Bert N. La Du

Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: Review of world literature (1584–1962)

Abstract The biomedical literature on alcaptonuria, ochronosis and ochronotic joint disease, including 604 cases reported from thirty-five countries, is reviewed. The history of the development of our knowledge concerning this hereditary metabolic disorder, from 1584 to 1962, is recapitulated. The nature of the biochemical defect, a deficiency of homogentisic acid oxidase, in alcaptonuria is described and the pattern of genetic transmission traced. The geographic and racial distribution, and the multisystemic clinical manifestations of ochronosis are summarized. The diagnostic features and differential diagnostic considerations are presented. The gross, histopathologic and electron microscopic changes as well as pathogenesis are discussed. The various types of treatment attempted, without success, are mentioned.

THE ROLE OF ASCORBIC ACID IN TYROSINE METABOLISM

It has been known for many years that animals and man deficient in ascorbic acid metabolize tyrosine incompletely when given extra amounts of this amino acid. In fact, the need for vitamin C to maintain normal tyrosine oxidation has been referred to many times as one of the best examples of a requirement for this vitamin in a specific biochemical reaction. This paper will review briefly the historical development of our knowledge concerning the relationship between ascorbic acid and tyrosine metabolism. Data supporting our present concept of the role of the vitamin in tyrosine metabolism and an interpretation of these results in connection with the general problem of understanding other biochemical and physiological functions of this vitamin will also be given. The first evidence that ascorbic acid is needed for the complete metabolism of tyrosine was obtained by Sealock and Silberstein in 1939l and 1940.2 These investigators observed that scorbutic guinea pigs fed L-tyrosine excreted homogentisic acid, p-hydroxyphenylpyruvic acid, and p-hydroxyphenyllactic acid. However, the excretion of these aromatic acids ceased when L-ascorbic acid was given to these animals. A similar defect in tyrosine metabolism in infants was reported by Levine et aZ. in 19393 and 1941.4~~ Premature infants on a relatively high intake of protein were found to excrete p-hydroxyphenylpyruvic acid and p-hydroxyphenyllactic acid, and full-term infants excreted the aromatic acids when given extra tyrosine or phenylalanine. The defective metabolism in these infants was also corrected by the administration of vitamin C. I t is of interest that the defect in scorbutic guinea pigs could be corrected not only by ascorbic acid but, as Woodruff and Darby reported,‘j by the administration of relatively large amounts of folic acid. Further data concerning the relationship of folk acid and ascorbic acid will be presented in this paper. One of the most important papers concerning the role of ascorbic acid in tyrosine metabolism is that of Painter and Zilva,’ who studied the quantitative relationship between the amount of vitamin C required to prevent the excretion of tyrosyl metabolites as the amount of tyrosine fed to guinea pigs was increased. Two findings of particular interest in their paper were: (1) scorbutic guinea pigs on a moderate intake of dietary tyrosine did not excrete tyrosyl metabolites; that is, the defect appeared only upon feeding extra tyrosine to the guinea pigs; and (2) when large amounts of tyrosine were fed to scorbutic guinea pigs, the amount of ascorbic acid required to prevent tyrosyluria greatly exceeded the amount of the vitamin necessary to prevent scurvy. Painter and Zilva, with keen insight, questioned whether ascorbic acid was acting as a vitamin in maintaining normal tyrosine oxidation. They concluded,’ “The dependence of complete degradation of 1-tyrosine in high doses on the presence of excess 1-ascorbic acid in the guinea-pig system does not necessarily indicate a connexion between the normal function of Z-ascorbic acid and the normal metabolism of aromatic amino-acids.”

Oxidation of homogentisic acid catalyzed by horse-radish peroxidase

Horse-radish peroxidase catalyzes the oxidation of homogentisic acid in the presence of sulfhydryl compounds to form products similar to those obtained by the spontaneous reaction of benzoquinoneacetic acid with sulfhydryl agents. Other heme proteins, such as catalase, cytochrome c, hemoglobin and methemoglobin, do not catalyze this oxidation. Studies on substrate specificity have indicated that a number of aromatic compounds containing disubstituted hydroxy or amino groups in the para position are oxidized in this system. A scheme is presented illustrating a mechanism to explain the formation of thioether derivatives of homogentisic acid and sulfhydryl agents in the presence of horse-radish peroxidase. Similar reactions may be involved in the formation of ochronotic pigment in the connective tissues of alcaptonuric subjects or after topical application of phenol or resorcinol.

Biochemical Abnormalities in Hereditary Diseases

Excerpt Dr. Joseph J. Bunim: In a recent Harvey lecture (1), Dr. James V. Neel stated that The ultimate basis of biogenetic traits resides in some 20 thousand pairs of genes. The term gene refers ...