Phenylketonuria Dopa decarboxylase

The answer is e. (Murray, pp 307-346. Scriver, pp 1667—1724. Sack, pp 121-138. Wilson, pp 287—3177) In humans, tyrosine can be formed by the hydroxylation of phenylalanine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase. A deficiency of phenylalanine hydroxylase results in the disease called phenylketonuria [PKU(261600)]. In this disease it is usually the accumulation of phenylalanine and its metabolites rather than the lack of tyrosine that is the cause of the severe mental retardation ultimately seen. Once formed, tyrosine is the precursor of many important signal molecules. Catalyzed by tyrosine hydroxylase, tyrosine is hydroxylated to form L-dihydroxyphenylalanine (dopa), which in turn is decarboxylated to form dopamine in the presence of dopa decarboxylase. Then, norepinephrine and finally epinephrine are formed from dopamine. All of these are signal molecules to some degree. Dopa and inhibitors of dopa decarboxylase are used in the treatment of Parkinson s disease, a neurologic disorder. Norepinephrine is a transmitter at smooth-muscle junctions innervated by sympathetic nerve libers. Epinephrine and dopamine are catecholamine transmitters synthesized in sympathetic nerve terminals and in the adrenal gland. Tyrosine is also the precursor of thyroxine, the major thyroid hormone, and melanin, a skin pigment. 

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. 

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]. 

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... 

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See also in sourсe #XX -- [ ]

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