Chapter ID 



INTRODUCTION AND THEORETICAL CONSIDERATIONS 



The preparation and testing of analogues of biologically active com- 

 pounds has long been an accepted approach in the search for more active 

 principles. This approach was very successful in the field of chemotherapy 

 and pharmacology but has yielded meager results with compounds 

 analogous to the B vitamins as far as nutrition is concerned. 



A few compounds have been found to be partially, but almost never 

 fully, active in replacing their analogous B vitamins in the nutrition of 

 various organisms. Other analogues have been observed to replace the 

 corresponding vitamin in carrying out some, but not all, of its biological 

 functions. In most instances, analogues have been found to be essentially 

 inert biologically; however, in some cases, certain analogues of the B 

 vitamins and of related metabolites have been found to be toxic for some 

 organisms. The action of substances which are toxic for an organism has 

 been presumed to involve a combination of the substance with an essen- 

 tial cell constituent. This type of action is usually represented by a 

 combination of the toxic agent with an enzyme in such a fashion that the 

 enzyme can no longer effectively serve as a catalyst. 



Much of our knowledge concerning enzymes has been obtained by the 

 use of toxic substances capable of reducing the velocity of enzymatic 

 reactions. According to the modes of action of these inhibitory substances, 

 the inhibitions can usually be classified into one of two general types. 

 One type is termed competitive inhibition, in which case the effectiveness 

 of the inhibitor in preventing an enzymatic reaction depends upon the 

 concentration of the substrate, and a direct relationship exists between 

 the rate of the reaction and the relative concentrations of inhibitor and 

 substrate. The inhibitor appears to compete with the substrate for the 

 same reactive groups of the enzyme. In the other type, noncompetitive 

 inhibition, the effective enzyme concentration is diminished by the in- 

 hibitor irrespective of the concentration of the substrate. 



Noncompetitive inhibitors such as fluoride, 1 - 2 - 3 which prevents the 

 functioning of enolase and allows the accumulation of 2-phosphoglycerate, 

 have been utilized successfully as specific enzyme "poisons" permitting 

 the substrate to accumulate in a biological system. In the fluoride inhibi- 

 tion of enolase, which converts 2-phosphoglycerate to 2-phosphopyruvic 



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