Phenylalanine to Tyrosine

This transformation, considered likely on the basis of experiments with the intact animal, was proved by the isotopic experiments of Moss and Schoenheimer (614), which also showed it to be an automatic process. Udenfriend and Cooper (886) found a highly specific enzyme in liver which carried out this reaction, possibly in two stages. The system required oxygen and DPN (diphosphopyridinenucleotide) and was considered responsible for the greater part of the normal metabolism of phenylalanine. 

Mitoma and keeper (605) resolved the system into two components, separated from rat liver homogenate supernatant by differential precipitation with ammonium sulfate. Their combined system of enzyme I, enzyme II, DPN (or reduced DPN), and an aldehyde or alcohol, specifically hy-droxylated L-phenylalanine but not other aromatic compounds. Enzyme I is labile and only a tenfold purification could be achieved. Enzyme II is relatively stable. Many, but not all, aldehydes and alcohols tested could participate in the reaction. 

The conversion of phenylalanine to tyrosine occurs in muscle as well as liver extracts (560) and is decreased in the liver of ACTH-treated rats (428). The reverse transformation, of tyrosine to phenylalanine, does not occur even in phenylalanine-deficient animals (309). 

The experiments described earlier showed that in liver homogenates and extracts this reaction is brought about by transamination, which is an obligatory first step in the oxidation of tyrosine by such systems. The existence of su( h a transaminating system was already known (133, 134, 393), and the observed pyridoxal phosphate-dependence when transamination was was made rate-controlling (489) was in accordance with the known behavior of transaminases (c/. 482). 

Conversion of p-Hydroxyphenylpyruvic Acid to 2,5-Dihydroxyphenyl-pyruvic and Homogentisic Acids. Function of Ascorbic Acid and of Hematopoietic Factors 

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Tyrosine. Phenylalanine hydroxylase converts phenylalanine to tyrosine (Figure 28-10). Provided that the diet contains adequate nutritionally essential phenylalanine, tyrosine is nutritionally nonessential. But since the reaction is irreversible, dietary tyrosine cannot replace phenylalanine. Catalysis by this mixed-function oxygenase incorporates one atom of O2 into phenylalanine and reduces the other atom to water. Reducing power, provided as tetrahydrobiopterin, derives ultimately from NADPH. 

Figure28-10. The phenylalanine hydroxylase reaction. Two distinct enzymatic activities are involved. Activity II catalyzes reduction of dihydrobiopterin by NADPH, and activity I the reduction of O2 to HjO and of phenylalanine to tyrosine. This reaction is associated with several defects of phenylalanine metabolism discussed in Chapter 30.

Cysteine, tyrosine, and hydroxylysine are formed from nutritionally essential amino acids. Serine provides the carbon skeleton and homocysteine the sulfur for cysteine biosynthesis. Phenylalanine hydroxylase converts phenylalanine to tyrosine. 

One of the first pieces of evidence for the mechanism of this reaction involved an attempt to develop a new assay for the activity of tyrosine synthase, which converts phenylalanine to tyrosine. A tritium was placed in the para position of phenylalanine, and it was assumed that oxidation of this position would lead to the loss of tritium and the rate of this loss would be a measure of the activity of the enzyme (Fig. 4.76). 

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. 

Eisinger(55) also noted that it is difficult to obtain accurate data with phenylalanine as the donor and either tryptophan or tyrosine as the acceptor. The source of this problem is the weak S, - S0 absorption of phenylalanine compared to that of tyrosine or tryptophan, which leads to considerable experimental uncertainty in measuring the sensitized acceptor emission. This error may account for the finding of Kupryszewska et al.<56> that the sensitization of the acceptor fluorescence was less than the quenching of the donor fluorescence in their study of phenylalanine-to-tyrosine energy transfer... 

D. G. Searcy, T. Montenay-Garestier, and C. Helene, Phenylalanine-to-tyrosine energy transfer in the archaebacterial histone-like protein HTa, Biochemistry 28, 9058-9065 (1989). 

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. 

The liver is also the principal metabolic center for hydrophobic amino acids, and hence changes in plasma concentrations or metabolism of these molecules is a good measure of the functional capacity of the liver. Two of the commonly used aromatic amino acids are phenylalanine and tyrosine, which are primarily metabolized by cytosolic enzymes in the liver [1,114-117]. Hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase is very efficient by the liver first pass effect. In normal functioning liver, conversion of tyrosine to 4-hy-droxyphenylpyruvate by tyrosine transaminase and subsequent biotransformation to homogentisic acidby 4-hydroxyphenylpyruvic acid dioxygenase liberates CO2 from the C-1 position of the parent amino acid (Fig. 5) [1,118]. Thus, the C-1 position of phenylalanine or tyrosine is typically labeled with and the expired C02 is proportional to the metabolic activity of liver cytosolic enzymes, which corresponds to functional hepatic reserve. Oral or intravenous administration of the amino acids is possible [115]. This method is amenable to the continuous hepatic function measurement approach by monitoring changes in the spectral properties of tyrosine pre- and post-administration of the marker. 

Figure 9-6. Synthesis of tyrosine from phenylalanine. Hydroxylation of phenylalanine to tyrosine is one of several reactions in the body that require tetrahydrobiopterin as a cofactor to provide electrons and hydrogen as reducing equivalents.

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

NADH-dependent reductase, thus allowing the biopterin cofactor to function catalytically (72JBC(247)6082). That the conversion of phenylalanine to tyrosine involves an arene oxide intermediate is suggested by the observation of the so-called NIH shift phenomenon (i.e. migration and retention of the para substituents such as deuterium, tritium, methyl and bromine when these para-substituted phenylalanines are enzymatically hydroxylated) <66BBR(24)720, 67MI11000). 

Cl Biochemical precursor-product relationships vary in complexity. Some pathways such as the conversion of phenylalanine to tyrosine involve only one en-... 

Phenylketonuria. A human disease caused by a genetic deficiency in the enzyme that converts phenylalanine to tyrosine. The immediate cause of the disease is an excess of phenylalanine. The condition can be alleviated by a diet low in phenylalanine. 

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. 

They lack the enzyme phenylalanine oxidase, which converts phenylalanine to tyrosine. Thus phenylalanine accumulates in the body and it is degraded to phenylpyruvate by transamination ... 

PKU is a serious lEM caused by a liver enzyme deficiency. In PKU, phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, is defective. Several different mutations are responsible for altering or reducing the activity of the phenylalanine hydroxylase gene. Because PKU patients cannot make the pigment melanin, 90% of PKU patients are blond-haired with blue eyes. Other clinical features include seizures, a mousy body odor, and eczema. Left untreated, accumu-... 

Essential amino acids are indispensable in that the body is incapable of replacing them simply by using its own synthesizing facilities they must either be supplied in adequate quantities from outside or generated by degradation of body proteins. Non-essential amino acids are synthesized in the liver, muscles, kidneys and intestine. Only the synthesis of arginine from ornithine and the hydroxylation of phenylalanine to tyrosine are liver-specific reactions. 

Tyrosine and tryptophan, as well as phenylalanine, are the aromatic amino acids. The body can convert phenylalanine to tyrosine. Thus, tyrosine is a dispensable (nonessential) amino acid. 

Tyrosine can spare the requirement for phenylalanine. In many species, about 50% of the phenylalanine requirement can be replaced by tyrosine. For this rea.son, the requirement for phenylalanine is sometimes expressed as the requirement for the sum of both amino adds. The biochemical relationship between phenylalanine and tyrosine is shown in Figure 8.28, Phenylalanine monooxygenase catalyzes the conversion of phenylalanine to tyrosine. This enzyme uses the cofactor tetrahydro-biopterin. Biopterin is not required in the diet. It is synthesized from GTR Folate (in plants and bacteria) and molybdopterin are also synthesized from GTP. Figure 8.28 also depicts the catabolic pathway for tyrosine. 

Fig. 10). Internal Claisen rearrangement on chorismic acid yields prephenic acid en route to phenylalanine. During the course of the hydroxylation of phenylalanine to tyrosine, there is a characteristic NIH shift of... 

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. 

In phenylketonuria (PKU), the conversion of phenylalanine to tyrosine is defective. Phenylalanine accumulates and is converted to compounds such as the phenylketones, which give the urine a musty odor. Mental retardation occurs. PKU is treated by restriction of phenylalanine in the diet. 

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