1. PERSPECTIVES OF METABOLIC INHIBITION 5 



tions to be calculated readily. Furthermore, these interactions are usually 

 with specific regions of the protein and are not general adsorption phe- 

 nomena. Comparison of structurally related inhibitors enables one to assign 

 specific energy terms to certains groups. Not only are more accurate data 

 needed but also more penetrating theoretical studies of the balance of 

 forces between such interacting molecules, the roles of water and ions and 

 the dielectric constant, the mapping of energy contours, and the config- 

 urations assumed by the interacting molecules. One can confidently look 

 forward to the time when enough will be known about the patterns of en- 

 zyme active centers and the forces involved in complex formation to predict 

 what types of substances will inhibit, just as drugs are now designed for 

 special purposes on the basis of what is known of cellular function at a dif- 

 ferent level. 



The biochemist also makes use of inhibitors in the investigation of the 

 multiple enzyme systems in linear or cyclic metabolic sequences. It is 

 often possible by using the proper inhibitors to determine the sequence in 

 which the components of a catenary chain react. There are several classical 

 examples of such analysis: the original assignment of the positions of the 

 enzymes in the oxidative pathway by Keilin, the discovery of unknown com- 

 ponents in specific loci in the electron-transport chain by Slater and Potter, 

 the elucidation of the glycolytic pathway by Lohmann, Embden, and Meyer- 

 hof, and the more recent mapping of the sites of oxidative phosphorylation 

 by Chance. In addition, the biochemist is occasionally able to isolate with 

 an appropriate inhibitor certain metabolic reactions that are to be studied; 

 relatively simple examples would be the use of malonate to block succin- 

 oxidase in studying the oxidation of «-ketoglutarate in mitochondria, and 

 the blocking of pyruvate entry into the tricarboxylic acid cycle by arsenicals 

 in order to investigate the transformations of glycogen or glucose into py- 

 ruvate. Such techniciues have been relatively little developed but hold 

 much promise for the future study of metabolic pathways in tissues or whole 

 organisms. 



It may be noted incidentally that no manner of investigation so well 

 demonstrates the inherent differences in the metabolism of various tissues 

 or organisms as does that of enzyme inhibition. It is to be deduced from 

 the markedly variable responses of cells or tissues to inhibitors that respi- 

 ration and glycolysis, for example, are not the simple ubiquitously uniform 

 processes usually presented in textbooks, but that each type of cell has 

 its particular metabolic organization, that the enzymes catalyzing the same 

 reaction in different cells are kinetically different, and that there are va- 

 riations in the controlling factors governing the metabolic balance in va- 

 rious cells. This is not to detract from the concept of the obvious and fun- 

 damental uniformity of enzyme types and general metabolic systems 

 throughout living material, but it serves to emphasize that these units of 



