Biochemical Genetics (/) 



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mally converted to tyrosine by the addition 

 of an oxygen to the top carbon; tyrosine is 

 normally converted to p-OH phenylpyruvic 

 acid by replacing the amine (NH2) group by 

 an oxygen; p-OH phenylpyruvic acid is 

 converted, by still other chemical reactions, 

 to alcapton. Alcapton is normally converted 

 to acetoacetic acid, by a process which in- 

 volves the splitting-open of the benzene ring; 

 it is the first step in this conversion which 

 fails in alcaptonurics. This hypothesized 

 pathway from phenylalanine via alcapton to 

 acetoacetic acid has been confirmed in sub- 

 sequent work, as the result of which six en- 

 zymatically catalyzed steps have been identi- 

 fied. 



It should be realized, however, that tyro- 

 sine, which is an essential component of pro- 

 tein, can also partake in biochemical path- 

 ways other than the one that leads to alcapton 

 (Figure 31-3). It has been found, for ex- 

 ample, that tyrosine is part of the pathway 

 of chemical reactions leading to melanin 

 formation. So, tyrosine, by a different chemi- 

 cal pathway, is also a precursor of melanin. 

 Albinism (lack or absence of melanin) could 

 be caused genetically by the defective pro- 

 duction of an enzyme necessary for the con- 

 version of tyrosine to melanin. 



In another disease, which is 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 pleiotro- 

 pism has been directly correlated with the 

 presence of phenylpyruvic acid, which is 

 toxic, in the urine of affected individuals. It 

 has been shown that the normal conversion 

 of phenylalanine to tyrosine fails to occur in 

 affected individuals, and instead, the amine 

 in phenylalanine is replaced by an oxygen 

 (thus forming a keto group), so that phenyl- 

 pyruvic acid is produced (Figure 31-4). 

 Diseased persons are therefore phenylpyruvics 

 or phenylketonurics (see Chapter 27). The 

 disease, phenylketonuria, can be partially 



/ 



FIGURE 31-4. 



Formula for 

 phenylpyruvic acid. 



H-C C-H 



II I 



H-C. ^C-H 



C 



I 



H— C— H 



I 



c=o 



COOH 



alleviated, or circumvented, if dietary phenyl- 

 alanine is reduced to an amount that is enough 

 for protein synthesis (for the presence of this 

 amino acid is also essential in our proteins), 

 but not enough so that any appreciable 

 amount is converted to phenylpyruvic acid. 

 Note that since tyrosine is also needed for 

 human protein, this substance must also be 

 included in sufficient quantity in the diet of 

 phenylketonurics. Finally, it should be noted 

 that a parahydroxylase enzyme that converts 

 phenylalanine to tyrosine and is normally 

 present in the liver has been found missing, 

 or defective, in phenylketonurics. What is 

 meant when an enzyme is said to be missing? 

 This may mean either the total absence of 

 the enzyme molecule, or else its presence in 

 such a modified form that the molecule has 

 lost the ability to perform its characteristic 

 catalysis. 



These studies of metabolic defects have 

 been of great service in identifying the places 

 where genes act to direct metabolic processes. 

 They also permit the determination of pre- 

 cursors of a genetically defected step, and aid 

 in the final elucidation of chains of biochemi- 

 cal reactions, and of metabolic pathways. 

 For example, substance X is proven a pre- 

 cursor of substance Y, if mutant 1 cannot 

 form Y but accumulates X, and if mutant 2 

 cannot form Y unless X is supplied (Figure 

 31-5). But biochemical genetics is of especial 

 interest in another respect. We have seen, in 

 the cases most thoroughly investigated, that 



