CHAPTER 3 



THE KINETICS OF ENZYME INHIBITION 



Inhibition of an enzyme implies a decrease in the rate of the particular 

 reaction that is experimentally measured or metabolically important. An 

 inhibitor generally will reduce the rate of enzyme catalysis whatever cri- 

 terion is applied, whether it be utilization of substrate or formation of 

 products. In some situations, however, where two or more products are form- 

 ed, the inhibition may refer to only one product whereas the formation of the 

 others may be unaffected or actually accelerated. In oxidative phosphoryla- 

 tion an uncoupling agent inhibits the formation of the biologically important 

 ATP while the oxidation of substrate, uptake of oxygen, and formation of 

 other products may be increased. Many so-called inhibitors are not truly 

 enzyme inhibitors but alter the pattern of the over-all reaction to divert 

 the course away from some product. Substances such as this, not specifically 

 inhibiting some enzyme, might be termed metabolic inhibitors more appro- 

 priately because their final effect is to disturb or reduce the normal cellu- 

 lar flow of matter and energy. A substance that interferes metabolically 

 with the function of a cell is an inhibitor, by whatever means it produces 

 this effect. 



A general definition of an inhibitor might be made in the terminology 

 of Peters by stating that an inhibitor induces a biochemical lesion in a cell, 

 providing we extend somewhat the concept of biochemical lesion. Originally 

 the term was applied to the defect created in brain metabolism and function 

 by a deficiency in vitamin B^ (Gavrilescu and Peters, 1931) and was later 

 extended to the effects produced by certain substances, such as the arsen- 

 icals, on cellular enzymes. The term might profitably include any dislo- 

 cation of metabolism by agents acting directly on metabolic systems. The 

 definition of an inhibitor could be made in a more straightforward manner 

 but the approach above introduces the idea of a biochemical lesion, compa- 

 rable to other types of lesions in cells and tissues, an idea of some conceptual 

 significance, and a term of use in designating the manifold perturbations 

 that inhibitors can induce in cells. In the present chapter we shall limit the 

 discussion to inhibitors that act directly on and inhibit individual enzymes, 

 since the purpose here is an exposition of the kinetics of isolated enzymes. 

 These results will be applied later to more complex systems and intra- 

 cellular inhibitons. 



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