482 



2. ANALOGS OF ENZYME REACTION COMPONENTS 



INHIBITIONS BY COENZYME ANALOGS 



This field in which interest was stimulated by the demonstration of the 

 mechanism of sulfonamide action is a large one because of the great amount 

 of work done on the growth inhibition of microorganisms by these analogs, 

 so that here the presentation will be restricted to those aspects directly re- 

 lated to enzyme inhibition and specific metabolic disturbance. The competi- 

 tion between a coenzyme analog and a coenzyme for combination with the 

 apoenzyme for which the coenzyme is essential is basically of the same 

 nature as the examples of substrate analogs discussed previously. However, 

 there are usually additional complexities due primarily to the greater num- 

 ber of sites for antagonism. Figure 2-16 indicates some of the reactions 



Fig. 2-16. General scheme for the formation and possible reactions 

 of coenzymes in cells. C = a unit of the active coenzyme (e.g., 

 nicotinamide, adenine, or thiamine), CP = the active coenzyme, 

 E-CP = the active enzyme-coenzyme complex for the reaction 

 A -> B, and X = any derived substance from the unit C, which 

 may be inactive, or active to some degree after phosphorylation, 

 or capable of interfering with the formation or action of the coen- 

 zyme. Reaction 1 may be a simple diffusion into the cell or be 

 mediated by facilitated diffusion or active transport; reaction (2) 

 occurs in cells which synthesize the coenzyme from precursors; re- 

 action (3) is usually a phosphorylation; reaction (4) is a dephos- 

 phorylation; and reaction (5) represents the complexing of the 

 coenzyme with the apoenzyme. 



involved in coenzyme formation, destruction, and function. Inasmuch as 

 the catalytically active forms of most coenzymes are formed within cells 

 from precursors, these reactions and the membrane processes responsible 

 for entrance of the precursors must be considered as possible loci for analog 

 interference. Furthermore, in many instances the analogs are metabolized 

 along the same pathways as the coenzymes to form inhibitory products. 

 Certain coenzymes are active in phosphorylated forms and the reaction 

 immediately forming the active coenzyme is often a phosphorylation in- 



