Biochemistry and Evolution 49 



structures had been built up on the fundamental plan, further 

 mutations would only be viable if they were consistent with the 

 fundamental plan itself and with the maintenance of everything that 

 had already been superadded to the system. Something of this kind 

 must surely be at the bottom of the fact that the vast majority of 

 random mutations are lethal. 



When we come to study spontaneous or artificially induced muta- 

 tions in modern organisms, ranging from Neurospora to man himself, 

 it seems an almost invariable rule that each mutation that turns up 

 results in either the loss or some unfavorable modification of at least 

 one enzyme. 



There is an abundance of evidence for this; inherited metabolic 

 disorders such as phenylketonuria, alkaptonuria, hemophilia, and the 

 like have long been known (see Garrod, 1909). Another well-known 

 example on the evolutionary scale is the serial loss of uricolytic 

 enzymes among vertebrate animals ( Baldwin. 1949; Florkin, 1949). 

 Fishes in general possess urico-oxidase, allantoinase, and allantoicase, 

 but in some groups and families allantoicase has already disappeared. 

 At the other end of the scale, most mammals possess urico-oxidase but 

 lack allantoicase and allantoinase. Finally, among the primates, even 

 urico-oxidase has been lost. 



These last-mentioned enzymes are concerned only with end prod- 

 ucts of metabolism. If. however, the lost or altered enzyme is one that 

 plays an integral part in intermediary metabolism and normally 

 catalyzes the conversion of A into B, A will tend to accumulate in the 

 cells and the organism thenceforward will be able to survive only in 

 media in which B is present and available. A familiar example is 

 found in a mutant of Escherichia coli, which lacks the enzyme that 

 converts 4-amino-5-iminazole-carboxamide-ribosyl-5'-phosphate into 

 inosinic acid (Gots, 1953). 







II 



H 2 N^ ^ \ 



CH 



H 2 N ^N 



R® 

 [R® =ribosyl-5'-phosphate] 



This is an important step in the biosynthesis of purines and their 

 nucleotides and was our first clue to the nature of the synthetic mech- 

 anism. 



