CHAPTER 11 

 METABOLITE ANTAGONISTS 



This chapter and the one following will deal with chemical compounds 

 which inhibit, injure, or kill fungi. Much can be learned about "normal" 

 physiological processes by studying the factors which interfere with them. 

 The ideas to be discussed here are applicable to the entire field of phys- 

 iology, and some of our illustrative material will deal with organisms 

 other than fungi. The reviews of Woolley (1944), Welch (1945), Wright 

 (1947), Mcllwain (1947), and Roblin (1946, 1949) are extensive and well 

 documented and should be consulted for additional references. 



Metabolites are chemical substances which are essential for the func- 

 tioning and maintenance of living cells. Metabolites may be synthesized 

 by the organism or obtained from the medium, e.g., vitamins, amino 

 acids, etc. 



An antimetabolite, or antagonist, is a compound which interferes with 

 the utilization of a normal metabolite. Wright (1947) has classified 

 antagonists (more specifically antivitamins) on the basis of their mode of 

 action: (1) those which act by virtue of destroying or inactivating a 

 metabolite; (2) those which combine irreversibly with enzymes (non- 

 competitive inhibition) ; and (3) those which combine with enzymes but 

 w^hich may be displaced by increased concentration of the normal metabo- 

 lite (competitive inhibition). 



Noncompetitive enzyme inhibition is so called because an increase in 

 the concentration of the normal coenzyme or metabolite molecules does 

 not reverse the inhibition. Inhibitors of this type act by combining 

 with some atom or molecular group of either a coenzyme or an apoenzyme. 

 Among inhibitors of this type we may list the heavy metals, various 

 organic mercury and arsenic compounds, iodoacetate, and quinones, 

 which inactivate enzymes by combining with free sulfhydryl groups (see 

 Singer, 1945, and McElroy, 1947, for references). Among the inhibitors 

 which act on the iron-porphyrin enzymes are cyanide, azide, hydrogen 

 sulfide, and carbon monoxide. Most of the discussion to follow will deal 

 with competitive antagonists. 



Metabolite antagonists are analogues of normal metabolites, but not 

 all analogues of a metabolite are necessarily antagonists. These "for- 

 eign" molecules, because of their close resemblance to normal metabolites, 

 combine with enzymes in the same manner as normal metabolites. How- 



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