Phenylketonuria Phenylalanine hydroxylase

Maternal phenylketonuria Phenylalanine hydroxylase Same as above Untreated PKU in the mother causes inteUectual disability, congenital heart disease, low birth weight, and microcephaly in offspring Phenylalanine restriction, tyrosine supplementation None... 

In the case of hyperphenylalaninaemia, which occurs ia phenylketonuria because of a congenital absence of phenylalanine hydroxylase, the observed phenylalanine inhibition of proteia synthesis may result from competition between T.-phenylalanine and L-methionine for methionyl-/RNA. Patients sufferiag from maple symp urine disease, an inborn lack of branched chain oxo acid decarboxylase, are mentally retarded unless the condition is treated early enough. It is possible that the high level of branched-chain amino acids inhibits uptake of L-tryptophan and L-tyrosiae iato the brain. Brain iajury of mice within ten days after thek bkth was reported as a result of hypodermic kijections of monosodium glutamate (MSG) (0.5—4 g/kg). However, the FDA concluded that MSG is a safe kigredient, because mice are bom with underdeveloped brains regardless of MSG kijections (106). 

Phenylketonuria AR Phenylalanine hydroxylase White matter is up to 40% deficient in myelin hypomyelination may be caused by inhibition of amino acid transport and/or protein synthesis by the high level of phenylalanine that accumulates 1, Ch. 40... 

Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase 672... 

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

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). 

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. 

Phenylalanine (Phe or F) (2-amino-3-phenyl-propanoic acid) is a neutral, aromatic amino acid with the formula HOOCCH(NH2)CH2C6H5. It is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. Tyr and Phe play a significant role not only in protein structure but also as important precursors for thyroid and adrenocortical hormones as well as in the synthesis of neurotransmitters such as dopamine and noradrenaline. The genetic disorder phenylketonuria (PKU) is the inability to metabolize Phe. This is caused by a deficiency of phenylalanine hydroxylase with the result that there is an accumulation of Phe in body fluids. Individuals with this disorder are known as phenylketonurics and must abstain from consumption of Phe. A nonfood source of Phe is the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester), which is metabolized by the body into several by-products including Phe. The side chain of Phe is immune from side reactions, but during catalytic hydrogenations the aromatic ring can be saturated and converted into a hexahydrophenylalanine residue. ... 

Phenylalanine hydroxylase deficiency, giving rise to phenylketonuria (PKU) (Box 3.9). 

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. 

Classic phenylketonuria (PKU) is due to deficiency of phenylalanine hydroxylase, which leads to brain damage due to the neurotoxic effects of accumulated Phe or its metabolites. 

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... 

Phenylketonuria <8 Conversion of phenylalanine to tyrosine Phenylalanine hydroxylase Neonatal vomiting mental retardation... 

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). 

A deficiency in phenylalanine hydroxylase results in the disease phenylketonuria (PKU). 

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

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... 

Because enzymes are required in all metabolic pathway reactions, a missing or damaged enzyme may result in a metabolic disorder, meaning that the pathway can no longer produce what it should because there is an interruption in the series of required reactions. When this happens, cells may have too much of some substances or too little of others. For example, a disorder called phenylketonuria is caused by the lack of an enzyme called phenylalanine hydroxylase. The enzyme converts the amino acid phenylalanine to another amino acid, tyrosine. When the enzyme is missing, phenylalanine... 

Inborn errors of metabolism are inherited metabolic disorders caused by the absence of an enzyme in a metabolic pathway. Alkaptonuria is caused by the lack of homogentisate oxidase and is harmless, whereas phenylketonuria, which is due to a lack of phenylalanine hydroxylase, can cause severe mental retardation. 

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-... 

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.

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,... 

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. 

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