Biochemistry of Amino Acids - A. Majster 1961

Disorders of Amino Acid Metabolism in Certain Pathological Conditions
Phenylalanine and Tyrosine Metabolism
Alcaptonuria

A characteristic feature of alkaptonuria is The excretion of homogentisic acid in the urine; the primary metabolic defect lies in the loss of The ability to oxidize homogentisic acid (apparently due to a deficiency of homogentisic acid oxidase, see p. 420).

Patients with alkaptonuria may excrete up to 0,5 g of homogentisic acid per day in their urine. A characteristic feature is the black color acquired by urine upon standing due to The oxidation of homogentisic acid by atmospheric oxygen. Judging by reports of patients whose urine darkened upon standing, this condition is apparently centuries old [107]. Garrod refers to cases of alkaptonuria in a schoolboy (described in 1584) and a monk (described in 1609) whose health remained unimpaired despite excreting black urine for long periods of time. The first thorough description of alkaptonuria belongs to Bödeker [108]; later, homogentisic acid was isolated and identified [109]. The disorder can be detected at an early age because infants' diapers quickly darken in the air. Homogentisic acid is also found in other Body Fluids [110]. Patients with alkaptonuria typically exhibit no other symptoms of the disease, save for the darkening of tendons and Cartilage in older age—a symptom known as ochronosis. Ochronosis may manifest externally as a darkening of the Nose, ears, and sclerae; autopsy reveals pigment deposits in the cartilage. Other products of Tyrosine or phenylalanine METABOLISM do not appear in the urine of alkaptonuria patients [111]. The concentration of homogentisic acid in the Blood is very low [110— 112]; apparently, the renal threshold for this compound is low. The renal clearance of homogentisic acid is extremely high; it has been suggested that the Kidneys excrete homogentisic acid not only via simple filtration, but also through active secretion. The homogentisic acid in the urine is likely formed primarily in the kidneys [111—113].

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When homogentisic acid is administered to a patient with alkaptonuria, it is excreted entirely in the urine. In healthy individuals, by contrast, this acid undergoes rapid degradation, and—except when doses of homogentisic acid are very high—no alkaptonuria is observed [113—115]. Patients with alkaptonuria excrete "excess" homogentisic acid following the ingestion of tyrosine, phenylalanine, p-hydroxyphenylpyruvic, phenyllactic, or 2,5-dihydroxyphenylpyruvic acid [111, 116—119]. In contrast, o-tyrosine, m-tyrosine, and their corresponding a-keto acids, as well as p-hydroxyphenyllactic acid, do not cause an increase in homogentisic acid excretion.

In animal experiments, it was possible to induce the excretion of homogentisic acid by administering very large doses of phenylalanine [120—127]. The excretion of homogentisic acid observed following a tyrosine load in humans and guinea pigs under conditions of ascorbic acid deficiency is eliminated by the administration of ascorbic acid [128]. In Vitamin C Deficiency, p-hydroxyphenylpyruvic and p-hydroxyphenyllactic acids are also excreted in the urine. For instance, premature infants with vitamin C hypovitaminosis excrete p-hydroxyphenylpyruvate and p-hydroxyphenyllactate, especially on a high-protein diet; these metabolic products of tyrosine disappear from the urine after Treatment of the infants with ascorbic acid [129]. The disturbances observed in ascorbic acid deficiency are consistent with in vitro experiments showing that the enzymatic oxidation of p-hydroxyphenylpyruvate requires the presence of ascorbic acid (p. 420). It has been established that ascorbic acid deficiency plays no role in the genesis of true alkaptonuria, and the administration of ascorbic acid does not correct it [111, 130, 131].

The excretion of homogentisic acid in animal experiments has also been induced by diets deficient in Sulfur-Containing Amino Acids. The resulting excretion of homogentisic acid and p-hydroxyphenylpyruvic acid was eliminated by the administration of Cysteine [132, 133]. The excretion of homogentisic acid noted in these studies, as well as in experiments with scorbutic guinea pigs, may depend both on a discoordination in Amino acid metabolism and on impaired renal function [132].