Phenylalanine, metabolism

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.

Hirsch W, H Schagger, G Fuchs (1998) Phenylglyoxalate NAD+ oxidoreductase (CoA benzoylating), a new enzyme of anaerobic phenylalanine metabolism in the denitrifying bacterium Azoarcus evansii. Eur J Biochem 251 907-915. 

Valine, leucine, and isoleucine biosynthesis Lysine biosynthesis Lysine degradation Arginine and proline metabolism Histidine metabolism Tyrosine metabolism Phenylalanine metabolism Tryptophan metabolism Phenylalanine, tyrosine, and tryptophan biosynthesis Urea cycle and metabolism of amino groups... 

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. 

In individuals with PKU, a secondary, normally little-used pathway of phenylalanine metabolism comes into play. In this pathway phenylalanine undergoes transamination with pyruvate to yield phenylpyruvate (Fig. 18-25). Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name phenylketonuria. Much of the phenylpyruvate, rather than being excreted as such, is either decarboxylated to phenylacetate or reduced to phenyllactate. Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. This may be caused by excess phenylalanine competing with other amino acids for transport across the blood-brain barrier, resulting in a deficit of required metabolites. 

Pathways of phenylalanine metabolism in normal individuals and in patients with phenylketonuria... 

The lignans comprise a class of natural products, derived from cinnamic acid derivatives, which are related biochemically to phenylalanine metabolism. 

Dopamine, which is essential for the control of movement, is made from tyrosine (or phenylalanine, because tyrosine is a direct product of phenylalanine metabolism). 

Phenylketonuria is due to an inborn error of phenylalanine metabolism. Typically, it is due to a deficiency of phenylalanine hydroxylase. Atypically, it can be caused by a deficiency of dihydrobiopterin reductase and a resultant inability to synthesize biopterin. All these conditions cause an accumulation of phenylalanine, which can be transaminated to phenylpyruvic acid. 

Hypopigmentation Lack of color in skin or hair due to the absence or low quantity of the skin and hair pigment melanin, a product of tyrosine (and phenylalanine) metabolism. 

Phenylketonuria The presence of elevated amounts of phenylketones, primarily phenylpyruvate, in urine a primary indication of disturbance of phenylalanine metabolism resulting from elevated transamination of phenylalanine due to reduction in phenylalanine hydioxylalion to tyrosine. 

The catabolic enzyme 2-oxopent-4-enoate hydratase (E.C. 4.2.1.80) is involved in l-phenylalanine metabolism and in the degradation of a number of aromatic hydrocarbons as well 3). It catalyzes the selective addition of water to a terminal C-C double bond of cis-2-hydroxypent-2,4-dienoic acid and forms 4-hydroxy-2-oxopentanoic acid. The enzyme also accepts ds-2-hydroxyhex-2,4-dienoic acid as a substrate, but is not active on the trans-isomer [2l... 

Defective enzyme in phenylalanine metabolism (tyrosine hydroxylase) results in excess phenylalanine, leading to mental retardation, unless restricted by diet. 

On more definitive testing of Piquet Yuria s blood, the plasma level of phenylalanine was elevated at 18 mg/dL (reference range, <1.2). Several phenyl ketones and other products of phenylalanine metabolism, which give the urine a characteristic odor, were found in significant quantities in the baby s urine. 

One such problem concerns the tropic acid moiety (1) found in the tropane alkaloids. It is derived from phenylalanine and its formation involves a 1,2-shift of the carboxy-group in the amino-acid. The mechanism and the substrate for rearrangement are uncertain, however (this Report, p. 12). There is a similar rearranged phenylalanine fragment in the microbial metabolite tenellin (2). That such a rearrangement should be observed both in a plant alkaloid and a microbial metabolite argues for a simple common diversion from phenylalanine metabolism. 

Phenylketonuria, an inborn error of phenylalanine metabolism, occurs with a frequency of about 1 in 10,000 births and is treated with a strict dietary regimen. Recently, some patients with PKU have been found to show increased tolerance towards phenylalanine intake, while receiving tetrahydrobiopterin (BH ) supplementation. We have treated two infants with BH -responsive PKU with BH for more than 2 years. No additional dietary control was required to maintain blood phenylalanine concentrations in the desired range. Both children have shown normal development. Generally, these results suggest that BH treatment might be an option for some patients with mild PKU, as it frees them from dietary restriction and thus improves their quality of life. 

In other areas of the brain, especially in the substantia nigra, phenylalanine metabolism ends at the stage of the neurotransmitter dopamine. Current therapeutic intervention of Parkinson s disease, a degeneration of the substantia nigra, aims primarily at substitution of the reduced dopamine levels. Since dopamine itself does not cross the blood-brain barrier, dihydroxy-phenylalanine (DOPA) is administered Instead. 

Fig. 9.1 Phenylalanine hydroxylase (PAH) and tetrahydrobiopterin (BH4) in the presence of molecular oxygen (02) convert phenylalanine to tyrosine. The alternate pathway of phenylalanine metabolism results in the accumulation of phenylalanine as well as phenylpyru-vic acid and other phenylketones that are excreted in the urine (Adapted from Scriver and Kaufman [4] and Acosta [1])...

Phenylalanine can also be transaminated to phenylpyruvic add as an alternative to hydroxylation by phenylalanine hydroxylase. Phenylpyruvic acid, along with other ketones, is excreted in the urine as phenylacetic acid, phe-acetylglutamine and phenyllactic acid. This pathway of phenylalanine metabolism is much less effective than hydroxylation [1,4]. 

Williams RA, Mamotte CD, Burnett JR. Phenylketonuria an inborn error of phenylalanine metabolism. Clin Biochem Rev. 2008 29(1) 31-41. 

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... 

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