Phenylketonuria completion

Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase. Phenylketonuria (PKU) is among the more common aminoacidurias (-1 20,000 live births). The usual cause is a nearly complete deficiency of phenylalanine hydroxylase, which converts phenylalanine into tyrosine (Fig. 40-2 reaction 1). 

Other data show that under disease state, transport systems may be less available to transport compounds into the brain. It was demonstrated that the transport of phenylalanine by LAT into the brain of patients with phenylketonuria was blocked (120). In addition, EEG analysis revealed that brain activity was acutely disturbed when phenylalanine was given orally without other LNAAs. Following administration with LNAAs, phenylalanine influx was completely blocked and no influence on EEG could be observed. 

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. 

Deficiency of phenylalanine hydroxylase, tetrahydrobiopterin, or dihydropteridine reductase results in phenylketonuria (PKU), an autosomal recessive trait. Because phenylalanine accumulates in tissues and plasma (hyperphenylalaninemia), it is metabolized by alternative pathways and abnormal amounts of phenylpyruvate appear in urine (Figure 17-22). Phenylalanine hydroxylase deficiency may be complete (classic PKU, type 1) or partial... 

Regulation of the dietary intake of amino acids can also be important when considering the treatment of certain defects in amino add biosynthesis. Phenylalanine is an essential amino acid that is also used to generate the nonessential amino add tyrosine. The enzyme that carries out this readion is the mixed function oxidase phenylalanine hydroxylase (PAH). Inherited deficiencies in PAH are associated with a condition known as phenylketonuria (PKU see Case 38). The absence of PAH results in elevations of phenylalanine and various phenylketones, the accumulation of which is associated with the neurologic defects seen in this disorder. PKU can be treated by controlling the dietary intake of phenylalanine. Diets low in phenylalanine will help prevent excessive elevations in phenylalanine. Phenylalanine can not be completely eliminated from the diet because it is an essential amino acid needed for protein synthesis. In the absence of PAH activity, tyrosine becomes an essential amino add because it cannot be generated from phenylalanine. 

The existence of a multiple specific enzymatic deficiency during phenylketonuria has been suggested by Boscott and Bickel (B26) to explain the abnormal excretion of aromatic acids other than phenyl-pyruvic acid, phenyllactic acid, and phenylacetylglutamine, as well as that of indolic acids. Jervis (J3) has, however, stated very recently that it is not necessary to postulate such a multiple enzymatic deficiency, since the complete biochemical urinary picture of phenylketonuria (including the presence of phenyl, hydroxyphenyl, and indolyl compounds) can be obtained temporarily in normal individuals following ingestion of large amounts of phenylalanine. 

As a specific example, let us consider the human disease phenylketonuria, which is caused by the lack of an essential enzyme, phenylalanine 4-monooxygenase. I shall return to this in the next chapter, and for the moment it is sufficient to say that people who lack the enzyme completely have the disease, but people who have only half of the normal amount of enzyme have no related health problems at aU half the normal amount of enzyme appears to be just as good as the full amount. How can this be If they have half the normal amount of enzyme (as they do, in this and other similar cases), then the reaction the enzyme catalyzes should proceed half as fast, and ought this not have at least some effect If not, does this not mean that normal individuals have at least twice as much of the enzyme as they need, and that the human species could evolve to become more efficient by decreasing the amount they make, thereby releasing precious resources for other purposes ... 

Nevertheless, all of this amazing functionality displayed by natural proteins seems to be based on a simple fact a complex and completely defined primary structure. In living cells, protein biosynthesis is carried out with an absolute control of the amino acid sequence, from the first amino acid to the last with a complete absence of randomness. In fact, the need for this absolute control is dramatically clear in some genetic disorders in which the lack or a substitution of a single amino acid in the whole protein leads to a complete loss of the original function, which can have dramatic consequences in some cases such as falciform anemia (sickle cell anemia), phenylketonuria, and cystic fibrosis [7]. 

Figure 5 Typical record of an SSCP analysis. Detection of point mutation (substitution of thymine to cytosine) causing phenylketonuria in a heterozygote. Four completely dissociated DNA strands with different sequences (two couples of complementary strands with and without the point mutation) are resolved as four conformers in a native separation environment. The large peak represents a portion of undissociated double-stranded DNA.

The results obtained using the screening techniques in mentally retarded children prompted us to try to study some inborn errors in animal models . Experimental phenylketonuria, for example, can be simulated by overloading with phenylalanine or by inhibiting the phenylalanine hydroxylase with /7-chlorophenylalanine. We have used both /w hloro-phenylalanine and esculin (to block the dihydropteridine reductase reaction), a treatment which leads to a complete inhibition of the enzyme< > > (Fig. 2). 

INBORN ERRORS OF THE METABOLISM. At times the metabolism of the nutrients cannot proceed normally due to some defect in the genetic information that exists at birth or shortly thereafter. These defects can affect the metabolism of carbohydrates, proteins, and fats hence, they are referred to as inborn errors of metabolism. Often they are due to production of a nonfunctional enzyme or complete lack of an enzyme involved in the metabolic scheme. Since enzymes are protein, their production relies upon correct genetic information. Many of these inborn errors have serious consequences, but fortunately most are rare. Familiar examples of errors in carbohydrate metabolism include lactose intolerance and galactosemia. Familiar examples of errors in protein metabolism include albinism, maple syrup urine disease, and phenylketonuria. The hyperlipoproteinemias are familiar examples of inborn errors of fat metabolism. 

One would therefore think that aspartame is completely safe. There is, however, one exeeption About 1 in 10,000 people has a genetie disorder eaUed phenylketonuria that prevents them from metabolizing phenylalanine. The ensuing accumulation of the amino acid, detected by the presence of its metabohte phenylketone (see below ) in the urine, causes abnormalities in brain function. In developed countries, phenylketonuria is included in the newborn screening panel and dealt with by medieation and a strict dietary regimen. 

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