Phenylalanine abnormal metabolism

Plasma and urine samples from atherosclerotic and control rats were comparatively analyzed by ultrafast liquid chromatography coupled with ion trap-time-of-flight (IT-TOF) MS (UFLC-IT/TOF-MS) (16). They identified 12 metabolites in rat plasma and 8 metabolites in rat urine as potential biomarkers. Concentrations of leucine, phenylalanine, tryptophan, acetylcar-nitine, butyrylcamitine, propionylcamitine, and spermine in plasma and 3-0-methyl-dopa, ethyl /V2-acety I -1. -argininate, leucylproline, glucuronate, A(6)-(A-threonylcarbonyl)-adenosine, and methyl-hippuric acid in urine were decreased in atherosclerosis rats ursodeoxycholic acid, chenodeoxycholic acid, LPC (06 0), LPC (08 0), and LPC (08 1) in plasma and hippuric acid in urine were increased in atherosclerosis rats. The altered metabolites demonstrated abnormal metabolism of phenylalanine, tryptophan, bile acids, and amino acids. Lysophosphatidylcholine (LPC) plays an important role in inflammation and cell proliferation, which shows a relationship between LPC in the progress of atherosclerosis and other inflammatory diseases. 

A rare inborn (recessive) abnormality of metabolism in man marked by the inability to complete the degradation of tyrosine and phenylalanine their metabolism ceases at homogentisic acid, which is excreted in the urine. The homogentisic acid oxidizes to black melanoid pigment hence, the urine of alcaptonurics slowly turns black. The defect appears to be harmless. 

The incidence of phenylketonuria is about 1 in 20,000 newborns. The disease is inherited in an autosomal recessive manner. Heterozygotes, who make up about 1.5% of a typical population, appear normal. Carriers of the phenylketonuria gene have a reduced level of phenylalanine hydroxylase, as indicated by an increased level of phenylalanine in the blood. However, this criterion is not absolute, because the blood levels of phenylalanine in carriers and normal people overlap to some extent. The measurement of the kinetics of the disappearance of intravenously administered phenylalanine is a more definitive test for the carrier state. It should be noted that a high blood level of phenylalanine in a pregnant woman can result in abnormal development of the fetus. This is a striking example of maternal-fetal relationships at the molecular level. Table 23.3 lists some other diseases of amino acid metabolism. 

Deficiency of phenylalanine hydroxylase, tetrahydrobiopterin, or dihydropteridine reductase results in phenylketonuria (PKU), an autosomal recessive trait. Because phenylalanine accumulates in tissues and plasma (hyperphenylalaninemia), it is metabolized by alternative pathways and abnormal amounts of phenylpyruvate appear in urine (Figure 17-22). Phenylalanine hydroxylase deficiency may be complete (classic PKU, type 1) or partial... 

Abnormal indole derivatives in the urine and low levels of serotonin (a product of tryptophan metabolism) in blood and brain point to a defect in tryptophan metabolism in PKU. 5-Hydroxytryptophan decarboxylase, which catalyzes the conversion of 5-hydroxytryptophan to serotonin, is inhibited in vitro by some of the metabolites of phenylalanine. Phenylalanine hydroxylase is similar to the enzyme that catalyzes the hydroxylation of tryptophan to 5-hydroxytryptophan, a precursor of serotonin. In vitro, phenylalanine is also found to inhibit the hydroxylation of tryptophan. The mental defects associated with PKU may be caused by decreased production of serotonin. High phenylalanine levels may disturb the transport of amino... 

Specific amino acids Analysis of a few or specific amino acids is useful and easy to perform. This often requested in the detection of inborn errors of metabolism (phenylketonuria or maple syrup disease). In these cases, the abnormal amino acids are present in high concentration that makes the analysis simple. Several amino acids have been determined by CE for this purpose, such as tyrosine, proline, and phenylalanine. 

At least 35 different hereditary changes in amino acid metabolism have been identified. One of the more well known is an inherited disease associated with abnormal aromatic amino acid metabolism. In phenylketonuria (PKU), there is a lack of the enzyme phenylalanine hydroxylase. As a result, phenylalanine cannot be converted to tyrosine, leading to the accumulation of phenylalaifine and its metabolites (phenylpyruvate and phenyl-acetate) in the tissues and blood ... 

The human body is made up of molecules, as are also bacteria and other vectors of disease. We might accordingly say that all diseases are molecular diseases, involving molecules in one way or another. For example, phenylketonuria, which causes feeble-mindedness or more serious mental impairment, is an inborn error of metabolism such that the patient is not able to carry out the oxidation of phenylalanine to tyrosine. This disease is due to an abnormal gene, present in double dose either the gene is not able to manufaeture the enzyme catalysing the oxidation reaction, or it manufactures abnormal enzyme molecules, with decreased effectiveness. 

The presence of indol derivatives in the urine of phenylketonuric patients is more difficult to understand. The experiments of Tyler and Armstrong [79] suggest that there are side effects of the main metabolic block. By keeping the patient on a diet containing only sufficient amounts of phenylalanine to maintain normal growth and normal protein synthesis, these authors demonstrated that all these patients biochemical symptoms disappeared, including the excretion of indole derivatives. Furthermore, it was demonstrated that hydroxytryptophan decarboxylase (an enzyme identical to dopa decarboxylase) is inhibited by the abnormal metabolites in a way analogous to that for dopa decarboxylase. This may explain both the low levels of phenyltryptamine in patients with phenylketonuria and the accumulation of unidentified indole compounds [80, 81]. 

Knowledge of metabolic pathways of phenylalanine and tyrosine has been obtained by study of certain inborn errors of metabolism in man (see Chapter 5). Of particular interest in human nutrition is the relationship of ascorbic acid and folic acid in the metabolism of these two amino acids. In premature infants or in persons with scurvy, the feeding of high protein diets or the administration of tyrosine leads to hydroxyphenyluria. Both ascorbic acid and folic acid (large doses) will prevent the excretion of abnormal quantities of hydroxyphenyl derivatives. Recently, Sealock... 

Several inborn errors of metabolism are concerned with the metabolism of L-phenylalanine and L-tyrosine in mammals. In several cases it has been possible to demonstrate that such biochemical disorders are associated with the absence or partial deficiency of a particular enzymatic activity. Phenylketonuria results from the absence of a normal L-phenylalanine hydroxylase activity and individuals suffering from this disease are unable to convert L-phenylalanine to L-tyrosine. Under these conditions the metabolism of the amino acid to phenylpyruvic acid, phenyl-lactic acid and phenyl acetyl glutamine is greatly exaggerated. Phenylketonuria is a severe disorder and results in a marked mental retardation, particularly in children. It is generally assumed that it is the accumulation of abnormal metabolites which is responsible for the mental symptoms associated with the disease. 

One would therefore think that aspartame is completely safe. There is, however, one exeeption About 1 in 10,000 people has a genetie disorder eaUed phenylketonuria that prevents them from metabolizing phenylalanine. The ensuing accumulation of the amino acid, detected by the presence of its metabohte phenylketone (see below ) in the urine, causes abnormalities in brain function. In developed countries, phenylketonuria is included in the newborn screening panel and dealt with by medieation and a strict dietary regimen. 

The problem of pathogenesis has received more attention in the case of phenylketonuria than in most other inborn errors of metabolism. As soon as the intoxication theory was put forward, and supporting evidence in the results of dietary treatment accumulated, the search began. Early hypotheses incriminated one or other of the abnormal metabolites of phenylalanine, e.g. phenylacetic acid [63], known to affect the C.N.S., o-tyramine [64] (which probably does not occur). Several of these metabolites can inhibit such enzymes as DOPA-decarboxylase, tryptophan hydroxylase and glutamic decarboxylase of brain [65]. In fact, the concentrations of serotonin, noradrenaline and adrenaline in the blood are low in phenylketonuria [65, 66] and some theories of pathogenesis have considered that lack of these and other neurotransmitter substances at the synapses, caused by inhibition of the relevant enzyme, was the cause of the neurological disease. This was difficult to combine with the demonstrable deficiencies in... 

Wadman, S.K., Van der Heiden, C., Ketting, D. and Van Sprang, F.J. (1971), Abnormal tyrosine and phenylalanine metabolism in patients with tyrosyluria and phenyketonuria gas-liquid chromatographic analysis of urinary metabolites. Clin. Chim. Acta, 34,277. 

Phenylalanine is normally primarily metabolized to tyrosine and is utilized for protein synthesis. When the hydroxylation of phenylalanine to tyrosine is defective (Fig. 16.11), phenylalanine accumulates in the tissues and is metabolized by alternative pathways that are essentially inactive in the normal subject. The metabolites that arise from these alternative pathways are therefore abnormal and their presence in urine may be taken as indicative of a... 

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