Biochemistry of Amino Acids - A. Meister 1961

Disorders of Amino Acid Metabolism in Certain Pathological Conditions
Phenylalanine and Tyrosine Metabolism
Phenylpyruvic Oligophrenia

This condition, described in 1934 by Følling, is characterized by a combination of impaired intellectual development and The excretion of phenylpyruvic acid in the urine [139–142]. The disease does not always lead to early death; however, patients generally require supervision, protection from infections, and an adequate, balanced diet. Mental impairments are often quite severe, though some patients exhibit only a mild decline in cognitive abilities. Phenylpyruvic oligophrenia is an inherited disorder, apparently associated with a recessive Gene. It has been estimated that this gene occurs in approximately 0.5% of the US population [143]. Data on the incidence of the overt disease should be considered minimal, as not all cases are likely diagnosed.

In addition to phenylpyruvic acid, patients also excrete relatively large amounts of phenyllactic acid, phenylalanine, and phenylacetylglutamine [140–150]. The daily excretion of phenylpyruvic and phenyllactic acids can reach 1–2 g for each of these acids; The amount of excreted phenylalanine reaches 900 mg, and that of phenylacetylglutamine up to 2.4 g per day. Healthy individuals excrete only small amounts of phenylalanine (Table 3) and no more than a few hundred milligrams of phenylacetylglutamine. Phenylalanine accumulates in the Blood of patients, with levels reaching 10–40 mg per 100 ml of plasma (normal values are 1–2 mg). The concentration of phenylalanine in the CEREBROSPINAL FLUID is approximately the same as in the plasma [146, 151, 152]. The content of phenylpyruvic and phenylacetic acids in the blood of patients is very low [151, 153]. The concentrations of Other Amino Acids in the blood do not deviate from normal.

In phenylketonuria, the administration of phenylalanine to patients leads to an increased excretion of phenylpyruvic acid and an elevated level of phenylalanine in the plasma, whereas the ingestion of other amino acids causes no such changes [146, 151, 154, 155]. At one time, it was suggested that D-phenylalanine might be formed in this disorder, since it is known that phenylpyruvic acid is formed more readily from D-phenylalanine than from its L-isomer. However, subsequent studies failed to detect D-phenylalanine in either the blood or the urine of phenylketonuria patients [156, 157]. Therefore, the hypothesis that phenylpyruvic oligophrenia is caused by the racemization or inversion of L-phenylalanine was discarded. On the contrary, experimental support was obtained for the hypothesis that The conversion of phenylalanine to Tyrosine is blocked in this disorder. Jervis [158] noted that while healthy individuals show an increase in blood compounds reacting with Millon's reagent after ingesting phenylalanine, patients suffering from phenylketonuria exhibit no such response. Udenfriend and Bessman [159] administered C¹⁴-labeled phenylalanine to such patients and obtained compelling evidence that the conversion of phenylalanine to tyrosine is impaired in this condition. However, their experiments showed that some tyrosine is still formed from the labeled phenylalanine in this metabolic defect. For example, in control subjects, The ratio of specific activities of tyrosine to phenylalanine was about 0.2, whereas in two children suffering from phenylketonuria, it was only 0.02. These authors suggest that their findings can be explained by: a) a decrease in (rather than the complete absence of) phenylalanine hydroxylase (p. 417); b) the conversion of phenylalanine to tyrosine As a result of intestinal bacterial flora or another enzyme system (e.g., a nonspecific aromatic hydroxylase); c) the absence of a cofactor for phenylalanine oxidase; and d) the presence of a phenylalanine oxidase inhibitor. Upon examining a Liver biopsy sample from a phenylketonuria patient, no activity of The enzyme catalyzing the conversion of phenylalanine to tyrosine could be detected in the liver tissue [160].

Published data do not provide grounds to consider the conversion of phenylalanine to tyrosine as completely blocked, but the inhibition of this conversion is large enough to account for most of the described facts. The restriction of phenylalanine conversion to tyrosine should lead to the accumulation of phenylalanine, and the Transamination of this amino acid to The formation of phenylpyruvic acid. Subsequent transformations of phenylpyruvate yield phenyllactic acid and elevated amounts of phenylacetylglutamine compared to normal levels. The presence of phenylacetic acid in the urine of phenylketonuria patients can be explained by the decarboxylation of phenylpyruvic acid, which possibly proceeds non-enzymatically. It is well established that ingested phenylacetic acid is excreted in humans as phenylacetylglutamine (p. 421). The presence of free phenylacetic acid in Tissues has not yet been established; it is possible that phenylacetic acid rapidly combines with glutamine as it is formed, or that phenylacetylglutamine is synthesized directly from phenylpyruvate (e.g., with The intermediate formation of phenylacetyl-coenzyme A).

The involvement of transamination reactions in the formation of phenylpyruvic acid is consistent with the fact that the oral administration of glutamine, glutamate, or asparagine decreases the excretion of phenylpyruvic acid. It has been suggested that the administered amino acids shift the equilibrium of transamination reactions in vivo in favor of phenylalanine. The administration of glutamine has no noticeable effect on the excretion of phenylacetylglutamine; apparently, the excretion of the latter does not lead to a significant depletion of the body's glutamine reserves [161].

Several hypotheses have been proposed regarding the chemical mechanism underlying the impairment of a child's mental development in phenylketonuria. It is possible that phenylacetic acid, whose toxic effect on The Nervous system is known [162], or other phenylalanine metabolites cause Brain damage. The possibility of a direct harmful effect of phenylalanine itself on the brain cannot be ruled out either. From this perspective, of considerable interest is the report that blood Proteins from patients with phenylpyruvic oligophrenia contain a higher-than-normal amount of phenylalanine [163] (see, however, [164]). It should also be noted that phenylalanine can competitively inhibit The activity of fungal tyrosinase [165]; it is possible that high concentrations of phenylalanine also inhibit other metabolic transformations of tyrosine.

Recently, reports have appeared on the Treatment of phenylketonuria patients using a diet low in phenylalanine and adequate in tyrosine [166–169]. Some patients receiving a phenylalanine-restricted diet showed a slight improvement in cognitive abilities. It is very likely, however, that this therapeutic approach, if effective at all, is useful only at an early age before permanent brain damage has developed. Restricting the amount of phenylalanine in the diet leads to a significant reduction in phenylketonuria and blood phenylalanine levels. It has been proposed to use glutamine administration alongside phenylalanine restriction for treatment. It is known that orally administered glutamine rapidly enters the brain and other tissues; maintaining a sufficiently high level of glutamine in tissues could help suppress the formation of phenylpyruvate in tissues [161].

One might have expected tyrosine METABOLISM to be impaired in phenylketonuria. In addition to the marked inhibition of tyrosine synthesis from phenylalanine, an inhibitory effect of excess phenylalanine on tyrosine transformations is also possible (cf. [165]). This assumption is supported by the tendency toward reduced pigmentation observed in phenylketonuria patients. In some patients who received a phenylalanine-restricted diet for several months, darkening of the Hair and Skin was noted. Patients suffering from phenylketonuria have been observed to exhibit hypersensitivity to adrenaline, which may indicate an impairment in endogenous adrenaline formation; there is no indication of thyroid dysfunction in such patients [144].

Due to the discovery of A number of unusual aromatic amino acid metabolites in the urine of phenylketonuria patients, the question arose as to the possible presence of other metabolic defects in this disorder. For example, p-hydroxyphenylacetic, o-hydroxyphenylacetic, and p-hydroxyphenyllactic acids were found in the urine of phenylketonuria patients [170–176]. Furthermore, the appearance of certain indole derivatives in the urine indicates a disturbance in Tryptophan Metabolism [177]. The formation of these compounds is likely a secondary consequence of the primary defect consisting of impaired tyrosine formation from phenylalanine (cf. [178]). Further study of The Mechanism of phenylalanine-to-tyrosine conversion will be of great importance; in particular, it is crucial to determine whether the primary metabolic defect lies in an enzyme deficiency or in a shortage of a specific cofactor (p. 417) that may participate in a series of enzymatic reactions.