864 16. SPECIFICITY OF INHIBITION 



systems of all cells. It is true that most of the basic pathways are the same 

 in different types of cells but the closer one looks into the kinetics and the 

 details of the individual steps, the greater is the divergence. The basis 

 of selectivity is often at the molecular level and not at the metabolic or 

 cellular level. The chemical composition of enzyme active centers, the topo- 

 graphy of enzyme surfaces, the patterns of electrical forces, and polariza- 

 bilities — these form the true basis for enzyme specificity and are also 

 responsible for much specificity on higher levels. 



Inhibitors rarely are specific for a single enzyme. Most often an inhi- 

 bitor will act upon several enzymes, although not, of course, with the same 

 potency. If an inhibitor is to be used as a tool to investigate the relations 

 between certain enzymes or pathways and the function of a cell or tissue, 

 the question of specificity is of the utmost importance. The more specific 

 the inhibitor, the more valuable will it be to the investigator. Although 

 inhibitors are seldom specific, they may often be used in a manner so that 

 a specific action is exerted or, at least, the maximal specificity obtained. 

 Theoretically, if one knew the action, or lack of action, of an inhibitor on 

 every enzyme involved in the system studied, including each particular 

 Ki, one could predict the specificity at any concentration of the inhibitor. 

 This would be true in relatively simple systems, but in studies on the cell 

 or whole animals, the many factors discussed previously interfere with 

 the knowledge of exactly what the inhibitor is doing. That is, if one knew 

 from isolated enzyme work the K^ of the inhibitor for each susceptible 

 enzyme, still in cellular work there would be elements of uncertainty due 

 to concentration factors, unknown intracellular substrate concentrations, 

 altered enzyme environments, and other difficulties. Nevertheless, one 

 should always attempt to reach the ideal of high specificity. One of the 

 things that stands between us and such a goal is the ignorance of the com- 

 plete spectrum of action of any inhibitor, and, indeed, for most inhibitors 

 we know regrettably little of their ranges of action. 



Many investigators appear to look upon certain inhibitors as quite spe- 

 cific for designated enzymes or metabolic pathways; for example, they 

 believe iodoacetate inhibits glycolysis only, or fluoride only enolase, or 

 arsenicals only keto acid oxidases, and so on. This arises in part from an 

 understandable wish for simplicity, in part from unjustifiable statements 

 made repeatedly so that eventually they come to be looked on as true, 

 and in part from inusfficient knowledge of the inhibitor's range of action. 

 If only a few enzymes have been studied with a particular inhibitor, it is 

 evident that the specificity in this limited sphere is apt to be high. This 

 important fact is well stated in Davenport's law: "The specificity of an 

 inhibitor is inversely proportional to how much is known about it," (ver- 

 bal communication). Here is meant the apparent specificity because there 

 is an absolute specificity that is untouched by experimental or mental de- 



