Urine homogentisate excretion

C. Excreted in the urine in the rare hereditary disease alkaptonuria. Homogentisic acid is easily oxidized in the air to dark-coloured polymeric products, so that urine from patients with alkaptonuria turns gradually black. It is formed from tyrosine and is an intermediate in tyrosine breakdown in the body. Alkaptonuria is due to the absence of the liver enzyme which cleaves the aromatic ring. 

Accumulation of homogentisic add in the blood causes its excretion in urine, after which it gradually darkens upon exposure to air. This sign of alcaptonuria is not present in all patients with the enzyme defidency. The dark pigment also accumulates over years in the cartilage (ochronosis), and most patients develop arthritis in adulthood. 

Homogentisic acid is excreted in urine, which darkens when left standing exposed to oxygen. 

Another inheritable disease of phenylalanine catabolism is alkaptonuria, in which the defective enzyme is homogentisate dioxygenase (Fig. 18-23). Less serious than PKU, this condition produces few ill effects, although large amounts of homogentisate are excreted and its oxidation turns the urine black. Individuals with alkaptonuria are also prone to develop a form of arthri-... 

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. 

Experimental alkaptonuria has also been produced in rats on a diet de-ficent in sulfur-containing amino acids (295). Similar excretory patterns were produced after additional phenylalanine, tyrosine, or their corresponding keto acids, and the condition was relieved on gi dng cysteine, but not ascorbic acid (644). Moreover the p-hydroxyphenylpyruvate excretion was much lower, relative to the homogentisic acid excretion, than in the type of ascorbate-dependent alkaptonuria studied by Sealock in the guinea pig (rats cannot in any case be made ascorbic acid-deficient). Xeuberger and Webster (644) also showed that this second type of experimental alkaptonuria could be produced in many types of amino acid imbalance, or in protein deficiency, and that the threshold intake of phenylalanine or tyrosine required to produce the condition varied with the nutritional state and also with the acid-base balance, acid urines being associated with a decreased homogentisic acid excretion (cf. also 150, 273, 787). 

Tyrosine Catabolism - The catabolism of tyrosine to fumarate and acetoacetate is depicted in Figure 21.21. A hereditary deficiency of the enzyme homogentisic acid dioxygenase causes a disease called alkaptonuria where homogentisic acid accumulates and is excreted in large amounts in the urine. It oxidizes on standing, causing the urine to become dark. 

Another genetic disease that results from a deficiency of an enzyme in the pathway for phenylalanine degradation is al-captonuria, which is caused by lack of homogentisate dioxygenase. The only ill effect of this enzyme deficiency is black urine. The urine of those afflicted with alcaptonuria turns black because the homogentisate they excrete immediately oxidizes in the air. 

Alkaptonuria is a rare inborn error of metabolism caused by a lack of the enzyme homogentisic acid oxidase. The deficiency causes a failure to oxidize homogentisate, which is excreted in the urine in abundance. Polymerization of the metabolite, especially under alkaline conditions in the presence of oxygen, leads to the production of a black polymer. This makes the urine black if it is exposed to air for a few hours and in vivo, cartilage and other connective tissues become pigmented and take on an orange color (hence the name ochronosis for this state of the tissues the ocher color is readily seen postmortem). In later years the patients develop severe arthritis. 

Alkaptonuria is an autosomal recessive, benign disorder with a normal life expectancy. It is caused by a deficiency of homogentisate oxidase (Fig. 47.2). Homogentisate accumulates, is excreted in the urine and is gradually oxidised to a black pigment when exposed to air. It is usually detected when the nappies (or diapers) show black staining. 

Medes observed further that the excretion of this compound paralleled the patient s protein or tyrosine intake and that administration of homogentisic acid did not affect urine composition. These findings suggested that the disease is due to a block of the transformation of tyrosine to homogentisic acid. Although this is the most probable interpretation, it has not yet received direct confirmation by analysis of enzyme activity in the liver. Furthermore, determination of the abnormal metabolite in the blood has not been included in the studies of tyrosinosis. The possibility of an abnormal excretion of the compound at the level of the renal tubules cannot be excluded entirely. 

Alkaptonuria is another disease of intermediate metabolism of aromatic amino acids. It was the first of a group of diseases discovered by Sir Archibald Garrod [84] called inborn errors of metabolism. The transformation of homogentisic acid into maleylacetoace-tate is blocked in alkaptonuria. Direct evidence for the location of the metabolic block was obtained by researchers who demonstrated a specific enzymatic block in the liver of alkaptonurics. These studies also indicated that the metabolic block was due to an absence of the enzyme rather than to the presence of an inhibitor or the lack of a cofactor. Consequently, whereas the urine of normal individuals contains no homogentisic acid (the renal threshold for that compound is low in both normal and diseased individuals), large amounts are recovered from the urine of alkap-tonuric patients, and the amount excreted parallels the patients protein and tyrosine intake. 

Sometimes alkaptonuria is associated with abnormal excretion of uric acid in the urine, and alkaptonuria might be associated with defective uric acid metabolism. However, it seems more likely that the high incidence of uricemia reported is attributable to errors in the colorimetric analysis— probably due to the high levels of homogentisic acid—because cases of hyperuricemia have been reported with the colorimetric method, but not when uricase was used [88]. 

Studies on alcaptonurics have been particularly informative, since these patients excrete homogentisic acid in their urine and are apparently unable to oxidize this acid further. Assuming that homogentisic acid is a normal intermediate of tyrosine oxidation, various compounds have been fed to alcaptonurics in order to discover whether they were an intermediate in the pathway preceding the formation of homogentisic acid. From the result of such studies a scheme of the catabolism of phenylalanine and tyrosine has been developed which has been extended and supplemented by other types of experiments, particularly in recent years by experiments wdth isotopic tracers and liver slices and enzyme preparations. 

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. 

Alcaptonuria.—An inability to metabolise all the phenylalanine and tyrosine of the diet, the surplus being excreted as homogentisic acid in the urine. 

Alcaptonnria, characterised by the excretion of homogentisic acid. The urine darkens, owing to oxidative changes, after addition... 

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