308 Discussion 



XMP), as well as the formation of inosinicase (the enzyme responsible 

 for the formation of IMP from its precursor, 4-formylamino 5-imidazole 

 carboxamide ribotide). Only the former of these reactions, which is the 

 first step of the branch pathway leading to GMP, is inhibited by GMP ; 

 the other reaction, which is a central step in the formation of both 

 adenine and guanine, is inhibited neither by GMP nor by AMP, nor by 

 any of their usual derivatives. Similarly, Dr. H. S. Moyed has found 

 that the enzyme catalysing the first step of the pathway leading 

 specifically to histidine, the condensation of AMP (or perhaps of ATP) 

 with an activated derivative of ribose 5-phosphate, is both inhibited 

 and repressed by histidine. The enzyme catalysing a subsequent step 

 in histidine biosynthesis, the conversion of the AMP-ribose phosphate 

 complex to imidazole glycerol phosphate, is repressed, but should not 

 be inhibited. 



I should add that Dr. Pardee has already made the point very 

 clearly that the inhibition of enzyme action and the repression of 

 enzyme formation do not have the same physiological function. The 

 actual control of the biosynthesis of the precursors of macromolecules 

 is achieved by inhibition of enzyme action; control by repression of 

 enzyme formation is sluggish and would be effective only after several 

 generations. Enzyme repression rather serves as a mechanism that 

 enables the cell to select the most suitable enzymic composition for 

 growth in a particular environment. 



Lehninger: I had been wondering — and Dr. Magasanik has partly 

 answered my query — why it would be strategically more desirable to 

 have the end product of a long series come back and inhibit an early 

 reaction. 



Pardee : If the inhibition were half-way along the pathway, then some 

 intermediate would accumulate in the pathway, presumably, and there 

 would be the problem of getting rid of it ; or at least the organism would 

 waste that carbon. 



Lehninger : Is there any other reason beyond the waste of intermedi- 

 ates that get stuck in the pathway? After all, there are branches here 

 and there, and other metabolic pathways. 



Pardee: In the threonine case which we have investigated lately 

 (Wormser, E. H., and Pardee, A. B. (1959). Arch. Biochem., in press), a 

 pathway starts from aspartate and goes to homoserine, where it then 

 branches and goes through perhaps two or three steps to threonine; 

 the other branch goes off through another series of reactions to methion- 

 ine. This was demonstrated (Watanabe, Y., and Shimura, K. (1955). 

 J. Biochem. (Japan), 42, 181) in yeast and confirmed by us in Esch. coli. 

 We find that threonine inhibits homoserine kinase. The block of the 

 threonine pathway is in the specific branch of the pathway that goes to 

 threonine, and does not influence the methionine pathway. 



Magasanik : You could continue that by saying that isoleucine acts 

 at the point at which its pathway branches off from the threonine 

 pathway. 



Pardee: It has been shown earlier that isoleucine blocks an enzyme 

 quite a few steps removed (Umbarger, H. E., and Brown, B. (1958). 



