Urine 5-hydroxytryptophan

Patients with aromatic L-amino acid decarboxylase deficiency present with clinical and biochemical manifestations that overlap those of the tyrosine hydroxylase deficiency states described previously. However, this deficiency state is characterized by additional decreases in CSF and urinary levels of 5-HIAA. Also, levels of L-dopa in urine, plasma, and cerebrospinal fluid are increased, and not decreased as in the other deficiency states. Levels of 5-hydroxytryptophan are similarly increased. 

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... 

Tryptophan appears to be converted to a larger number of metabolites than any of the other amino acids. The degradation of tryptophan in animals occurs mainly in two pathways, I and II (Figure 4.1). The first major pathway (I), initiated by the action of tryptophan dioxygenase, involves oxidation of tryptophan to N - fc > r my I ky n urenine and the formation of a series of intermediates and byproducts, most of which appear in varying amounts in the urine, the sum of which accounts for the total metabolism of tryptophan, approximately. The second pathway (II) involves hydroxylation of tryptophan to 5-hydroxytryptophan and decarboxylation of this compound to 5-hydroxytryptamine (serotonin), a potent vasoconstrictor found particularly in the brain, intestinal tissues, blood platelets, and mast cells. A small percentage (3%) of dietary tryptophan is metabolized via the pathway (III) to indoleacetic acid. Other minor pathways also exist in animal tissues. 

The hydroxylation of tryptophan produces 5-hydroxytryptophan, which can then be decarboxylated, catalyzed by tryptophan decarboxylase, a PALP-requiring enzyme, to 5-hydroxy tryptamine, also known as serotonin. Serotonin is an important compound in normal brain function and tranquility. Therefore, any disturbance of tryptophan metabolism via this pathway can lead to mental disturbances. Serotonin can be destroyed by the enzyme monoamine oxidase (a flavo protein), which catalyzes the formation of ammonia and 5-hydroxyindole acetaldehyde in an irreversible reaction. The aldehyde is rapidly oxidized enzymatically, utilizing NAD+ to form 5-hydroxy indoleacetate, which is then usually excreted. The formation and turnover of serotonin can be estimated by 5-hydroxy indoleacetate output in the urine. 

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]. 

An intermediate in the conversion of tryptophan to 5-hydroxy tryptamine (serotonin). In some cases of carcinoid syndrome it i excreted in large amounts in the urine, even though the 5 hydroxyindoleacetic acid excretion may be normal. This i thought to be because the cells lack the decarboxylase whicl converts 5-hydroxytryptophan to 5-hydroxytryptamine. 

To form serotonin from trsrptophan requires hydroxylation of the latter. Such a hydroxylating enzyme has not yet been detected in animal tissues. 5-Hydroxytryptophan, the hydroxylated product, has been observed in toads 366), the urine of carcinoid patients (366), and in bacteria (367). 

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