THE CONCEPT OF INHIBITION BY ANALOGS 259 



into a substance in which the F atom, because of its electronegative char- 

 acter, interferes in some way with the catalytic reaction. Another consid- 

 eration arises when phosphorylation of the substrate is an initial step in 

 the metabolic sequence. Here one must be careful not to alter the groups 

 involved in the phosphorylation, but to modify groups that are reactive in 

 a later enzymic step. 



DEVELOPMENT OF THE CONCEPT OF INHIBITION 

 BY ANALOGS 



This important concept, which today plays a major role in the fields 

 of enzymology and biochemistry and is becoming more and more important 

 in pharmacology, chemotherapeutics, and pathology, has an interesting 

 history illustrating a typical growth pattern of a scientific idea. The de- 

 velopment of the general concept has been traced by Martin (1951), Wool- 

 ley (1952), and Albert (1960), so that here it is necessary only to present a 

 cursory exposition related particularly to enzyme inhibition. However, 

 it must be realized that many fields of study — including immunology, 

 drug antagonism, and microbial growth inhibition among others — con- 

 tributed in one way or another to this concept. 



Despite the fact that numerous examples of competitive inhibition by 

 analogs had been demonstrated since 1910, and that the analog concept 

 had been quite clearly stated around 1930, general recognition of the basic 

 principles did not occur until after 1940. Wohl and Glimm (1910) reported 

 the inhibition of amylase by glucose and galactose, as well as by the reac- 

 tion product, maltose, and shortly Michaelis described the inhibition of 

 /5-fructofuranosidase by fructose and a-methylglucoside (Michaelis and 

 Pechstein, 1914), and the inhibition of a-glucosidase by glucose (Michaelis 

 and Rona, 1914). Isolated, unpremeditated, and unrecognized discoveries, 

 such as the inhibition of arginase by ornithine (Gross, 1921) and the inhi- 

 bition of /?-fructosidase by /^-glucose but not by cf-glucose (Kuhn, 1923) un- 

 fortunately gave no impetus to the formulation of a general concept. Even 

 the classic work of Quastel on malonate inhibition, described in the previous 

 chapter, wherein competitive inhibition by structural analogs was considered 

 in a modern fashion, apparently did not activate anyone outside Cambridge, 

 where Bernheim (1928) studied the aconitate inhibition of citrate oxidation, 

 Murray (1929) and Murray and King (1930) applied the principles of 

 analogs (although in a somewhat naive way) to the inhibition of lipase by 

 various ketones and alcohols, Richter (1934) proved the inhibition of ca- 

 techol oxidase by resorcinol to be competitive, Keilin and Hartree (1936) 

 reported potent competitive inhibition of uricase by the methylurates, and 

 Green (1936) extended the malonate inhibition of succinate dehydrogenase 

 to the inhibition of malate dehydrogenase by several dicarboxylates. 



