Hydroxylation of phenylalanine

Finally, a quinonoid 6,7,8-trihydropterin structure (49) absorbing at 303 nm plays an important role as a labile intermediate in the tetrahydrobiopterin-dependent enzymatic hydroxylation of phenylalanine <67JBC(242)3934). 

FIGURE 3.16 Hydroxylation of phenylalanine followed by rearrangement to 2,5-dihydroxyphenylpyruvate. 

Ishimitsu, S., Fujimoto, S. and Ohara, A. (1984). Studies on the hydroxylation of phenylalanine by 6,7-dimethyl-5,6,7,8-tetrahydropteridine. Chem. Pharm. Bull. 32, 752-765. 

Kaur, H., Fagerheim, L, Grootveld, M., Puppo, A. and Halliwell, B. (1988). Aromatic hydroxylation of phenylalanine as an assay for hydroxyl radicals application to activated human neutrophils and to the haem protein leghaemoglobin. Anal. Biochem. 172, 360-367. 

An example of an amino acid interconversion that has pathological significance is the hydroxylation of phenylalanine to form tyrosine in the liver (Figure 6.4). 

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.

Among the essential amino acids, the aromatic amino acids (phenylalanine, tyrosine, and tryptophan) form by a pathway in which chorismate occupies a key branch point. Phosphoribosyl pyrophosphate is a precursor of tryptophan and histidine. The pathway to histidine is interconnected with the purine synthetic pathway Tyrosine can also be formed by hydroxylation of phenylalanine (and thus is considered conditionally essential). The pathways for the other essential amino acids are complex. 

Phenylalanine and tyrosine Hydroxylation of phenylalanine leads to the formation of tyrosine (Figure 20.7). This reaction, catalyzed by phenylalanine hydroxylase, is the first reaction in the catabolism of phenylalanine. Thus, the metabolism of phenyl alanine and tyrosine merge, leading ultimately to the formation of fumarate and acetoacetate. Phenylalanine and tyrosine are, therefore, both glucogenic and ketogenic. 

Maskos Z, Rush JD, Koppenol WH (1992) The hydroxylation of phenylalanine and tyrosine A comparison with salicylate and tryptophan. Arch Biochem Biophys 296 521-529 Mason RP, Knecht KT (1994) In vivo detection of radical adducts by ESR. Methods Enzymol 233 112-117... 

Phenylalanine Hydroxylase (EC 1.14.16.1). In arene hydroxylation of phenylalanine to produce tyrosine, mammalian phenylalanine hydroxylase (PAH) requires nonheme iron and tetrahydropterin cofactor. The role of the metal is... 

Fujimoto S, Ishimitsu S, Hirayama S, Kawakami N, Ohara A (1991) Hydroxylation of phenylalanine by myeloperoxidase-hydrogen peroxide system. Chem Pharm Bull 39 1598-1600... 

The reductant here is tetrahydrohiopterin, an electron carrier that has not been previously discussed and is derived from the cofactor biopterin. Because biopterin is synthesized in the body, it is not a vitamin. Tetrahydrohiopterin is initially formed by the reduction of dihydrobiopterin by NADPH in a reaction catalyzed by dihydrofolate reductase (Figure 23.28). NADH reduces the quinonoid form of dihydrobiopterin produced in the hydroxylation of phenylalanine back to tetrahydrohiopterin in a reaction catalyzed by dihydropteridine reductase. The sum of the reactions catalyzed by phenylalanine hydroxylase and dihydropteridine reductase is... 

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. 

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... 

Tyrosine, obtained from the diet or by hydroxylation of phenylalanine, is converted to homogentisate, whose aromatic ring is opened and cleaved, forming fumarate and acetoacetate (Figure 7-12). 

Tryptophan is hydroxylated in a tetrahydrobiopterin-requiring reaction similar to the hydroxylation of phenylalanine. The product, 5-hydroxy-tryptophan, is decarboxylated to form serotonin. 

Phenylalanine is an essential amino acid. Tyrosine is synthesized by hydroxylation of phenylalanine and therefore is not essential. However, if the hydroxylase system is deficient or absent, the tyrosine requirement must be met from the diet. These amino acids are involved in synthesis of a variety of important compounds, including thyroxine, melanin, norepinephrine, and epinephrine... 

Structure of folic acid showing its components. The numbered part participates in one-carbon transfer reactions. In nature, folate occurs largely as polyglutamyl derivatives in which the glutamate residues are attached by isopeptide linkages via the y-carboxyl group. The pteridine ring structure is also present in tetrahydrobiopterin, a coenzyme in the hydroxylation of phenylalanine, tyrosine, and tryptophan (Chapter 17). 

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. 

Hydroxylation of phenylalanine is a typical reaction of hydroxyl radicals, in which the resultant tyrosine is hydroxylated at the ortho- meta- or paraposition, and produces three isomeric tyrosines, u-tyrosine (2-hydroxyphenylalanine), m-tyrosine (3-hydroxyphenylalanine), and p-tyrosine (4-hydroxyphenylala-nine) [108], shown in Scheme 15. This reaction has been used extensively to trap hydroxyl radicals in vivo, and thereby facilitate their measurement [108]. 

The following were administered separately to P. cyclopium [carboxyl- and [ N]-anthranilic acid, phenylalanine with labels at positions 1,2, and 3, and also N-labelled phenylalanine and [methyl- C]methiomne. The results show an intact incorporation of all the atoms of phenylalanine and anthranilic acid into both (49) and (50), with L-phenylalanine preferred over the D-isomer. The iV-methyl group originates from the S-methyl group of methionine. The cyclic dipeptide formed from these two amino-acids is presumably an intermediate on the pathway to the alkaloids. As phenylalanine serves as a precursor for cyclopenol, the origin of the hydroxy-group is by meta-hydroxylation of phenylalanine. Further, m-tyrosine and tyrosine are only unspecific precursors. 

The reaction catalyzed by phenylalanine-4-monooxygenase is irreversible. The electrons required for the hydroxylation of phenylalanine are carried to O, from NADPH by tetrahydrobiopterin. 

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