Scurvy tyrosine metabolism

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. 

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). 

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. 

The metabolic defect in tyrosine metabolism is therefore induced by the extra tyrosine fed and is not a necessary part of scurvy. The fact that it can be induced in animals whose tissues are less than saturated with ascorbic acid, but not in animals saturated with ascorbic acid, supports the value of high nutritional intakes of vitamin C. 

Folic Acid—Ascorbic Acid Relationships. Folic acid and ascorbic acid have some interesting metabolic relationships, among which is a role in tyrosine metabolism. Abnormal excretion of tyrosine metabolites occurs in human infants with scurvy, and in premature infants when the diet is high in this amino acid. Folic acid, in large doses, will prevent or relieve this abnormal excretion, as does ascorbic acid. Folic acid exerts a similar action in scorbutic guinea pigs. ... 

Tyrosyluria (the excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyl-lactate and 4-hydroxyphenylacetate with hypertyrosinaemia) occurs in some normal newborn babies, particularly premature babies, scurvy (ascorbate or vitamin C deficiency), tyrosinosis (Medes, 1932), hepatic cytosol tyrosine transaminase deficiency (oculo-cutaneous tyrosinaemia) (Kennaway and Buist, 1971), in hereditary tyrosinaemia ( inborn hepatorenal dysfunction with tryosyluria ) (LaDu and Gjessing, 1978) and as a secondary phenomenon to a number of liver diseases, including several inherited metabolic diseases unassociated directly with tyrosine metabolism (for example, propionic acidaemia) or involving disorders of carbohydrate metabolism (for example, galactosaemia and fructosaemia). 

In addition to collagen metabolism and scavenging ROS species to limit inflammation as noted above, ascorbate is required for the synthesis of norepinephrine from tyrosine, of carnitine from y-butyrobetaine whose immediate precursor is made by trimethylating lysine, for folinic acid production from folic acid. In the absence of ascorbate, the reduced activity of these processes slows nerve, energy and cardiac output, causingthe affected person to become exhausted and irritable. Scurvy is the old English word for ill-tempered. 

Knowledge of metabolic pathways of phenylalanine and tyrosine has been obtained by study of certain inborn errors of metabolism in man (see Chapter 5). Of particular interest in human nutrition is the relationship of ascorbic acid and folic acid in the metabolism of these two amino acids. In premature infants or in persons with scurvy, the feeding of high protein diets or the administration of tyrosine leads to hydroxyphenyluria. Both ascorbic acid and folic acid (large doses) will prevent the excretion of abnormal quantities of hydroxyphenyl derivatives. Recently, Sealock... 

Although ascorbic acid has been shown to have many biologic functions, little is known of its chemical role in metabolic processes. Recently, Sealock and Goodland and Knox and LeMay-Knox have demonstrated that ascorbic acid is a coenzyme in the oxidation of tyrosine. This is the only section of the vitamin s activity in which the molecular processes that depend on it are clearly understood (Chapter 11). This explains the abnormal excretion of tyrosine metabolites in human scurvy and the return to... 

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