Homogentisic acid oxidation

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. 

Five enzyme steps have been demonstrated to be required in the conversion of tyrosine to fumaric and acetoacetic acid. These consist of a transamination to p-hydroxyphenylpyruvate, a simultaneous oxidation, migration of the side chain and decarboxylation to form homogentisic acid, oxidation of the latter to maleylacetoacetic acid, isomerization of this compound to fumarylacetoacetic acid, and hydrolysis of this acid to fumaric acid and acetoacetic acid. 

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. 

The fundamental role of ascorbic acid in metabolic processes is not well understood. There is some evidence that it may be involved in metabolic hydroxylation reactions of tyrosine, proline, and some steroid hormones, and in the cleavage-oxidation of homogentisic acid. Its function in these metabolic processes appears to be related to the ability of vitamin C to act as a reducing agent. 

The allyl group in the allylphenols can be oxidized, after protecting the hydroxyl group, to yield substituted phenylacetaldehydes 78 - 76 76 and phenylacetic acids. Thus, homogentisic acid LXIII is prepared readily by ozonizing the dibenzoate of allylhydroqumone LXIV, which is obtained by rearrangement of the allyl ether of hydroquinone mono-... 

In oxidation reactions of ascorbic acid, homogentisic acid and hydroquinone by poly(l-histidine) — Cu(II) complex, the reaction profile shows a Michaelis-Menten type curve in the reaction condition of pH ranging from 5—6. These oxidation reaction rates are higher than the oxidation rates by the catalyst without poly(l-histidine). On the other hand, the rate of oxidation of a positively charged substrate, phenylenedi-... 

Table 18. Oxidation of ascorbic acid, homogentisic acid and p-hydroquinone by poly(L-Iysine)-Cu(II) complex...

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. 

Early experiments by Bernheim, Felix, Sealock, and their co-workers on oxidation of tyrosine by liver breis showed an uptake of four atoms of oxygen per mole of tyrosine, with the production of one molecule each of carbon dioxide and acetoacetate, but no ammonia (60, 61, 261, 262, 789, 976). Felix and Zorn (261) found alanine to be formed and considered this to arise from a direct splitting of the tyrosine side chain. Although the experiments with man and intact animals already described made it seem very probable that p-hydroxyphenylpyruvic acid and homogentisic acid were normal intermediates in tyrosine metabolism, and although homogentisic acid was known to be readily metabolized by normal liver (e.g., 208, 695, 976) Felix and co-workers (262) considered p-hydroxyphenylpy-ruvic acid and homogentisic acid not to be intermediates in the breakdown of tyrosine by the liver system. 

Alcaptonuria is a rare metabolic hereditary disease in which homogentisic acid is eliminated in urine, which darkens upon exposure to air owing to oxidation of... 

The amino acids phenylalanine and its hydroxylated derivative, tyrosine, are both catabolised in the livers of animals to fumaric acid and acetoacetic acid via homogentisic acid. This is formed by the oxidation of 4-hydroxyphenylpyruvate, catalysed by the copper containing enzyme 4-hydroxyphenylpyruvate dioxygenase, which requires vitamin C for its activity. The complete sequence is shown in Figure 5.13. The dioxygenase is so called because both the atoms of the... 

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. 

Biogenetic-type oxidation of p-hydroxyphenylpyruvic acid to homogentisic acid. < Photooxidation of p-hydroxyphenylpymvic acid (1) with Rose Bengal... 

La Du, 8.N. Zannoni, V.G. The Tyrosine Oxidation System of Liver II Oxidation of p-Hydroxylphenylpyruvic Acid to Homogentisic Acid (1955) 217 777-787... 

Phenylalanine is ultimately catabolized to acetoacetate and fumarate, so it is both ketogenic and glucogenic. Initially, phenylalanine is hydroxylated to tyrosine, then transaminated to j5-hydroxyphenylpyruvate. This is farther oxidized to homogentisic acid and then to fumarate and acetoacetate. What happens to a patient if the enzyme that is required for the cleavage of the aromatic ring is absent ... 

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. 

Saito, I., Y. Chujo, H. Shimazu, M. Yamane, T. Matsuura, and H. J. Cahnmann Non Enzymic Oxidation of p-Hydroxyphenylpyruvic Acid with Singlet Oxygen to Homogentisic Acid. A Model for the Action of p-Hydroxyphenylpyruvate Hydroxylase. J. Amer. Chem. Soc. 97, 5272 (1975). 

Although plants and bacteria do not have the ability to do so, most animals can convert phenylalanine to tyrosine (Haslam, 1974). C6-C2 compounds are probably formed by a-oxidation of ketoacids such as phenylp)nuvic (10) and p-hydroxypyruvic acid (11). One well-known example, phen-ylacetic acid (8), is common in plants (Gross, 1981). Mammals and some microorganisms convert phenylalanine and t5rrosine to another C6-C2 compound, homogentisic acid (9) (Fig. 8.3). 

In alkaptonuria, homogentisic acid (28) is excreted in excessive amounts indicating that in this metabolic disease the opening of the aromatic ring and complete oxidation to CO2 and H2O is blocked. In albinism, there is a deficiency of the enzyme systems responsible for the formation of melanin from tyrosine (24) (Figure 3.7). 

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