Phenylketonuria Metabolic alterations

Metabolic Alterations, Many of the biochemical anomalies of phenylketonuria can be explained by the inhibition or absence of phenylalanine hydroxylase. The evidence in favor of this mode of pathogenesis is both direct and indirect. The indirect evidence is based on the metabolic experiments of Jervis, who administered a variety of amino acids to phenylketonuric patients and demonstrated that only phenylalanine increases the urinary excretion of phenylalanine and all its derivatives phenylpyruvic, phenyllactic, and phenylacetic acids. These experiments suggest that the block in the phenylalanine-tyrosine pathway is located beyond phenylalanine. Since tyrosine administration to phenylketonuric patients did not produce such effects, the block was assumed to be located between phenylalanine and tyrosine. This was confirmed by isotope experiments. When labeled phenylalanine is administered to normal patients, radioactivity is soon recovered in tyrosine and in proteins. In phenylketonuric patients, most of the radioactivity is recovered in the urine, and practically none is found in the protein. The administration of phenylpyruvic acid and phenylacetic acid demonstrated that in the phenylketonuric patient there is no block in the conversion of these compounds into phenylalanine. However, the most conclusive evidence was obtained when Jervis studied autopsy specimens from normal and phenylketonuric individuals and demonstrated that phenylalanine hydroxylase activity is practically nonexistent in phenylketonuric patients [76]. 

Using this isotope labeling approach, metabolites in human plasma have been quantified (38) and altered metabolites have been detected in urine that are due to metabolic disorders such as tyrosinemia type II, argininosuccinic aciduria, homocystinuria, and phenylketonuria (20). Most recently, a smart isotope tag, 15N-cholamine, has been developed for effective detection of the same metabolites using both NMR and MS methods. This approach maximizes the combined strengths of two powerful analytical techniques for a variety of metabolomics applications. 15N-cholamine possesses dual characteristics an NMR-sensitive heteronuclear isotope with good chemical shift dispersion and a permanent charge that improves MS sensitivity (48). 

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... 

Despite the relatively few steps in intermediary metabolism of the aromatic amino acids, a large number of metabolic errors have been reported. Some, like phenylketonuria, lead to dramatic clinical situations, whereas others, like alkaptonuria, are less clinically important, and still others, like tyrosinosis, have no clinical significance. The reasons for many errors in a given pathway are not understood. Metabolic errors may be as common in other metabolic pathways, but they are not observed either because they do not lead to clinical alterations or because they are lethal. However, the genes concerned with the appearance of each enzyme involved in a specific metabolic pathway may be located on adjacent loci in the chromosome, and these loci are perhaps more prone to spontaneous mutation. 

Parahydroxyphenylpyruvic, phenylacetic, and phenyllactic acids inhibit tyrosinase, but whereas the first of these compounds is a potent inhibitor, the others are only weak inhibitors. It seems that if this inhibitory effect were important in phenylketonuria, pigment metabolism would be more apparently altered in tyrosinosis than in phenylketonuria, which seems not to be the case. However, the enzyme block might explain why small doses or dietary amounts of tyrosine have no effect on the pigmentation of patients with phenylketonuria. Only when large doses of the amino acid are administered are pigmentation and epinephrine biosynthesis restored to normal, probably because tyrosine competes with phenylalanine metabolites for melanocyte tyrosinase and dopa decarboxylase. 

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