METABOLITE ANTAGONISTS 



227 



ever, these foreign molecules are not transformed by the enzyme to which 

 they are bound. If the antagonist is an analogue of a coenzyme, it 

 presumably forms a pseudoholoenzyme which is unable to function. The 

 close structural relation between a metabolite (p-aminobenzoic acid) and 

 its antagonist (sulfanilamide) is shown in Fig. 46. 



6.7 A. 



H H 



N 



J A ! 



— ►|2.3A.|-^ 

 p-Aminobenzoate Ion 



—►[2.4 A. 

 Sulfanilamide 



Fig. 46. Interatomic distances and structural relationships of p-aminobenzoate ion 

 and sulfanilamide. (Courtesy of Roblin, Chem. Eng. News 27 : 3624, 1949. Published 

 by permission of American Chemical Society.) 



In spite of the large number of compounds which have been tested for 

 antagonism, it is not possible to specify exactly what changes in metabolite 

 molecules are required to produce antagonists. A single modification of a 

 metabolite molecule is more hkely to produce an antagonist than two or 

 more changes in structure. This is to be expected, for an antagonist 

 must closely resemble the corresponding metabolite. Replacing a 

 carboxyl group with a sulfonic-acid group has been effective in many 

 instances. 



The specific action of enzymes has been likened to the relation of a 

 lock and its key. Unless an enzyme and a substrate molecule are related 

 in this fashion, no reaction will take place. A modern diagrammatic 

 representation of the lock-and-key simile is shown in Fig. 47. The 

 mechanism of competitive inhibition may be visuahzed by referring to 

 this figure. Metabolite antagonists may be thought of as "wrong" keys, 

 which jam the lock mechanism. As long as a false key is in the lock, 

 it prevents the true key from entering and opening the lock. 



Compounds which resemble coenzymes in structure compete for the 

 active surface of apoenzymes. Because of similarity in structure, an 

 apoenzyme-foreign molecule complex, or pseudoholoenzyme is formed. 

 Such a pseudoenzyme is unable to function. The reversal of enzyme 

 inhibition in such instances is caused by the addition of more coenzyme 

 molecules. The argument is the same when substrate analogues are 

 involved. For example, 3-fluorophenylalanine inhibits the utihzation 



