ENZYMES 



other words, the natural substance, yz.c-,/'-aminobenzoic acid, competes 

 with the drugs for the protein partner with which it forms the enzyme 

 complex. The degree of inhibition is determined by the relative con- 

 centrations of /^-aminobenzoic acid and drug and by their relative 

 affinities for the protein partner. The phenomenon of competitive 

 inhibition is well known in the enzyme literature and is perhaps the 

 most characteristic hallmark of enzymic phenomena. 



The sulfonamides inhibit the growth of susceptible bacteria 

 only when they are actively growing. Once active growth has taken 

 place, the sulfonamides are without effect even on susceptible bacteria. 

 This observation suggests that the sulfonamides interfere with the 

 process of synthesizing the /^-aminobenzoic acid enzyme complex 

 rather than with the activity or function of /i-aminobenzoic acid in its 

 final catalytic form. Unquestionably, there are many alternative 

 pathways in bacteria by which /^-aminobenzoic acid can be coupled 

 with other substances to form the final catalytic complex. Only one 

 pathway may be sulfonamide-sensitive, and only those bacteria which 

 share that method of synthesizing the /)-aminobenzoic acid catalytic 

 complex will be susceptible to the action of the sulfonamides. These 

 considerations must be borne in mind in evaluating the enzymic theory 

 of sulfonamide action. Ghemotherapeutic drugs may interfere either 

 with the working of a key enzyme or with some stage in the process 

 by which the key enzyme is synthesized. Since the synthesis of en- 

 zymes is also enzymic in nature, the primary action of chemothera- 

 peutic drugs must still be considered as one of interference with 

 enzymes. 



The interpretation in terms of enzymes of the mode of action 

 of sulfonamides is by no means in general currency. The so-called 

 "essential metabolite" theory of Fildes (2) has gathered many adherents 

 and is generally accepted among workers in the field of chemotherapy. 

 This theory assumes that/^-aminobenzoic acid is an essential metabolite 

 for the growth of certain microorganisms rather than a part of an 

 essential enzyme system. A metabolite is usually defined as a sub- 

 stance which undergoes chemical transformation; and the term is 

 usually applied to substances like amino acids, fatty acids, etc. which 

 are present in considerable concentration, and which are degraded or 

 converted into more complex substances by enzyme systems. Since 

 the amount of /^-aminobenzoic acid present in microorganisms is 



^57 



