Human diseases Phenylketonuria

Having briefly defined these four endpoints, I would like to ask, Are they related to known human disease Can they be measured quantitatively and Can they be measured with facility for inclusion in an overall plan for environmental bioassay Table I lists examples of gene locus mutations resulting in human disease phenylketonuria, histidinemia, Hartnup disease, and cvstinuria. Phenvlketonuria is... 

As a specific example, let us consider the human disease phenylketonuria, which is caused by the lack of an essential enzyme, phenylalanine 4-monooxygenase. I shall return to this in the next chapter, and for the moment it is sufficient to say that people who lack the enzyme completely have the disease, but people who have only half of the normal amount of enzyme have no related health problems at aU half the normal amount of enzyme appears to be just as good as the full amount. How can this be If they have half the normal amount of enzyme (as they do, in this and other similar cases), then the reaction the enzyme catalyzes should proceed half as fast, and ought this not have at least some effect If not, does this not mean that normal individuals have at least twice as much of the enzyme as they need, and that the human species could evolve to become more efficient by decreasing the amount they make, thereby releasing precious resources for other purposes ... 

Phenylketonuria. A human disease caused by a genetic deficiency in the enzyme that converts phenylalanine to tyrosine. The immediate cause of the disease is an excess of phenylalanine. The condition can be alleviated by a diet low in phenylalanine. 

An inability to degrade amino acids causes many genetic diseases in humans. These diseases include phenylketonuria (PKU), which results from an inability to convert phenylalanine to tyrosine. The phenylalanine is instead transaminated to phenylpyruvic acid, which is excreted in the urine, although not fast enough to prevent harm. PKU was formerly a major cause of severe mental retardation. Now, however, public health laboratories screen the urine of every newborn child in the United States for the presence of phenylpyru-vate, and place children with the genetic disease on a synthetic low-phenylalanine diet to prevent neurological damage. 

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. 

The intact animal can be improved for experimental purposes if it is rendered abnormal in some way, by genetic malfunction, by illness, or by operation. Genetic defects, or mutations, are used widely in the study of bacterial metabolism, where they can be read ily induced, for example through irradiation by X-rays or from a radioactive source. Genetic defects frequently reveal themselves in the form of the absence of one specific enzyme, and metabolic studies with such enzymically defective preparations are of the same type as those made possible by the use of a specific enzymic inhibitor which we discussed above. Genetic defects in animals are rarer, but classic cases of the absence of specific enzymes and hence the accumulation of abnormal metabolites are provided in humans by the genetically carried diseases of phenylketonuria and alkaptonuria. In both, unusual substances are excreted in the urine, and the analysis of the reasons for their appearance has led to valuable information about the mechanism of amino acid metabolism in the body. 

This happens to be an example that has been very thoroughly studied in the human species, as phenylketonuria is a serious disease that is easily diagnosed... 

Phenylketonuria. Many enzyme deficiency diseases have been discovered that affect the pathways of amino acid metabolism. These deficiency diseases have helped researchers to elucidate the pathways in humans, in whom experimental manipulation is, at best, unethical. These spontaneous mutations ( experiments of nature), although devastating to patients, have resulted in an understanding of these diseases that now permit treatment of inborn errors of metabolism that were once considered to be untreatable. 

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. 

Orthomolecular psychiatric therapy is the treatment of mental disease by the provision of the optimum molecular environment for the mind, especially the optimum concentrations of substances normally present in the human body ). An example is the treatment of phenyl-ketonuric children by use of a diet containing a smaller than normal amount of the amino acid phenylalanine. Phenylketonuria (2) results from a genetic defect that leads to a decreased amount or effectiveness of the enzyme catalyzing the oxidation of phenylalanine to tyrosine. The patients on a normal diet have in their tissues abnormally high concentrations of phenylalanine and some of its reaction products, which, possibly in conjunction with the decreased concentration of tyrosine, cause the mental and physical manifestations of the disease (mental deficiency, severe eczema, and others). A decrease in the amount of phenylalanine ingested results in an approximation to the normal or optimum concentrations and to the... 

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