GENETIC CONTROL OF CELL INTEGRATION 331 



ready be glimpsed from the existing data, although the identity of the 

 actual operating inducer and repressor molecules is unknown. Thev 

 have been pictured as structurally related and competing metabolites. 

 Both inducers and repressors show some structural resemblance to the 

 substrates of the enzyme whose synthesis they regulate, but they are not 

 necessarily identical with it. This evidence has led to the suggestion 

 that inducers and repressors may combine with the enzyme, not at its 

 "active site' but at a related "controlling site. 



Although the study of repression of enzyme synthesis is very recent, 

 some models have already been developed. For instance, it is proposed 

 that repressors block enzyme formation by tying down the newly formed 

 protein molecules onto the site of their synthesis. The repressor is visu- 

 alized as a bipartite molecule with a metabolite-moiety, which combines 

 with the controlling site of the enzyme, and an R-moiety, which may be 

 a polynucleotide, capable of combining with a nucleotide sequence of 

 the enzyme-forming site. The inducer is an analogue of the metabolite- 

 moiety, and can compete for the controlling site. When the inducer 

 wins, the enzyme is liberated, and enzyme formation can proceed. Thus, 

 the rate of enzyme formation can be delicately controlled by the ratio 

 of inducer-to-repressor molecules. 



This model provides a number of potentially rate-limiting reactions 

 from different metabolic pathways, any one of which could set the final 

 rate of enzyme formation. They include synthesis of inducer and re- 

 pressor molecules, and of a condensing enzyme. The bipartite repressor 

 is of particular interest, since the R-moiety may be a primary gene 

 product, representing a direct pipeline of gene control, while the meta- 

 bolite-moiety as well as the inducer may speak for the state of the cell 

 milieu. 



Repression has been observed not only with the enzymes of biosyn- 

 thetic pathways but also in the formation of other enzymes. In the 

 /3-galactosidase system, the analysis has been complicated by the chang- 

 ing permeability of cells to the inducers, repressors, and substrates being 

 investigated. To clarify what follows, we must digress briefly to describe 

 some recent developments in the understanding of cell permeability. 



Permeases 



When wild-type cells of E. coli are grown on a carbon source such as 

 succinate, their differential rate of synthesis of |8-galactosidase after 

 adding an inducer, such as TMG (lO^^M), is constant. However, as 

 can be seen in Figure 11.14, at low concentrations of inducer, these 

 simple kinetics are no longer obtained. An understanding of this phe- 



