INHIBITION TYPES UNIQUE TO ORGANIZED SYSTEMS 437 



Markham (1958). We shall restrict the discussion to cases in which an en- 

 zyme inhibitor is formed and omit the incorporation of unnatural analogs 

 (such as the analogs of amino acids, purines, or pyrimidines) into proteins 

 or nucleic acids, since these interfere with metabolism indirectly. Some 

 examples of lethal synthesis in this restricted sense would be: the forma- 

 tion of fiuorocitrate from fluoroacetate, resulting in the inhibition of 

 aconitase; the transformation of deoxypyridoxine to deoxypyridoxine pho- 

 sphate, which interferes with enzymes utilizing pyridoxal phosphate; the 

 formation of DPN and TPN analogs from the acetylpyridines, resulting in 

 disturbances of electron transport; and the formation of 5-fluoronicotin- 

 amide from 5-fluoronicotinic acid, blocking the phosphorylation of nico- 

 tinamide riboside. 



The precursor is usually chemically related to the normal substrate of 

 the enzyme that forms the inhibitor since otherwise it is unlikely that it 

 would combine with the enzyme. The precursor may differ from the sub- 

 strate in a single group; the following substitutions are frequently effective, 

 as pointed out by Markham — CI, Br, or I for a CHg group; F for H; SH 

 for OH or =S for =0; >i-propyl for isopropyl; — N= for — CH==; — S — 

 for — CH=CH— ; Se for S or As for P. It is impossible to predict if the 

 analog will directly inhibit the enzyme or if it will serve as an abnormal 

 substrate. The advantage of an inhibitor formed by lethal synthesis is that 

 it is often quite specific and directed efforts to discover effective precursors 

 are now common. 



The kinetics of inhibition resulting from lethal synthesis will depend 

 on the relationship of the enzyme inhibited to the the enzyme forming the 

 inhibitor. If the inhibited enzyme bears no direct relationship to the 

 lethal synthesis, it is evident that the inhibition will be progressive with 

 time, in that the inhibitor will increase in concentration, unless there is 

 a limited supply of the precursor or the inhibitor is eliminated by some 

 mechanism as it is formed. The rise in inhibition will depend, too, on the 

 spatial configuration or compartmentalization of the system because the 

 inhibitor concentration will increase more rapidly if the inhibitor is restricted 

 to the region where it is formed. The great potency of fluoroacetate is in 

 part due to the accumulation of the fiuorocitrate in the mitochondria. 



Two simple cases of lethal synthesis may be taken as illustrative of the 

 more general properties of such inhibition. If the inhibition is exerted on 

 the enzyme forming the inhibitor: 



E 



S ^ P V 



E 



X -^ I 



(X) + K, 



