Phenylpyruvate phenylketonuria

PheDH L-Phenylalanine, phenylpyruvate, phenylketonuria, cell destraction by shock wave... 

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... 

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. 

Phenylalanine hydroxylase (PH) which requires tetrahydrobiopterin (BH4) as a cofactor, is defective in cases of phenylketonuria (PKU). This is a rare (prevalence 1 / 15 000 in the United Kingdom) genetic condition characterized by fair complexion, learning difficulties and mental impairment. If PH is either not present in the hepatocytes or is unable to bind BH4 and is therefore non functional, phenylalanine accumulates within the cells. Enzymes in minor pathways which are normally not very active metabolize phenylalanine ultimately to phenylpyruvate (i.e. a phenylketone). To use the traffic flow analogy introduced in Chapter 1, the main road is blocked so vehicles are forced along side roads. Phenylpyruvate is excreted in the urine (phenyl-ketone-uria), where it may be detected but a confirmatory blood test is required for a reliable diagnosis of PKU to be made. 

Today aspartame is used in more than 6,000 food products. Aspartame is 160 times as sweet as sucrose based on mass equivalents. Approximately 16,000 tons are consumed annually on a global basis, with approximately 8,000 tons used in the United States and 2,500 tons in Europe. In the body aspartame is metabolized into its three components aspartic acid, phenylalanine, and methanol (Figure 11.1). Aspartic acid is a nonessential amino acid and phenylalanine is an essential amino acid. The condition called phenylketonuria (PKU) is a genetic disorder that occurs when a person lacks the enzyme phenylalanine hydroxylase and cannot process phenylalanine. This results in high phenylalanine blood levels that are metabolized into products one of these is phenylpyruvate, which contains a ketone group and... 

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 phenylalanine 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. 

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. 

DISCUSSION. Caution should be exercised when interpreting chromatograms from a complex mixture of aromatic compounds in urine. This is especially true when excretion of the catechols is very high. When the derivatives of the compound extracted from urine of patients with phenylketonuria are prepared decomposition products of the large amounts of phenylpyruvic acid present give rise to peaks which interfere with and resemble HVA. When difficulties of this type are suspected, differential extraction of the urine can be performed. When alkaptonuria urine is extracted with dichloromethane, homovanillic acid is extracted preferentially, leaving the spurious compounds behind. 

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. 

J4. Jervis, G. A., Phenylpyruvic oligophrenia (phenylketonuria). Research Pubis. Assoc. Research Nervous Mental Disease 33, 259-282 (1954). 

M10. Meister, A., Udenfriend, S., and Bessman, S. P., Diminished phenylketonuria in phenylpyruvic oligophrenia after administration of L-glutamine, L-glutamate, or L-asparagine. J. Clin. Invest. 36, 619-626 (1956). 

An inability to degrade amino acids causes many genetic diseases in humans. These diseases include phenylketonuria (PKU), which results from an inability to convert phenylalanine to tyrosine. The phenylalanine is instead transaminated to phenylpyruvic acid, which is excreted in the urine, although not fast enough to prevent harm. PKU was formerly a major cause of severe mental retardation. Now, however, public health laboratories screen the urine of every newborn child in the United States for the presence of phenylpyru-vate, and place children with the genetic disease on a synthetic low-phenylalanine diet to prevent neurological damage. 

Phenylalanine Phenylpyruvic acid Phenylethylamine Phenylpyruvic acid is found in the serum of patients with phenylketonuria... 

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-... 

The first enzyme activity (dihydrobiopterin reductase) catalyzes the transfer of hydrogen to dihydrobiopterin, which is thus reduced to tetrahydrobiopterin. The second enzyme activity is a hydroxylase containing two Fe3+ atoms, and this catalyzes the reduction of Oz such that one oxygen atom is incorporated into phenylalanine to form tyrosine and the second into water. At the same time tetrahydrobiopterin is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is an example of a mixed-function oxidase. An inherited deficiency of phenylalanine hydroxylase results in the accumulation of phenylalanine that is not converted to tyrosine but is excreted as phenylpyruvate. This condition, which affects young infants, is known as phenylketonuria and is associated with severe mental retardation. 

The disease phenylketonuria, which causes severe mental retardation, is characterized by the urinary excretion of phenylpyruvate. Why is this formed ... 

Phenylketonuria is due to an inborn error of phenylalanine metabolism. Typically, it is due to a deficiency of phenylalanine hydroxylase. Atypically, it can be caused by a deficiency of dihydrobiopterin reductase and a resultant inability to synthesize biopterin. All these conditions cause an accumulation of phenylalanine, which can be transaminated to phenylpyruvic acid. 

C-7) Phenylketonuria (deficiency of phenylalanine hydroxylase). Occasionally, the defect is not in the enzyme but in the ability to regenerate tetrahydrobiop-terin, which is also necessary for the reaction. There is a buildup and excretion of phenylpyruvate in the urine, giving it a mousy odor. Mental retardation is a prominent feature. Diagnosis can be made by routine urine testing for phenylpyruvate or serum testing for elevated phenylalanine levels. The condition is treated with a diet low in phenylalanine. Sometimes, tetrahydrobiopterin deficiency may be treated by supplying biopterin,... 

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. 

Indeed, the initial description of phenylketonuria in 1934 was made by observing the reaction of phenylpyruvate with FeCl3, which turns the urine olive green. Almost all untreated phenylketonurics are severely mentally retarded. In fact, about 1% of patients in mental institutions have phenylketonuria. The brain weight of these people is below normal, myelination of their nerves is defective, and their reflexes are hyperactive. The life expectancy of untreated phenylketonurics is drastically shortened. Half are dead by age 20 and three-quarters by age 30. The biochemical basis of their mental retardation is an enigma. 

Phenylketonuria 2-Hydroxyphenylacetic, 3-phenyllactic, 2-phenylpyruvic, madelic, 4-hydroxy-phenyllactic, 4-hydroxyphenylpyruvic... 

Phenylalanine catabolism, 468 chemical structure, 19 plasma conoentralion, 46o sparing by tyrosine, 467,469 Phenylketonuria, 467,469 Phenylpyruvic acid, 469 FhIP,889,B90 Phlebotomy, 759 Phlorizin hydrolase, 109-110 Phorbol esters, cancer and, 916 Phosphatases, 54, 66 Phosphate, 694 in biologLcal fluids, 696 in bore, 697... 

Phenylketonuria (PKU) is an inborn error of metabolism by which the body is unable to convert surplus phenylalanine (PA) to tyrosine for use in the biosynthesis of, for example, thyroxine, adrenaline and noradrenaline. This results from a deficiency in the liver enzyme phenylalanine 4-mono-oxygenase (phenylalanine hydroxylase). A secondary metabolic pathway comes into play in which there is a transamination reaction between PA and a-keto-glutaric acid to produce phenylpyruvic acid (PPVA), a ketone and glutamic acid. Overall, PKU may be defined as a genetic defect in PA metabolism such that there are elevated levels of both PA and PPVA in blood and excessive excretion of PPVA (Fig. 25.7). 

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... 

Phenylketonuria The presence of elevated amounts of phenylketones, primarily phenylpyruvate, in urine a primary indication of disturbance of phenylalanine metabolism resulting from elevated transamination of phenylalanine due to reduction in phenylalanine hydioxylalion to tyrosine. 

The provision of reducing equivalents to phenylalanine hydroxylase is dependent on reduction of dihydrobiopterin by NADH catalyzed by the enzyme dihydropteridine reductase, as shown in Figure 38-2. This reduction is dependent on the availability of biopterin and therefore on the biopterin synthetic pathway. Thus any genetic or protein folding defect in either dihydropteridine reductase or the biopterin biosynthetic enzymes would compromise the efficacy of phenylalanine hydroxylation to tyrosine resulting in hyperphenylalaninemia and also phenylketonuria resulting from inaease transamination of phenylalanine to phenylpyruvate. 

Phenylketonuria, caused by a deficiency of phenylalanine hydroxylase, is one of the most common genetic diseases associated with amino acid metabolism. If this condition is not identified and treated immediately after birth, mental retardation and other forms of irreversible brain damage occur. This damage results mostly from the accumulation of phenylalanine. (The actual mechanism of the damage is not understood.) When it is present in excess, phenylalanine undergoes transamination to form phenylpyruvate, which is also converted to phenyllactate and phenyl-acetate. Large amounts of these molecules are excreted in the urine. Phenylacetate gives the urine its characteristic musty odor. Phenylketonuria is treated with a low-phenylalanine diet. 

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