine, and isoleucine in the blood and urine. 

The concentration of phenylalanine in the blood of neonates is used to screen for phenylketonuria (PKU). Explain the biochemical basis for the correlation of elevated blood phenylalanine concentration and PKU. Explain why restriction of dietary phenylalanine is critically important for youngsters with PKU. 

A number of genetic disorders are associated with phenylalanine and tyrosine metabolism. The best known is the classic phenylketonuria, discovered in 1934 by Foiling. It is characterized by the virtual absence of phenylalanine hydroxylase from the organism. As a result, phenylalanine is converted to a large extent to phenylpyruvate, phenyllactate, and phenylacetate (Figure 20.22). Their levels and that of phenylalanine in the bloodstream are elevated. Hyper-phenylalaninemia may also result from the absence of dihydrobiopterin reductase or any enzyme required for dihydrobiopterin biosynthesis from GTP. Although the etiologies of such disorders differ from that of classic phenylke-... 

Erlandsen H, PeyAL, Gamez A, et al. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc. Natl. Acad. Sci. (USA) 101 16903-16908,... 

Phenylketonuria is perhaps the best known of the diseases of amino acid metabolism. Phenylketonuria is caused by an absence or deficiency of phenylalanine hydroxylase or, more rarely, of its tetrahydrobiopterin cofactor. Phenylalanine accumulates in all body fluids because it cannot be converted into tyrosine. Normally, three-quarters of the phenylalanine is converted into tyrosine, and the other quarter becomes incorporated into proteins. Because the major outflow pathway is blocked in phenylketonuria, the blood level of phenylalanine is typically at least 20-fold as high as in normal people. Minor fates of phenylalanine in normal people, such as the formation of phenylpyruvate, become major fates in phenylketonurics. 

The incidence of phenylketonuria is about 1 in 20,000 newborns. The disease is inherited in an autosomal recessive manner. Heterozygotes, who make up about 1.5% of a typical population, appear normal. Carriers of the phenylketonuria gene have a reduced level of phenylalanine hydroxylase, as indicated by an increased level of phenylalanine in the blood. However, this criterion is not absolute, because the blood levels of phenylalanine in carriers and normal people overlap to some extent. The measurement of the kinetics of the disappearance of intravenously administered phenylalanine is a more definitive test for the carrier state. It should be noted that a high blood level of phenylalanine in a pregnant woman can result in abnormal development of the fetus. This is a striking example of maternal-fetal relationships at the molecular level. Table 23.3 lists some other diseases of amino acid metabolism. 

Errors in amino acid metabolism served as sources of some of the first insights into the correlation between pathology and biochemistry. Although there are many hereditary errors of amino acid metabolism, phenylketonuria is the best known. This condition is the result of the accumulation of high levels of phenylalanine in the body fluids. By unknown mechanisms, this accumulation results in mental retardation unless the afflicted are placed on low phenylalanine diets immediately after birth. 

Thousands of diseases related to deficient or defective enzymes occur, many of which are rare. For example, in phenylketonuria (which has an incidence of 1 in 10,000 births in whites and Asians), the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is deficient. Phenylalanine accumulates, and tyrosine becomes an essential amino acid that is required in the diet. Mental retardation is a result of metabolic derangement. A more common problem is lactase deficiency, which occurs in 69% to 90% of American Indians, blacks, and Asians, and in 10% of whites. Lactose is not digested normally and accumulates in the gut where it is metabolized by bacteria. Bloating, abdominal cramps, and watery diarrhea result. 

In phenylketonuria (PKU), the conversion of phenylalanine to tyrosine is defective. Phenylalanine accumulates and is converted to compounds such as the phenylketones, which give the urine a musty odor. Mental retardation occurs. PKU is treated by restriction of phenylalanine in the diet. 

For higher organisms, e.g., mammals, phenylalanine and tryptophan are so-called essential amino acids, i.e., they cannot be synthesized by the animal and must be supplied in the diet (for man, see 728, 729). Tyrosine is derived, as we shall see later, from phenylalanine, and is not therefore itself an essential amino acid as long as the phenylalanine intake is adequate (726, 950) if the conversion of phenylalanine to tyrosine is inhibited, as in phenylketonuria, tyrosine can become essential (65). The essential nature of the aromatic amino acids is a reflection of the general inability of higher organisms to synthesize the benzene ring. 

More recent isotopic investigations by Undenfriend and Bessman (880) have shown that a small conversion of phenylalanine to tyrosine can occur in phenylketonuria. Four possible explanations of the primary block were advanced 1) there may be a reduced amount of the appropriate enzyme system, L-phenylalanine oxidase, in the liver, or (f) a complete absence of the enzyme with conversion by alternative pathways cf. 174), or (3) a normal amount of apoenzyme with a coenzyme missing or (4) a normal amount of enzyme inactivated by an inhibitor. It is known from work on microorganisms that metabolic blocks are by no means always complete (cf., e.g., 187, 188) and this may well apply to phenylketonuria, but which one or more of the above four possibilities is correct must await further work. 

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