Homogentisate, accumulation

Homogentisate accumulates, forming polymers that cause urine to darken on standing. 

Alcaptonuria occurs when homogentisate, an intermediate in tyrosine metabolism, cannot be further oxidized because the next enzyme in the pathway, homogentisate oxidase, is defective. Homogentisate accumulates and auto-oxidizes, forming a dark pigment, which discolors the urine and stains the diapers of affected infants. Later in life, the chronic accumulation of this pigment in cartilage may cause arthritic joint pain. 

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. 

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. 

Correct answer = B. Alkaptonuria is a rare metabolic disease involving a deficiency in homogentisic acid oxidase, and the subsequent accumulation of homogentisic acid in the urine, which turns dark upon standing. The elevation of methylmalonate (due to methylmalonyl CoA mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase deficiency), a-ketoisovalerate (due to branched-chain a-ketoacid dehydrogenase deficiency), and homocystine (due to cystathionine synthase deficiency) are inconsistent with a healthy child with darkening of the urine. 

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. 

B. PKU is caused by a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. A defect in tyrosine degradation causes homogentisic acid to accumulate and produce dark pigments (alcaptonuria). A defect in the conversion of tyrosine to the skin pigment melanin causes albinism. 

Inhibition of homogentisic acid oxidase, leading to local accumulation of homogentisic acid followed by polymerization that forms the ochronotic blue-black pigment. 

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. 

The oxidative breakdown of the amino acid tyrosine contains a stage in which homogentisic acid is converted to maley-lacetoacetic acid, a reaction catalysed by homogentisic acid oxidase. A deficiency of this enzyme results in the accumulation... 

An organic acid found in the urine of patients with alkaptonuria, a hereditary condition in which there is a deficiency of homo-gentisic acid oxidase, one of the enzymes of tyrosine metabolism. As a result, homogentisic acid accumulates in the blood, tissues and urine. Urines containing homogentisic acid turn dark on standing due to oxidation and polymerization of the compound to the black pigment alkapton. 

Fig. 2. Effect of homogentisate (HGA) on phytoene accumulation in the third leaves of early watergrass 6 days after treatment. Error bars are SE of the means. Re Mx>duced with the permission from ref. 12. Copyright Blackwell Publishing Ltd.

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