The Control of the Formation of Specific Proteins in Bacteria and in Animal Cells.

In 1953, Monod and Cohen-Bazire as well as Cohn, Cohen, and Monod showed that an amino acid may repress the last enzyme in the biochemical pathway which leads to the formation of that amino acid. Four years later, H. J. Vogel found that arginine, when added to a growing bacterial culture, represses the formation of acetyl ornithinase (one of the early enzymes along the biochemical pathway leading to arginine), which converts acetyl-ornithine into ornithine. This observation provided rather strong circumstantial evidence in favor of the view that enzyme repression may be part of the normal regulatory mechanism of enzyme formation in bacteria. Subsequently, it occurred to Werner Maas that inducers which enhance the formation of an enzyme when added to a growing bacterial culture may perhaps be capable of doing so only because there is a repressor present in the cell, and that the inducer might perhaps do no more than inhibit some enzymes which are involved in the formation of the repressor. Thus the inducer would enhance the formation of an enzyme only because it reduces the concentration of the repressor in the cell. (Oral communication, April, 1957.) At that time, the best investigated case of enzyme induction was the induction of the enzyme f-galactosidase. Milton Weiner helped my understanding of the induction of this enzyme greatly by pointing out that its induction must be considered in conjunction with the biochemical pathway leading from galactose to glucose-1-P. (Oral communication, January, 1957.) The induction of ,3-galactosidase in a culture of bacteria growing on succinate or lactate, as the carbon source, is inhibited by adding glucose to the growing culture. From this I was led to infer that some metabolite, intermediate in the sequence of metabolites lying between galactose and glucose-1-P, is the precursor of the repressor of f8-galactosidase. Further, in line with the above quoted suggestion of Werner Maas, I was led to surmise that certain galactosides may induce f3-galactosidase, by inhibiting enzymes which lie on the biochemical pathway between glucose 1-P and the intermediate metabolite that may be the precursor of the repressor of this enzyme. I believe that some such galactosides may in fact inhibit one of these enzymes and this may explain, in part, why the rate of formation of fl-galactosidase rises faster than linearly with the intracellular concentration of the inducing galactoside. However, since I was not able to explain on any similar basis the induction of the degradative enzymes by their substrate, I was led to assume that the inducer must be able to exert an effect which goes beyond inhibiting the formation of a repressor. In particular, I was led to believe that a repressor may reduce the rate of formation of the enzyme by combining with an enzyme molecule which is still attached to its enzyme-forming site, and that it may thereby somehow prevent the attached enzyme molecule from leaving its enzyme-forming site.t According to this view the