DISORDERS ASSOCIATED WITH THE METABOLISM OF PHENYLALANINE AND TYROSINE

Disorders of incomplete metabolism of phenylalanine and tyrosine are outstanding examples of gene-enzyme interrelationships. Phenylpyruvic oligophrenia, alkaptonuria, tyrosyluria, and albinism have been discussed and an attempt has been made to correlate clinical findings with biochemical alterations. An over-all scheme of the metabolism of phenylalanine and tyrosine and the associated enzymatic blocks is summarized in Figure 15. Phenylalanine is an essential amino acid and, in contrast to microorganisms, mammals cannot synthesize a benzene ring, de novo. The importance of phenylalanine and tyrosine metabolism is evidenced by the formation of such vital substances as protein, melanin, epinephrine, and thyroxine. Formation of protein,75 tyrosine-O-sulfate and thyroxine appear to be the preferential synthetic pathways. The function of the tyrosmne-O-sulfate is unknown but it is a constituent of fibrinogen. Most of the phenylalanine is usually converted to tyrosine which in turn is degraded to acetoacetate and fumarate. When a block occurs in the conversion of phenylalanine to tyrosine, as in phenylpyruvic oligophrenia, there is an alternate pathway available and phenylalanine is transaminated. It is impressive that there are four welldefined disorders associated with this single pathway. The clinical characteristics of some of these permit them to be easily recognized. There are probably other disorders of incomplete metabolism which are not detectable clinically or have still not been identified. Table VI summarizes a group of disorders in which the major biochemical defect appears to be related to incomplete metabolism of amino acids. Within the past year, Hartnup disease and the "maple sugar" syndrome have been identified as members of this group. The enzymes involved in four of these disorders have been identified but only in phenylpyruvic oligophrenia and tyrosyluria has lack of activity of the specffic enzyme been actually proved. It is not known whether these disorders are due to diminished enzymatic activity or actual deficiency in the enzyme. Cystinuria results from an apparent inability of the renal tubular cells to absorb cystine, lysine, arginine and ornithine. This finding suggests that permeability and carrier systems are also initially dependent on genetic factors. Haldane states that studies of the relation of the gene to permeability mechanisms will open a new area of biochemistry. [SEE TABLE VI IN SOURCE PDF] Presumably, the gene relays information to the cell for the direction of protein synthesis. The biochemistry of the gene has been studied intensively for many years and it is now generally agreed that desoxyribonucleic acid is probably the basic component of the gene. The description of the gene has been clarified by the construction of a realistic model indicating how a molecule of desoxyribonucleic acid (DNA) may exist in space and how it may replicate itself. If DNA is the genetic substance, then any slight chemical or spatial change in this molecule may result in a new gene which in turn could be exactly reproduced. The relation of gene to enzyme was suggested more than 50 years ago by the classic experiments of Cuenot. He stated that the inheritance of color in mice was dependent on the mnemone (gene) acting in the formation of specific enzymes for the production of specific pigments. This mechanism has since been verified and was the subject of two recent symposia. The formation of a specffic protein is dependent on the gene transmitting information to the template. The template is considered to be a mold, consisting of pentose nucleic acid, so that a specific and exact protein will form from the amalgamation of immediate precursors. By this system the formation of a protein is removed from the realm of chance and the result is a copy, an exact biochemically predictable molecule. When the gene is altered a new but similarly identfiable protein is formed, as has been shown by the outstanding studies of sickle cell anemia. This variation in structure may cause a diminished or total absence of activity of the enzyme and an incomplete or complete block of metabolism. The activities of certain enzymes which are markedly diminished in fetal tissue, increase with maturation, and rapidly attain the level of activity found in the adult tissue. Tyrosine transaminase, p-hydroxyphenylpyruvate oxidase, phenylalanine hydroxylase and phenylalanine transaminase are examples of this developmental pattern which are particularly pertinent to this discussion. Thus, early in life, enzymatic characteristics of disorders associated with incomplete metabolism exist in the presence of the normal genetic constitution. Environment and metabolic demands of fetal life can modify the action of the gene; for example the administration of teratogenic agents to pregnant animals or the surgical removal of endocrine glands from the fetus, results in gross abnormalities in the offspring. We have used the term,"disorders associated with incomplete metabolism," in preference to "inborn errors in metabolism" to describe phenylpyruvic oligophrenia, alkaptonuria, tyrosyluria, and albinism. "Errors of metabolism" denotes an aberrant or new pathway, while "inborn" connotes an unalterable, incontrovertible genetic state with therapeutic inhibitions. In contrast, the suggested operational term, disorders associated with incomplete metabolism, emphasizes the presence of a normal metabolic pathway with quantitative limitations, no necessary genetic implications and is therefore theoretically surmountable.