| Alkaptonuria (black urine disease)
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| A full-term infant, born to a normal and healthy mother and father, was observed to have a marked lack of pigmentation. The infant, who appeared to be otherwise normal, had blue eyes and very light blond, almost white, hair. This lack of pigmentation was confirmed as classical albinism on the basis of a family history and the establishment of a lack of the enzyme, tyrosinase, which is responsible for a two-step hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA) and a subsequent further oxidation to a quinone, a precursor of melanin in melanocytes. |
| Comment. A separate DOPA-producing enzyme, tyrosine hydroxylase, is involved in biosynthesis of the catecholamine neurotransmitters, so albinos do not appear to have neurological deficits. As a result of their lack of pigmentation, however, they are quite sensitive to damage from sunlight and must take added precautions against ultraviolet radiation from the sun. Albinos have normal eyesight, in spite of the lack of pigmentation, but are generally very sensitive to bright light. (See Fig. 18.12.) |
| PHENYLALANINE HYDROXYLASE |
| The hydroxylation of phenylalanine is a critical step in the catabolism of that amino acid and its conversion to tyrosine, thyroid hormone and the catecholamine hormones. Phenylalanine hydroxylase is an example of a mixed-function oxidase, an enzyme that uses a reduced cofactor and molecular oxygen to carry out a hydroxylation reaction. The cofactor is tetrahydrobiopterin, which is oxidized to dihydrobiopterin during the hydroxylation reaction. The residual hydrogens and oxygen are released as water. In order for this reaction to continue, the dihydrobiopterin must be reduced to its tetrahydro form, and this requires a second enzyme, dihydrobiopterin reductase, which uses NADH to drive the reduction. The further hydroxylation of tyrosine, in the pathway that leads to catecholamines, requires a similar mixed-function oxidase, tyrosine hydroxylase. (See Fig. 18.12.) |
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In addition to the 20 common amino acids found in proteins, a 21st amino acid has recently been discovered and shown to be an active site amino acid in several enzymes, including the antioxidant enzyme glutathione peroxidase (see Chapter 35) and 5'-deiodinases (Fig. 37.6). Selenocysteine is incorporated into protein by a transfer ribonucleic acid (tRNA) with a UCA anticodon, which is initially aminoacylated with serine. The tRNA is then modified to a selenocysteine-bearing species through the action of selenophosphatase. Selenocysteine has unique properties, and there is at least one report that the substitution of selenocysteine with cysteine resulted in a marked decrease in enzyme activity. It is because of the need for selenocysteine that trace amounts of selenium are required in the diet. |
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| A second inherited defect in the phenylalanine-tyrosine pathway involves a deficiency in the enzyme that catalyzes the oxidation of homogentisic acid, an intermediate in catabolism of tyrosine and phenylalanine. In this condition, which occurs in 1 in 1 000 000 live births, homogentisic acid accumulates and is excreted in urine. This compound oxidizes on standing or on treatment with alkali, and gives the urine a dark color. Unfortunately, individuals with alkaptonuria
ultimately suffer from deposition of dark (ochre-colored) pigment in cartilage tissue, with subsequent tissue damage, including severe arthritis; the onset of these symptoms is generally in the 3rd or 4th decade of life. This autosomal recessive disease was the first of several that Garrod considered in proposing his initial hypothesis for inborn errors of metabolism. Although alkaptonuria is relatively benign compared with PKU, little is available in the way of treatment, other than symptomatic relief. High doses of ascorbic acid have
been used in some patients, to retard the deposition of pigment on collagen, but the progress of the disease is not significantly affected by this strategy.
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