260 2. ANALOGS OF ENZYME REACTION COMPONENTS 



Several accidental observations were made of the toxicity of metabolite 

 analogs while they were being tested for activity in animals, for example, 

 the discovery that ethionine is toxic to rats (Dyer, 1938) and that pyridine- 

 3-sulfonate is lethal to dogs suffering from nicotinic acid deficiency (WooUey 

 et al., 1938), but the importance was not immediately recognized. Appar- 

 ently the stimulus for the formulation of the general theory had to come 

 from a discovery of clinical importance, and this was provided by the find- 

 ing of the antagonism by p-aminobenzoate of the action of the sulfona- 

 mides by Woods (1940). Between 1940 and 1943 many examples of analog 

 antagonism were reported, and from 1943 to 1946 it was shown that vi- 

 tamin deficiency symptoms could be produced in animals by the administra- 

 tion of the appropriate analogs of all the known vitamins. It was then 

 possible to return to the enzyme level and apply the principles formulated 

 long before to the new results. Since 1946 there has been a steadily increas- 

 ing interest in analog inhibitors, which is reflected in the large numbers of 

 publications on this subject each year (Fig. 2-1). At the present time a paper 

 on analog enzyme inhibition as covered in this chapter appears every other 

 day; this does not include all of the investigations on analog inhibitors 

 that are to be treated separately (such as fluoroacetate, arsenate, carbon 

 monoxide, parapyruvate, and others), or analogs commonly used clinically 



Fig. 2-1. Curve showing the annual number of publications on analog inhibition 



of enzymes. 



