102 H. A. Krebs 



(3) The action of many drugs, especially the blocking 

 agents. Cholinergic blocking agents (atropine, curare, tetra- 

 ethyl ammonium ions) are assumed to prevent the attachment 

 of the acetylcholine to the hypothetical receptor site, whilst 

 adrenergic blocking agents (ergotoxin, veratrin) analogously 

 block the adrenergic transmission. 



(4) The toxic, or some of the toxic, effects of fiuoroacetate 

 which replaces acetate in the formation of citrate and there- 

 by yields fiuorocitrate which in turn is a powerful enzyme 

 inhibitor. 



In view of the widespread occurrence of this type of inter- 

 ference the idea suggests itself that it might also be responsible 

 for some of the effects of radiation; that the decomposition 

 products of water arising from ionizing irradiation so modify 

 cell constituents that they become noxious and that the 

 noxiousness is due to the similarity to normal constituents. 



Conclusions 



To sum up, the main thesis put forward in this contribu- 

 tion is the concept that some stages of metabolism in living 

 cells are more vulnerable than others to attack by extraneous 

 agents. The vulnerable stages are those which control the 

 rates of metabolic processes — the "pacemaker" reactions. 

 The enzyme systems responsible for these reactions are 

 expected to work to full capacity under physiological condi- 

 tions, so that any change in the amount of active enzymes will 

 modify the rate of metabolic processes. In contrast, the 

 enzymes operating at other stages are present in excess of the 

 available substrate, and a partial destruction of the enzymes 

 therefore does not affect the rate of metabolism. Information 

 on the nature and mechanism of action of "pacemaker" 

 reactions is still limited, but the available information for the 

 case of energy transformations confirms that interference by 

 extraneous agents with cell metabolism is more often than not 

 due to interference with pacemaker reactions. 



