Enzyme phenylalanine hydroxylase

There are many excellent examples of experiments using isotopic labeling in both organic chemistry and biochemistry. An interesting example is the case of lydroxylation of the amino acid phenylalanine which is carried out by the enzyme phenylalanine hydroxylase. 

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. 

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... 

The general scheme of the biosynthesis of catecholamines was first postulated in 1939 (29) and finally confirmed in 1964 (Fig. 2) (30). Although not shown in Figure 2, in some cases the amino acid phenylalanine [63-91-2] can serve as a precursor it is converted in the liver to (-)-tyrosine [60-18-4] by the enzyme phenylalanine hydroxylase. Four enzymes are involved in E formation in the adrenal medulla and certain neurons in the brain tyrosine hydroxylase, dopa decarboxylase (also referred to as L-aromatic amino acid decarboxylase), dopamine-P-hydroxylase, and phenylethanolamine iV-methyltransferase. Neurons that form DA as their transmitter lack the last two of these enzymes, and sympathetic neurons and other neurons in the central nervous system that form NE as a transmitter do not contain phenylethanolamine N-methyl-transferase. The component enzymes and their properties involved in the formation of catecholamines have been purified to homogeneity and their properties examined. The human genes for tyrosine hydroxylase, dopamine- 3-oxidase and dopa decarboxylase, have been cloned (31,32). It is anticipated that further studies on the molecular structure and expression of these enzymes should yield interesting information about their regulation and function. 

In vivo tolerance to copper is quite high, however, deficiency and excess are serious problems. Infants are particularly vulnerable as they take time to assimilate the correct levels and it is known that trace copper from cooking utensils or water pipes can cause childhood cirrhosis. Copper deficiency leads to arterial weakness and heart enlargement. This is probably caused by a decrease in catecholamine neurotransmitters derived from the biosynthesis of adrenaline which requires the copper-containing enzymes phenylalanine hydroxylase, dopamine P-monooxygenase and tyrosinase. 

Some diseases are caused by enzyme deficiencies. The congenital disease phenylketonuria is caused by the deficiency of the enzyme phenylalanine hydroxylase, resulting in a build-up of compounds that cause brain damage and mental retardation. This damage can be lessened and prevented by a diet containing a low amount of the amino acid phenylalanine. The complaint is caused by a genetic mutation. 

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. 

The answer is e. (Murray, pp 307-346. Scriver, pp 1667—1724. Sack, pp 121-138. Wilson, pp 287—3177) In humans, tyrosine can be formed by the hydroxylation of phenylalanine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase. A deficiency of phenylalanine hydroxylase results in the disease called phenylketonuria [PKU(261600)]. In this disease it is usually the accumulation of phenylalanine and its metabolites rather than the lack of tyrosine that is the cause of the severe mental retardation ultimately seen. Once formed, tyrosine is the precursor of many important signal molecules. Catalyzed by tyrosine hydroxylase, tyrosine is hydroxylated to form L-dihydroxyphenylalanine (dopa), which in turn is decarboxylated to form dopamine in the presence of dopa decarboxylase. Then, norepinephrine and finally epinephrine are formed from dopamine. All of these are signal molecules to some degree. Dopa and inhibitors of dopa decarboxylase are used in the treatment of Parkinson s disease, a neurologic disorder. Norepinephrine is a transmitter at smooth-muscle junctions innervated by sympathetic nerve libers. Epinephrine and dopamine are catecholamine transmitters synthesized in sympathetic nerve terminals and in the adrenal gland. Tyrosine is also the precursor of thyroxine, the major thyroid hormone, and melanin, a skin pigment. 

It is most often due to deficiency of the enzyme phenylalanine hydroxylase which causes the accumulation of harmful metabolites, including phenylketones. 

As part of a standard neonatal screen, an infant is diagnosed with a loss of function genetic defect in the enzyme phenylalanine hydroxylase. Defects in this enzyme can result in a condition known as phenylketonuria (PKU), which results from the toxic effects of phenylalanine derived phenylketones. Fortunately, this condition can be managed by regulating the amount of phenylalanine provided in the diet. Which of the following nonessential amino acids will need to be supplied in the diet of this infant ... 

Conservation of amino acids filtered at the glomerulus is made possible by the existence of four main transport systems for specific amino acids that facilitate active reabsorption of these amino acids from the proximal tubule. A lack or deficiency of the transport system responsible for the absorption of valine, alanine, cystine, and tryptophan, and of the transport system for arginine, lysine, cystine, and ornithine, leads to excretion of these specific amino acids in urine, which is characterized as renal aminoaciduria to distinguish it from overflow aminoaciduria. In the latter situation, the production of amino acids far exceeds the proximal tubular reabsorption capacity, thus leading to overflow of amino acids into urine. This can occur due to defective metabolism of amino acids, as is the case when phenylalanine cannot be metabolized due to the deficiency of the enzyme phenylalanine hydroxylase, or to the inability to deaminate amino acids in liver disease. 

Phenylalanine, an essential amino acid, can be converted to tyrosine in the liver, catalyzed by the enzyme phenylalanine hydroxylase. If phenylalanine hydroxylase is genetically insufficient, phenylketonuria results, with the excretion of phenylpyruvate. In this disease, tyrosine becomes an essential amino acid. This disease can be treated by feeding low-phenylanine diets. 

In both chemical and enzymic (phenylalanine hydroxylase) oxidation of tetrahydropteridines.ortho-quinonoid dihydropterins... 

Classic PKU is caused by mutations in the gene located on chromosome 12 that encodes the enzyme phenylalanine hydroxylase (PAH). This enzyme normally catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in the major pathway by which phenylalanine is catabolized. 

With the enzyme, phenylalanine hydroxylase, a variety of substrates have been found to undergo hydroxylation-induced migrations. 4-Deu-tero- (i5), 4-tritio- (i4), 4-chloro-, 4-bromo- (i3), or 4-methylphenyl-alanine (7) are hydroxylated to the corresponding 3-substituted tyrosines, while only small amounts of unsubstituted tyrosine are formed (Figure 1). By contrast, hydroxylation of 4-fluorophenylalanine leads to formation of tyrosine with complete loss of the substituent as fluoride ion (20). 

Ditritio-N-acetyl- 3-Tritio-N-acetyldop-tyramine amine Enzyme phenylalanine hydroxylase. " Microsomal aryl hydroxylase. Tryptophan-5-hydroxylase. Tyrosine hydroxylase. 0 ... 

Phenylketonuria is an inherited disorder caused by the deficient function of the enzyme phenylalanine hydroxylase this results in increased phenylalanine levels, which damage the developing brain and result in mental retardation. The aim of dietary management is to maintain a normal plasma phenylalanine level by restricting the routine... 

Answers (b), (c), and (e) are correct. Phenylketonuria is a metabolic disorder arising from an absence or deficiency in the enzyme phenylalanine hydroxylase or (more rarely) its cofactor tetrahydrobiopterin. It results in the build-up of phenylalanine in the body and is treated -with a diet low in phenylalanine. 

A disease in which hypomyelination occurs in specific forebrain tracts, but neurons and their axons are spared, is the autosomal recessive disorder PKU (Malamud, 1996 Dyer et al., 1996). As already mentioned, PKU is caused by a rise in blood phenylalanine (Phe) levels, due to a deficiency in the enzyme phenylalanine hydroxylase (PHA) (Scriver et al., 1995), which is expressed primarily in liver and not in brain, and catalyzes the conversion of Phe to tyrosine (Lee et al. 2003a and Lee et al. 2005). Blood Phe levels normally are about 121 mmol however, in untreated individuals (and mice) with PKU, levels may increase to 1,200 p. or more. For the past several decades, newborns diagnosed with PKU are placed on a low Phe diet for life. The low Phe diet decreases Phe levels in blood and brain, thereby allowing myelination to proceed (Thompson et al., 1993 Pietz et al., 1995). Individuals with PKU that are continuously treated from birth avoid the severe mental retardation that occurs in untreated individuals (Levy et al., 1994). 

At least 35 different hereditary changes in amino acid metabolism have been identified. One of the more well known is an inherited disease associated with abnormal aromatic amino acid metabolism. In phenylketonuria (PKU), there is a lack of the enzyme phenylalanine hydroxylase. As a result, phenylalanine cannot be converted to tyrosine, leading to the accumulation of phenylalaifine and its metabolites (phenylpyruvate and phenyl-acetate) in the tissues and blood ... 

Some individuals lack the enzyme phenylalanine hydroxylase required for this conversion, and any L-phenylalanine that would ordinarily be converted to L-tyrosine is converted to phenylpyruvic acid by transamination. 

Mutations that fully abolish protein function are referred to as null mutations. Null mutations generally result in severe disease. Mutations that reduce but do not abolish protein function may result in less severe disease. For example, two null mutations in the enzyme phenylalanine hydroxylase result in classic PKU. A less severe mutation results in moderate or mild hyperphenylalaninemia. 

Phenylketonuria (PKU) is an inherited autosomal recessive metabolic disease characterized by characterized by decrease activity of enzyme phenylalanine hydroxylase (PAH) [1], The Norwegian biochemist and physician Asbjom Foiling discovered PKU in 1934 by detecting phenylketones in the urine of siblings with mental retardation, with subsequent identification of altered... 

Phenylketonuria (PKU) is an inborn error of metabolism caused by a genetic mutation resulting in dysfunction in the hepatic enzyme phenylalanine hydroxylase (PAH) responsible for metabolizing the essential amino acid... 

With the failure to demonstrate that norbelladine or its relatives plays a role in the biosynthesis of the mesembrine alkaloids, a reevaluation led to a modified approach in which attempts to identify the sequence of occurrence of the post-tyrosine and post-phenylalanine intermediates were made. There is now a substantial body of information available to suggest that phenylalanine and tyrosine have separate metabolic roles in plants belonging to the order Dictolyoden. Not only do they lack the enzyme phenylalanine hydroxylase (phenylalanine 4-monooxygenase) which is necessary for the conversion of phenylalanine to tyrosine, but the metabolic pathways of these two amino acids are generally quite different in secondary metabolism (70). Phenylalanine is involved in initial conversion to cinnamic acid and subsequent transformation to structural units of the so-called phenyl-propanoid pathway, which include Ar—C3, Ar—C2, and Ar—Cj structural entities. On the other hand, the role of tyrosine in the biosynthesis of secondary metabolities is most frequently seen as the precursor of Ar—Cj—N and Cg—C2—N units, and somewhat less frequently, as Ar—C2 and Q—C2 units. 

The key starting materials for the synthesis of 10 nonessential amino acids are intermediates of the glycolysis pathway and the citric acid cycle (see B Figure 24.11). Tyrosine, the only nonessential amino acid with an aromatic side chain, is produced from the essential amino acid phenylalanine in a conversion that requires a single oxidation step catalyzed by the enzyme phenylalanine hydroxylase ... 

Some inherited metabolic disorders are extremely damaging while the effects of others are so mild that they can hardly be called diseases. For example, alkaptonurics are usually quite healthy although in later life they are prone to a particular form of arthritis. Similarly the conditions of fructosuria and pentosuria, in which fructose and pentose sugars respectively appear in the urine, have no pathological consequences. At the other end of the scale is phenylketonuria in which the enzyme phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine, is lacking. In this condition phenylpyruvic acid and other intermediate products of phenylalanine metabolism accumulate in the blood and tissues and are so injurious to the central nervous system that, although physical development is essentially normal, there is severe mental retardation. 

We will use the catabolism of phenylalanine as an example of how an amino acid is metabolized (Figure 25.4). Phenylalanine is one of the essential amino acids, so it must be included in our diet (Section 22.1). The enzyme phenylalanine hydroxylase converts phenylalanine to tyrosine. Thus, tyrosine is not an essential amino acid, unless the diet lacks phenylalanine. 

Phenylalanine (P) is an essential AA that participates in protein synthesis. It is converted to tyrosine via hydroxylation (see Section 15.6.7). Phenylalanine is both glncogenic and ketogenic." Phenylketonuria (PKU) is a rare disease (generally diagnosed at birth) caused by an inborn error in the abihty to metabolize P (lacking the enzyme phenylalanine hydroxylase). In affected people, if the diet is not controlled by severe restriction of P intake, PKU can lead to serious irreversible neurological disorders, such as mental retardation. 

A genetic disease is the result of a defective enzyme caused by a mutation in its genetic code. For example, phenylketonuria (PKU) results when DNA cannot direct the synthesis of the enzyme phenylalanine hydroxylase, required for the conversion of phenylalanine to tyrosine. In an attempt to break down the phenylalanine, other enzymes in the cells convert it to phenylpyruvate. If phenylalanine and phenylpyruvate accumulate in the blood of an infant, it can lead to severe brain damage and mental retardation. If PKU is detected in a newborn baby, a diet is prescribed that eliminates all the foods that contain phenylalanine. Preventing the buildup of the phenylpyruvate ensures normal growth and development. 

Phenylalanine is hydroxylated to tyrosine by the enzyme phenylalanine hydroxylase. The inborn disease phenylketonuria is characterized by a deficiency of this enzyme. 

Reaction 1, the substitution of a hydroxyl group for hydrogen in the para position, involves an enzyme, phenylalanine hydroxylase (EC 1.14.3.1) acting with tetrahydrobiopterin and molecular oxygen to yield tyrosine, quinonoid dihydrobiopterin and water [44]. Catalase and another, unidentified, protein are necessary for full enzymic activity—the reaction mechanism and the structure of phenylalanine hydroxylase are not yet fully understood. A second enzyme, dihydropteridine reductase, catalyses the reduction by NADH of the quinonoid dihydrobiopterin to tetrahydrobiopterin. 

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