Errors in amino acid metabolism provided some of the first examples of biochemical defects linked to pathological conditions. For instance, alcaptonuria, an inherited metabolic disorder caused by the absence of homogentisate oxidase, was described in 1902. Homogentisate, a normal intermediate in the degradation of phenylalanine and tyrosine (Figure 23.27), accumulates in alcaptonuria because its degradation is blocked. Homogentisate is excreted in the urine, which turns dark on standing as homogentisate is oxidized and polymerized to a melanin-like substance.

Although alcaptonuria is a relatively harmless condition, such is not the case with other errors in amino acid metabolism. In maple syrup urine disease, the oxidative decarboxylation of α-ketoacids derived from valine, isoleucine, and leucine is blocked because the branched-chain dehydrogenase is missing or defective. Hence, the levels of these α-ketoacids and the branched-chain amino acids that give rise to them are markedly elevated in both blood and urine. The urine of patients has the odor of maple syrup—hence the name of the disease (also called branched-chain ketoaciduria). Maple syrup urine disease usually leads to mental and physical retardation unless the patient is placed on a diet low in valine, isoleucine, and leucine early in life. The disease can be readily detected in newborns by screening urine samples with 2,4-dinitrophenylhydrazine, which reacts with α-ketoacids to form 2,4-dinitrophenylhydrazone derivatives. A definitive diagnosis can be made by mass spectrometry. Table 23.4 lists some other diseases of amino acid metabolism.

706

Phenylketonuria is perhaps the best known of the diseases of amino acid metabolism. Phenylketonuria, which occurs with a prevalence of 1 in 10,000 births, is caused by an absence or deficiency of phenylalanine hydroxylase or, more rarely, of its tetrahydrobiopterin cofactor. Phenylalanine accumulates in all body fluids because it cannot be converted into tyrosine. Normally, three-quarters of phenylalanine molecules are converted into tyrosine, and the other quarter become incorporated into proteins. Because the major outflow pathway is blocked in phenylketonuria, the blood level of phenylalanine is typically at least 20-fold as high as in normal people. Minor fates of phenylalanine in normal people, such as the formation of phenylpyruvate, become major fates in phenylketonurics. Indeed, the initial description of phenylketonuria in 1934 was made by observing the reaction of phenylpyruvate in the urine of phenylketonurics with FeCl₃, which turns the urine olive green.

Almost all untreated phenylketonurics are severely mentally retarded. The brain weight of these people is below normal, myelination of their nerves is defective, and their reflexes are hyperactive. The life expectancy of untreated phenylketonurics is drastically shortened. Half die by age 20 and three-quarters by age 30. Phenylketonurics appear normal at birth but are severely defective by age 1 if untreated. The therapy for phenylketonuria is a low-phenylalanine diet supplemented with tyrosine, because tyrosine is normally synthesized from phenylalanine. The aim is to provide just enough phenylalanine to meet the needs for growth and replacement. Proteins that have a low content of phenylalanine, such as casein from milk, are hydrolyzed and phenylalanine is removed by adsorption. A low-phenylalanine diet must be started very soon after birth to prevent irreversible brain damage. In one study, the average IQ of phenylketonurics treated within a few weeks after birth was 93; a control group treated starting at age 1 had an average IQ of 53.

Early diagnosis of phenylketonuria is essential and has been accomplished by mass screening programs of all babies born in the United States and Canada. The phenylalanine level in the blood is the preferred diagnostic criterion because it is more sensitive and reliable than the FeCl₃ test. Prenatal diagnosis of phenylketonuria with DNA probes has become feasible because the gene has been cloned and the exact locations of many mutations have been discovered in the protein.

The biochemical basis of retardation is not firmly established, but one hypothesis suggests that the lack of hydroxylase reduces the amount of tyrosine, an important precursor to neurotransmitters such as dopamine. Moreover, high concentrations of phenylalanine prevent amino acid transport of any tyrosine present as well as tryptophan, a precursor to the neurotransmitter serotonin, into the brain. Because all three of the amino acids are transported by the same carrier, phenylalanine will saturate the carrier, preventing access to tyrosine and tryptophan. Finally, high blood levels of phenylalanine result in higher levels of phenylalanine in the brain, and evidence suggests this elevated concentration inhibits glycolysis at pyruvate kinase, disrupts myelination of nerve fibers and reduces the synthesis of several neurotransmitters.

707