406 



( HAPTER 32 



zygotes for the normal allele. When alcap- 

 tonurics are fed five grams of alcapton, 



approximately this additional amount is ex- 

 creted in the urine. But when normal 

 individuals are fed the same quantity of al- 

 capton, none is found in the urine. If. how- 

 ever, normal individuals are fed eight grams 

 of alcapton, some is found in the urine. We 

 can conclude from these observations that 

 normal people have the ability to metabolize 

 alcapton to another form which does not 

 change color upon exposure to air and that 

 this ability has been lost, apparently com- 

 pletely, by alcaptonurics. The abnormal 

 gene, therefore, does not produce its effect 

 by forming alcapton as a unique substance. 

 Alcapton seems to be a normal metabolic 

 product which does not accumulate in normal 

 individuals because it is rapidly metabolized, 

 but which does accumulate in alcaptonurics. 

 The blood of alcaptonurics proves to be de- 

 ficient in a normally present enzyme which 

 catalyzes the conversion of alcapton by oxi- 

 dation to a noncolor-producing substance. 

 This enzyme, homogentisic oxidase, is, in 

 fact, missing in the liver of the alcaptonuric; 

 thus, it must be this enzyme which is changed 

 in alcaptonurics. 



It is clear, therefore, that alcapton is not 

 produced by the gene for alcaptonuria but 

 is a normal metabolic intermediate. Since 

 it is not part of the normal diet, alcapton 

 should have chemical precursors. If such a 

 precursor of alcapton is added to the diet 

 of alcaptonurics, it should be converted to 

 alcapton which, in turn, would be excreted in 

 increased amounts. When alcaptonurics are 

 fed an excess of glucose, the amount of al- 

 capton found in the urine is unchanged, in- 

 dicating that glucose is not a precursor of 

 alcapton. But, if p-OH phenylpyruvic acid 

 or if either of the amino acids, tyrosine or 

 phenylalanine, is increased in the diet of 

 alcaptonurics, their excretion of alcapton is 

 increased almost correspondingly. We can, 

 therefore, postulate that alcapton has a series 



of chemical precursors (Figure 32-1 ). In 

 the scheme illustrated, phenylalanine is con- 

 verted to tyrosine by the addition of an oxy- 

 gen to the top carbon; tyrosine is converted 

 to p-OH phenylpyruvic acid by replacing the 

 amine (NH L . ) group by an oxygen; p-OH 

 phenylpyruvic acid is converted by still other 

 chemical reactions to alcapton. Normally, 

 alcapton is converted to acetoacetic acid by 

 a process which involves the oxidation and 

 splitting-open of the benzene ring; it is the 

 first step in this conversion which fails in 

 alcaptonurics. This hypothesized pathway 

 from phenylalanine through alcapton to ace- 

 toacetic acid has been confirmed in subse- 

 quent work and seven enzymatically-cata- 

 lyzed steps have been identified. 



It should be realized, however, that tyro- 

 sine, an essential component of protein, can 

 also partake in biochemical pathways other 

 than the one leading to alcapton (Figure 

 32-1 ). For example, tyrosine is part of the 

 pathway of chemical reactions leading to 

 melanin formation; and so tyrosine, by a 

 different chemical pathway, is also a precur- 

 sor of melanin. Albinism (lack or absence 

 of melanin) could be caused genetically by 

 the defective production of an enzyme nec- 

 essary for the conversion of tyrosine to mel- 

 anin. 



In another disease due to a single, rare, 

 recessive gene, affected individuals are 

 feebleminded or of lower than normal mental 

 ability and have other phenotypic changes 

 including light pigmentation. This pleio- 

 tropism is directly correlated with the pres- 

 ence of phenylpyruvic acid in the urine of 

 affected individuals. The normal conversion 

 of phenylalanine to tyrosine fails to occur in 

 such individuals; instead, the amine in 

 phenylalanine is replaced by an oxygen (thus 

 forming a keto group), so that phenylpyruvic 

 acid is produced (Figure 32-2). Diseased 

 persons are therefore called phenylpyruvics 

 or phenylketonurics (Chapter 15 ). The dis- 

 ease, phenylketonuria, can be partially allevi- 



