Tyrosine metabolism abnormalities

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. ... 

In pernicious anemia, the bone marrow is hyperplastic and contains many large young cells which are designated megaloblasts. The peripheral blood shows severe macrocytic anemia, leucopenia with a high percentage of old polymorphonuclear leucocytes, and thrombocytopenia. Erythrocyte destruction is excessive, as manifested by an increase in the level of bilirubin in serum and a rise in urobilin excretion in the urine. An abnormality of tyrosine metabolism is demonstrated by the excretion of certain phenolic compounds in the urine. Hydrochloric acid is absent from the gastric juice. 

Protein phosphorylation is arguably one of the most important and ubiquitous events, with 30-60% of all proteins known to exist at one time or other as phosphoproteins. Phosphorylation is a key component of many cellular processes, including proliferation, differentiation, metabolism, signal transduction, and adaptation to environmental stress and in the function of many proteins, hormones, neurotransmitters, and enzymes. An abnormal regulation of phosphorylation often results in disease. Phosphorylation most commonly occurs on serine, threonine, and tyrosine residues whereby the OH group is replaced by a phosphate group, resulting in increase in the mass of those residues by 80 Da. Phosphorylation is a reversible process, mediated by phosphotransferase enzymes, called protein kinases, and are reversed by protein phosphatases. 

Melanin is the normal pigment of the skin and mammalian hair. Carcinomatous growths in which abnormal melanin formation occurs are known as melanomas. A congenital metabolic defect in w hich skin pigmentation does not occur is known as albinism, and is inherited as a recessive Mende-lian character (cf. 40). Albinos occur in many species besides man (e.g., the pink-eyed white rabbit). As adrenaline formation is apparently unimpaired in albinos, the metabolic block presumably lies in the conversion of dihydroxyphenylalanine to melanin, as shown in diagram 6, rather than in the conversion of tyrosine to dihydroxyphenylalanine. However, the exact nature of the block has not been established. 

Specific amino acids Analysis of a few or specific amino acids is useful and easy to perform. This often requested in the detection of inborn errors of metabolism (phenylketonuria or maple syrup disease). In these cases, the abnormal amino acids are present in high concentration that makes the analysis simple. Several amino acids have been determined by CE for this purpose, such as tyrosine, proline, and phenylalanine. 

At least 35 different hereditary changes in amino acid metabolism have been identified. One of the more well known is an inherited disease associated with abnormal aromatic amino acid metabolism. In phenylketonuria (PKU), there is a lack of the enzyme phenylalanine hydroxylase. As a result, phenylalanine cannot be converted to tyrosine, leading to the accumulation of phenylalaifine and its metabolites (phenylpyruvate and phenyl-acetate) in the tissues and blood ... 

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. 

The fourth type of inborn error of thyroid hormone metabolism is characterized by the presence of a butanol-insoluble iodinated component in the serum. When this component was further purified and submitted to the action of proteolytic enzymes, iodinated tyrosines and thyronines were released in the digest. Except that these abnormal iodinated proteins have been identified, the molecular defect responsible for this form of cretinism is not understood. It is often assumed that the defect results from the absence of one or more enzymes involved in thyroglobulin degradation. 

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... 

Thyroxine (see the model above ) is an aromatic compound and a key hormone that raises metabolic rate. Low levels of thyroxine (hypothyroidism) can lead to obesity, lethargy, and an enlarged thyroid gland (goiter). The thyroid gland makes thyroxine from iodine and tyrosine, which are two essential components of our diet. Most of us obtain iodine from iodized salt, but iodine is also found in products derived from seaweed, like the kelp shown above. An abnormal level of thyroxine is a relatively common malady, however. Fortunately, low levels of thyroxine are easily corrected by hormone supplements. After we study a new class of reaction in this chapter called electrophilic aromatic substitution, we shall return to see how that reaction is related to thyroxine in "The Chemistry of... Iodine Incorporation in Thyroxine Biosynthesis."... 

A rare inborn error of metabolism in which there is abnormal tyrosine and methionine metabolism. The exact enzyme defect is... 

Several inborn errors of metabolism are concerned with the metabolism of L-phenylalanine and L-tyrosine in mammals. In several cases it has been possible to demonstrate that such biochemical disorders are associated with the absence or partial deficiency of a particular enzymatic activity. Phenylketonuria results from the absence of a normal L-phenylalanine hydroxylase activity and individuals suffering from this disease are unable to convert L-phenylalanine to L-tyrosine. Under these conditions the metabolism of the amino acid to phenylpyruvic acid, phenyl-lactic acid and phenyl acetyl glutamine is greatly exaggerated. Phenylketonuria is a severe disorder and results in a marked mental retardation, particularly in children. It is generally assumed that it is the accumulation of abnormal metabolites which is responsible for the mental symptoms associated with the disease. 

A rare inborn (recessive) abnormality of metabolism in man marked by the inability to complete the degradation of tyrosine and phenylalanine their metabolism ceases at homogentisic acid, which is excreted in the urine. The homogentisic acid oxidizes to black melanoid pigment hence, the urine of alcaptonurics slowly turns black. The defect appears to be harmless. 

Wadman, S.K., Van der Heiden, C., Ketting, D. and Van Sprang, F.J. (1971), Abnormal tyrosine and phenylalanine metabolism in patients with tyrosyluria and phenyketonuria gas-liquid chromatographic analysis of urinary metabolites. Clin. Chim. Acta, 34,277. 

Phenylalanine is normally primarily metabolized to tyrosine and is utilized for protein synthesis. When the hydroxylation of phenylalanine to tyrosine is defective (Fig. 16.11), phenylalanine accumulates in the tissues and is metabolized by alternative pathways that are essentially inactive in the normal subject. The metabolites that arise from these alternative pathways are therefore abnormal and their presence in urine may be taken as indicative of a... 

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