Homogentisate oxidase and

Inborn errors of metabolism are inherited metabolic disorders caused by the absence of an enzyme in a metabolic pathway. Alkaptonuria is caused by the lack of homogentisate oxidase and is harmless, whereas phenylketonuria, which is due to a lack of phenylalanine hydroxylase, can cause severe mental retardation. 

The dioxygenases, which incorporate two atoms of oxygen into one molecule of the substrate, are enzymes which are frequently involved in the cleavage of bonds in an aromatic ring. Typical of these are homogentisate oxidase and L-tryptophan oxidase (L-tryptophan pyrrolase) and two bacterial oxygenases pyrocatechase and metapyrocatechase. ... 

Tracer studies of the fate of oxygen consumed during protocate-chuic acid cleavage have not been carried ocit, but because of oxygen stoichiometry, dependence of the enzyme upon ferrous ions, and resemblance of the over-all reaction to those catalyzed by pyrocate-chase, homogentisate oxidase, and 3-hydroxyanthranilate oxidase (compare 171), it is reasonable to classify protocatechuic acid oxidase as an oxygen transferase. 

Examples include the liver enzymes, homogentisate dioxygenase (oxidase) and 3-hydroxyantliranilate dioxygenase (oxidase), that contain iron and L-trypto-phan dioxygenase (tryptophan pyrrolase) (Chapter 30), that utilizes heme. 

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. 

The metabolism of phenylalanine will now be considered in some detail, as two inborn errors of metabolism are known that affect this pathway. Phenylalanine is first hydroxylated by phenylalanine hydroxylase to form another aromatic amino acid tyrosine (Fig. 8). The coenzyme for this reaction is the reductant tetrahydrobiopterin which is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is classified as a monooxygenase as one of the atoms of 02 appears in the product and the other in HzO. The tyrosine is then trans-aminated to p-hydroxyphenylpyruvate, which is in turn converted into homogentisate by p-hydroxyphenylpyruvate hydroxylase. This hydroxylase is an example of a dioxygenase, as both atoms of 02 become incorporated into the product (Fig. 8). The homogentisate is then cleaved by homogentisate oxidase, another dioxygenase, before fumarate and acetoacetate are produced... 

The major quantitative pathway of tyrosine catabolism produces acetoacetate and fumarate. If homogentisate oxidase is missing, the result is alcaptonuriadark urine. 

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. 

Homogentisic acid is oxidized by a ferrous ion-requiring enzyme, as shown by Suda and Takeda, and confirmed by several others. Homogentisic oxidase also requires a sulfhydryl compound. One molecule of oxygen is consumed in the reaction, presumably in a single step. The product has been identified as maleylacetoacetate by Knox and Edwards (V). ... 

Alcaptonuria was the first of Garrod s inborn errors of metabolism to be recognised and is caused by the absence of homo-gentisate oxidase and hence results in an inability to metabolise homogentisic acid further. It is characterised by the excretion of relatively large amounts (up to half a gram daily) of homogentisic... 

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