146 NITROGEN METABOLISM 



does not constitute proof that its mode of action against the 

 intact organism is necessarily expUcable in such terms. 

 Before the latter can be attempted, precise and quantitative 

 information is required deaUng with the significance of that 

 enzyme in the general economy of the cell (e.g. turnover 

 numbers). Moreover, ideally the observed results should be 

 produced by drug concentrations of the same order as those 

 used therapeutically. But, since the concentration of cells 

 in washed suspension experiments is often many times 

 greater than those in growing cultures or infected animals, 

 it has been argued that this proviso can be ignored [14]; 

 furthermore, it is also feasible that the drug enters growing 

 and dividing cells more readily than resting cells [10]. 



Sulphonamides 



The first major contribution towards understanding the 

 mode of action of the sulphonamides was made by Woods 

 who prepared from yeast an aromatic carboxylic amine 

 which competitively antagonized the action of sulphanila- 

 mide in preventing the growth of Strep, haemolyticus. Fildes' 

 suggestion that a chemotherapeutic agent might function 

 by virtue of its chemical structure being such that it was 

 adsorbed on to an enzyme in place of the natural substrate 

 led Woods to infer that the isolated material was ^-amino- 

 benzoic acid (PAB) and he showed that the latter did in fact 

 antagonize the sulphonamides in a competitive manner [28]. 

 In other words, the biological activity of the sulphonamides 

 could be explained on the grounds that they were non- 

 utilizable analogues of a natural metabolite, namely, PAB. 

 Until that time the importance of PAB in intermediary 

 metabolism had not been suspected, but evidence soon 

 became available that PAB was a growth factor for certain 

 organisms, and that a group of substances containing PAB 

 — the folic acid factors required by certain other organisms 

 — ^were of universal importance. The various folic acid 

 factors differ in the number of glutamic acid radicals in the 

 molecule, the degree of reduction of the pterin and the 

 presence or absence of a formyl group attached to one of 

 the nitrogen atoms of the pterin or PAB. For example, the 



