Phenylketonuria metabolic defects

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 tyrosine 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. l-23b), foods sweetened with aspartame bear warnings addressed to individuals on phenylalanine-controlled diets. 

Some inborn errors of metabolism can be characterized by excessive urinary excretion of aromatic acid metabolites. These acids are distinct from the vanillyl acids discussed in a previous section. Phenylketonuria, alkaptonuria, and tyrosinosis can be diagnosed by determination of the aromatic acid metabolites. Aromatic acid profiles are characteristic of specific metabolic defects, and can be used to confirm diagnoses obtained from amino acid and other studies. Quantification of the individual aromatic acid gives information as to the fate of ingested amino acid in diseases such as phenylketonuria, where there is a block in the metabolic pathway involving the particular amino acid. 

A birth defect, a synonym for the clinical term congenital anomaly , is defined as an anatomical and/or functional defect resulting from disturbance of normal developmental processes. This definition includes a wide range of defects, from a visualized structural defect such as spina bifida to microscopic and metabolic defects such as phenylketonuria. Terms such as malformation, disruption, deformation, and sequence have been utilized to describe various manifestations (Jones, 1988). 

The metabolic defect involved in alkaptonuria w as suggested by Bateson (34) as early as 1902 to be inherited as a recessive Mendelian character, and later evidence has supported this prediction (395, 643). Gross (322) in 1914 concluded that it was due to lack of a specific enzyme. Alkaptonuria, unlike phenylketonuria, is not accompanied by mental symptoms and is not an incapacitating disorder except insofar as it may lead to ochronosis and arthritis (c/. 598). 

When diketopiperazines are administered to humans intravenously, they are not assimilated and are excreted unchanged in the urine. However, oral administration of compound 148 results in the breakdown of the compound, presumably in the digestive tract, and it therefore cannot be detected in the urine. " In contrast, people with phenylketonuria, who are fed on a low phenylalanine diet, excrete large amounts of the diketopiperazine 149. Although this compound is found in small amounts in the urine of normal hiunans, the excessive excretion of this diketopiperazine has been shown not to be due to a metabolic defect. Instead the compound originates in the diet itself and is not metabolized in the human digestive tract. ... 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway 673... 

FIGURE 40-2 The phenylalanine hydroxylase (PAH) pathway. Phenylketonuria usually is caused by a congenital deficiency of PAH (reaction 1), but it also can result from defects in the metabolism of biopterin, which is a cofactor for the hydroxylase. Enzymes (1) Phenylalanine hydroxylase (2) Dihydropteridine reductase (3) GTP cyclohydrolase (4) 6-pyruvoyltetrahydrobiopterin synthase. BH4, tetrahydrobiopterin DEDT, o-erythro-dihydroneopterin triphosphate QH2, dihydrobiopterin. 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway. The electron donor for phenylalanine hydroxylase is tetrahydrobiopterin (BH4), which transfers electrons to molecular oxygen to form tyrosine and dihydrobiopterin (QH2 Fig. 40-2 reaction 2). BH4 is regenerated from QH2 in an NADH-dependent reaction that is catalyzed by dihydropteridine reductase (DHPR), which is widely distributed. In the brain, this... 

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. 

Inherited defects of amino acid catabolism, biosynthesis, or transport have been known for many years the number of novel defects is only slowly increasing [1,3,4, 10, 12]. In this respect, cystinuria was among the first four inherited metabolic diseases described by Garrod 100 years ago. The disease with the highest impact on the community - phenylketonuria (PKU) - was discovered as early as the 1930s. Despite its early discovery, PKU remains a mysterious disease in several aspects, and patient-oriented research of this condition continues today. 

T Given that many amino acids are either neurotransmitters 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 intermediates accumulate. For example, a genetic defect in phenylalanine hydroxylase, the first enzyme in the catabolic pathway for phenylalanine (Fig. 18-23), is responsible for the disease phenylketonuria (PKU), the most common cause of elevated levels of phenylalanine (hyperphenylalaninemia). 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Figure 19-4. Differences between the frequency of phenylketonuria (PKU) and hyper-phenylalaninemia (HPA) caused by problems in tetrahydrobiopterin (BH4) metabolism and reports of positive therapeutic responses to BH4 therapy. (A) Frequency of PKU and HPA cases documented to be caused by defects in BH4 metabolism. D, Clinical cases documented to be caused by defects in BH4 D, clinical cases presumable due to a defect in the phenylalanine hydroxylase enzyme. (II) Frequency of PKU and HPA cases that have been reported to respond positively to BH4 therapy. , Positive response to BH4 therapy 0, no response to BH4 therapy. Different reports in the literature varied with respect to the numbers of individuals responding to BH4 therapy. The differences in reported numbers of BH4 responders are indicated by the boxes with cross-hatching.

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. 

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). 

The intact animal can be improved for experimental purposes if it is rendered abnormal in some way, by genetic malfunction, by illness, or by operation. Genetic defects, or mutations, are used widely in the study of bacterial metabolism, where they can be read ily induced, for example through irradiation by X-rays or from a radioactive source. Genetic defects frequently reveal themselves in the form of the absence of one specific enzyme, and metabolic studies with such enzymically defective preparations are of the same type as those made possible by the use of a specific enzymic inhibitor which we discussed above. Genetic defects in animals are rarer, but classic cases of the absence of specific enzymes and hence the accumulation of abnormal metabolites are provided in humans by the genetically carried diseases of phenylketonuria and alkaptonuria. In both, unusual substances are excreted in the urine, and the analysis of the reasons for their appearance has led to valuable information about the mechanism of amino acid metabolism in the body. 

Mutations leading to deficiencies in enzymes are usually referred to as inborn errors of metabolism, because they involve defects in the DNA of the affected individual. Errors in enzymes that catalyze reactions of amino acids frequendy have disastrous consequences, many of them leading to severe forms of mental retardation. Phenylketonuria (PKU) is a well-known example. In this condition, phenylalanine, phenylpyruvate, phenyllactate, and phenylacetate all accumulate in the blood and urine. Available evidence suggests that phenylpyruvate, which is a phenylketone, causes mental retardation by interfering with the conversion of pyruvate to acetyl-CoA (an important intermediate in many biochemical reactions) in the brain. It is also likely that the accumulation of these products in the brain cells results in an osmotic imbalance in which water flows into the brain cells. These cells expand in size until they crush each other in the developing brain. In either case, the brain is not able to develop normally. 

Phenylketonuria (PKU) is an inborn error in phenylalanine metabolism caused by a deficiency of the phenylalanine hydroxylase (PAH) enzyme (Fig. 10.1). The cofactor for PAH is tetrahydrobi-opterin (BH4). In PKU, blood concentrations of phenylalanine accumulate, affecting myelin and neurotransmitter production (Box 10.1) [1,2], With the defect in PAH, phenylalatfine is not converted to tyrosine thus, tyrosine becomes a conditionally essential amino acid and must be... 

Classical phenylketonuria is an hereditary defect in the synthesis of Phe hydroxylase (the enzyme may be absent or inactive), which affects about 1 infant in 10,000. These individuals are unable to convert Phe into tyrosine, and the major route of Phe metabolism is thus blocked. Phenylpyruvate and phenylacetic acid are excreted in the urine. The condition is accompanied by defective pigmentation and, if untreated, by severe mental retardation (hence the other name, phenylpyruvic oligophrenia, also known as Polling s syndrome). Tlie urine of newborn infants is now routinely tested (Guthrie test) for the presence of phenylketones the condition can be compensated by a diet low in phenylalanine, and the typic mental retardation is thereby avoided. Other types of phenylketonuria are due to defective reduction or synthesis of dihydrobiopterin (see Inborn errors of metabolism). 

Armstrong, M.D., Tyler, F.H. Studies on phenylketonuria. I. Restricted phenylalanine intake in phenylketonuria. J. din. Invest. 34,565-580 (1955) McKean, C.M., Schanberg, S.M., Giarman, N.J. A mechanism of the indole defect in experimental phenylketonuria. Science 137,604-605 (1962) Godin, C., Dolan, G. Tryptophan metabolism in normal and phenylke-tonuric rats. Biochim. biophys. Acta (Amst.) 130, 535-537 (1966) Armstrong, M.D., Low, N.L., Bosma, J.F. Studies on phenylketonuria. IX. Further observations on the effect of phenylalanine-restricted diet on patients with phenylketonuria. Amer. J. din. Nutr. 5, 543-554 (1957) Medes, G. New error of tyrosine metabolism Tyrosinosis, intermediary metabolism of tyrosine and phenylalanine. Biochem. J. 26, 917-940 (1932)... 

Pare, C. M. B., Sandler, M. and Stacey, R. S., The relationship between decreased 5-hydroxyindole metabolism and mental defect in phenylketonuria. Arch. Dis. Childh. 34, 422 (1959). 

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