88 MOLECULES, VmUSES, AND BACTERLV 



amino acid isolated from the bacterial protein or the medium is non- 

 radioactive (Roberts, 1955), indicating that the externally supplied 

 amino acid must have blocked the synthesis of more molecules of itself. 

 As one would expect from numerous observations on inhibition of 

 enzyme function in vitro and in vivo, feedback inhibition responds very 

 rapidly to the presence or absence of the inhibitor. Thus, in the in vivo 

 inhibition of production of a tryptophan intermediate, the addition of 

 tryptophan caused a change in the rate of production of the inter- 

 mediate within 10 minutes, which was as rapid a response as could be 

 measured by the available methods (Novick and Szilard, 1954). Inhi- 

 bition of orotic acid pi-oduction disappeared virtually as soon as the 

 growth medium became deficient in pyrimidines (Yates and Pardee, 

 1957 ) . Feedback inhibition would therefore seem to be highly sensitive 

 to transient shifts in the concentrations of metabolites. 



Interrelation of pathways 



Repression and induction govern the rates of individual pathways 

 but do not explain how the numerous pathways are related to one an- 

 other. One possibility for the regulation of sets of pathways is through 

 the synthesis of macromolecules. Consider the synthesis of nucleic 

 acids; this requires both purine and pyrimidine nucleotides. The rate 

 of removal of the nucleotides from the intracellular pool will depend 

 largely on the rate of nucleic-acid formation. If one nucleic-acid com- 

 ponent is synthesized or provided at a rate greater than is required for 

 its utilization, feedback inhibition should inhibit the synthesis of more 

 of this compound. The rate of its production would thereby be corre- 

 lated with that of other bases to correspond to its proportion in the 

 nucleic acids. Similarly, in protein synthesis, which requires the pres- 

 ence of all the amino acids, any single amino acid would not be formed 

 faster than it is required for incorporation into the protein; feedback 

 inhibition would limit its production. Since protein and nucleic acids 

 together comprise about 80 per cent of the carbon of a bacterium, these 

 processes would seem adequate to provide considerable controls 

 against wasteful production of an excess of carbon compounds. 



Furthermore, the syntheses of proteins and of nucleic acids are 

 closely coupled in the normally growing cell. Synthesis of protein, like 

 the synthesis of nucleic acid, requires purines, and pyrimidines, as 

 Table II indicates (Pardee, 1954); presumably these are required for 

 activation and for transfer of the activated amino acids. Conversely, as 

 the table also shows, the formation of nucleic acid requires amino acids, 

 the building blocks of protein (Pardee and Prestidge, 1956; Gros and 

 Gros, 1958), for reasons as yet unknown. Therefore the pathways of 

 the small molecules leading to these macromolecules could be interre- 



