8 1. PERSPECTIVES OF METABOLIC INHIBITION 



tase, and this was soon followed by the enunciation of the principle of 

 catalysis by Berzelius in 1835, who included diastase as a catalytic agent. 

 The name " diastase " came to be used for all enzymes and the term " fer- 

 ment " was also soon applied because of the relationship of enzyme action 

 to fermentations. The name " enzyme " was introduced by Kiihne in 1878 

 and simply means " in yeast " inasmuch as yeast was at that time the 

 source of most of the known enzymes. A great advance was made by Emil 

 Fischer in 1894 in the recognition of the specificity of enzymes, and the 

 lock-and-key theory of the steric relationship between enzyme and sub- 

 strate may be attributed to him. Serious attempts to isolate and purify 

 enzymes did not begin until after 1920, most of the early work being done 

 by Willstatter and his colleagues between 1922 and 1928. Urease was ob- 

 tained in impure crystalline form by Sumner in 1926 and this was followed 

 by the crystallization of certain proteolytic enzymes by Northrop and his 

 students. The purification of intracellular enzymes did not begin until 1937. 

 These landmarks in enzymology are mentioned because the entire develop- 

 ment of the study of inhibitors is intimately related to the progress in the 

 knowledge of enzymes and metabolism. In one sense it is a tribute to the 

 early workers to have advanced so far in the understanding of enzyme 

 mechanisms and kinetics long before enzymes had been isolated or purified. 

 For example, the important concept of a complex between the enzyme 

 and the substrate was put forward by A. Brown in 1902 and by 1904 Arm- 

 strong was able to represent this complex in quite modern terms. This 

 picture of enzyme action enabled the correct kinetic expressions to be for- 

 mulated, first by Henri in 1903 and in more detail by Michaelis and Menten 

 in 1913. Inhil)ition mechanisms and kinetics have necessarily developed 

 hand in hand with such concepts. 



The early history of enzyme inhibition is amorphous. Some inhibitors 

 have been known for hundreds of years as poisons. It might be said that 

 classic toxicology led to the first studies of what are now known as enzyme 

 inhibitors — cyanide, arsenic, hydrazine, mercury, and certain other heavy 

 metals. Sporadic work on the effects of such substances on a variety of 

 plants, small animals, and microorganisms was reported from 1850 to 

 around 1890, and during the period from 1870 to 1900 there was increasing 

 attention given to inhibitions of general metabolic processes, such as fer- 

 mentation, glycolysis, and respiration, as well as to the actions of inhibitors 

 on whole animal metabolism. It is actually very difficult to determine in 

 this progressive development where the true study of inhibitors as inhibi- 

 tors began. Certainly before 1910 these substances were not considered as 

 primarily enzyme or metabolic inhibitors. Perhaps the modern study of 

 enzyme inhibition may be said to have been initiated by the demonstrations 

 of the depression of sea urchin egg respiration with cyanide by Warburg in 

 1910 and the inhibition of goose erythrocyte respiration with arsenite by 



