Tyrosine, metabolism

MH van Woert. Phenylalanine and tyrosine metabolism in Parkinson s disease treated with levodopa. Clin Pharmacol Ther 12 368-375, 1971. 

Valine, leucine, and isoleucine biosynthesis Lysine biosynthesis Lysine degradation Arginine and proline metabolism Histidine metabolism Tyrosine metabolism Phenylalanine metabolism Tryptophan metabolism Phenylalanine, tyrosine, and tryptophan biosynthesis Urea cycle and metabolism of amino groups... 

Inherited Metabolic Disorders Errors of Phenylalanine and Tyrosine Metabolism L. I. Woolf... 

Pharmacology Vitamin C, a water-soluble vitamin, is an essential vitamin in man however, its exact biological functions are not fully understood. It is essential for the formation and the maintenance of intercellular ground substance and collagen, for catecholamine biosynthesis, for synthesis of carnitine and steroids, for conversion of folic acid to folinic acid and for tyrosine metabolism. 

Homogentisate oxidase catalyzes an important reaction In tyrosine metabolism, which converts the substrate homogentisic acid to the product maleylacetoacetic acid. 

Wilcken B, Hammond JW, Howard N, Bohane T, Hocart C, Halpern (1981) Hawkinsinuria a dominantly inherited defect of tyrosine metabolism with severe effects in infancy. N Engl J Med 305 865-868... 

Albinism refers to a group of conditions in which a defect in tyrosine metabolism results in a deficiency in the production of melanin. These defects result in the partial or full absence of pigment from the skin, hair, and eyes. Albinism appears in different forms, and it may be inherited by one of several modes autosomal recessive, autosomal dominant, or X-linked. Complete albinism (also called tyrosinase-negative oculocutaneous albinism) results from a defi ciency of tyrosinase activity, causing a total absence of pigment from the hair, eyes, and skin (Figure 20.20). It is the most severe form of the condition. Affected people may appear to have white hair, skin, and iris color, and they may have vision defects. They also have photophobia (sunlight is painful to their eyes), they sun burn easily, and do not tan. 

An important product of tyrosine metabolism in vetebrates is the thyroid hormone101 of which the principal and most active forms are thyroxine (T4) and triiodothyronine (T3).102 The thyroid gland is rich in iodide ion, which is actively concentrated from the plasma to 1 pM free I. 103 This iodide reacts under the influence of a peroxidase (see Fig. 16-14 and accompanying discussion)104 to iodinate tyrosyl residues of the very large 660-kDa dimeric thyroglobulin, which is stored in large amounts in the lumen of the... 

D2. Dancis, J., and Balis, M. E., A possible mechanism for the disturbance in tyrosine metabolism in phenylpyruvic oligophrenia. Pediatrics 16, 63-67 (1955). 

M8. Medes, G., A new error of tyrosine metabolism tyrosinosis. The intermediary metabolism of tyrosine and phenylalanine. Biochem. J. 26, 917-940 (1932). 

Ascorbic acid is a vitamin in primates. In most other animals, it can be synthesized by a branch of the glucoronic acid pathway (Chapter 18). It is apparently not changed into any coenzyme in the human being and participates as a vitamin in a reducing capacity in several biochemical reactions. These include the post-translational hydroxylation of proline in collagen biosynthesis (Chapter 8) and in tyrosine metabolism (Chapter 20). Ascorbic acid is oxidized to dehydroascorbic acid, a diketo derivative of ascorbate. Scurvy is a deficiency disease caused by a shortage of dietary ascorbic acid. In children, this results in defective bone formation in adults, extensive bleeding occurs in a number of locations. Scurvy is to be suspected if serum ascorbic acid levels fall below 1 jug/mL. 

A number of genetic disorders are associated with phenylalanine and tyrosine metabolism. The best known is the classic phenylketonuria, discovered in 1934 by Foiling. It is characterized by the virtual absence of phenylalanine hydroxylase from the organism. As a result, phenylalanine is converted to a large extent to phenylpyruvate, phenyllactate, and phenylacetate (Figure 20.22). Their levels and that of phenylalanine in the bloodstream are elevated. Hyper-phenylalaninemia may also result from the absence of dihydrobiopterin reductase or any enzyme required for dihydrobiopterin biosynthesis from GTP. Although the etiologies of such disorders differ from that of classic phenylke-... 

Additional errors of phenylalanine and tyrosine metabolism include tyrosinosis, or hereditary tyrosinemia, neonatal tyrosinemia, and alcaptonuria. In the first case, there is a probable defect in p-hydroxyphenylpyruvate oxidase. In neonatal tyrosinemia, the problem is transient and may be solved by the administration of ascorbic acid. Ascorbic acid is apparently a cofactor for p-hydroxy-phenylpyruvate oxidase. Alcaptonuria is a benign disorder in which homogen-tisic acid oxidase is inoperative and homogentisic acid is excreted in the urine. Air oxidizes the homogentisic acid to a pigment, giving urine a black color. This pigment also accumulates in the patient s tissues. 

Tyramine [teye ra meen] is not a clinically useful drug, but it is found in fermented foods, such as ripe cheese and Chianti wine (see MAO inhibitors, p. 123). It is a normal by-product of tyrosine metabolism. Normally, it is oxidized by MAO, but if the patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes. Like amphetamine, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine acts on adrenoceptors. 

Bough, W.A. and Gander, J.E. (1971) Exogenous L-tyrosine metabolism and dhurrin turnover in Sorghum seedlings. Phytochemistry, 10, 67-77. 

L-Tyrosine metabolism and catecholamine biosynthesis occur laigely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andUpid metabolism. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bile acids and the detoxification process of aromatic drugs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabolism related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Physiological Function. The mechanism by which L-ascorbic acid benefits an insect is unknown. The vitamin is found in many tissues where it probably plays a variety of roles related to its redox potential. Besides the possible general function of detoxifying superoxide and hydrogen peroxide, L-ascorbic acid may be involved in metabolic processes such as tyrosine metabolism, collagen formation, steroid synthesis, detoxification reactions, phagostimulation, or neuromodulation. At this time one can only speculate about the function of vitamin C in some specific tissues. 

W22. Woolf, L. I., Inherited metabolic disorders Errors of phenylalanine and tyrosine metabolism. Advan. Clin. Chem. 6, 97-230 (1963). 

Diagram 6. Relationship of metabolic defects concerned with phenylalanine and tyrosine metabolism. For structural formulas see diagrams 8, 11, and 12. 

Experiments on, or related to, alkaptonuria led to a provisional picture of phenylalanine and tyrosine metabolism shown in diagram 7. 

The work already described on man and intact animals allowed a tentative scheme to be formulated for phenylalanine and tyrosine metabolism (diagram 7). In this section the enzymic and isotopic experiments will be described which have filled in many details of the picture. The subject will again be outlined in a semihistorical manner, but for convenience the complete pathway is summarized at this stage, in diagram 8. 

Early experiments by Bernheim, Felix, Sealock, and their co-workers on oxidation of tyrosine by liver breis showed an uptake of four atoms of oxygen per mole of tyrosine, with the production of one molecule each of carbon dioxide and acetoacetate, but no ammonia (60, 61, 261, 262, 789, 976). Felix and Zorn (261) found alanine to be formed and considered this to arise from a direct splitting of the tyrosine side chain. Although the experiments with man and intact animals already described made it seem very probable that p-hydroxyphenylpyruvic acid and homogentisic acid were normal intermediates in tyrosine metabolism, and although homogentisic acid was known to be readily metabolized by normal liver (e.g., 208, 695, 976) Felix and co-workers (262) considered p-hydroxyphenylpy-ruvic acid and homogentisic acid not to be intermediates in the breakdown of tyrosine by the liver system. 

The intermediate formation of 2,5-dihydroxyphenylpyruvic acid in this conversion has not been proved by isolation. But as this is readily metabolized by tyrosine-oxidizing systems (e.g., 489), unlike the possible alternative intermediate p-hydroxyphenylacetic acid, the pathway is not in doubt. On the other hand, the detailed mechanism of this conversion is probably the major unsolved problem in the study of tyrosine metabolism. 

The influence of ascorbic acid on tyrosine metabolism in man and intact animals has been discussed under alkaptonuria and tyrosinosis q.v.). Ty-rosyluria, also called hydroxyphenyluria, i.e., the excretion of p-hydroxy-phenyl compounds in the urine, can be affected by factors other than ascor-... 

The demonstration by Knox that ascorbic acid is a cofactor in tyrosine metabolism has been discussed earlier. Though ascorbic acid is essential both for this purpose and for the prevention of scurvy, the latter is probably not due to any appreciable extent to inadequate tyrosine metabolism (e.g., 723). Further experiments with liver preparations have shown that a number of other substances can replace ascorbic acid, o-isoascorbic acid being as effective as ascorbic acid itself (160, 489). Many other ene-diols are effective in tissue homogenates (522,791) but not necessarily in the intact animal, where poor absorption or retention reduces their efficacy (661,975). Substances such as 3-methylascorbic acid (791), which do not contain an ene-diol structure, cannot replace ascorbic acid. 

---