Extraneous Agents and Cell Metabolism 93 



the amounts of enzyme and substrate determine the maximum 

 rate of the process but maximum rates are exceptional under 

 physiological conditions. The limiting factor is usually 

 (though not always) the amount of substrate. The fact that 

 intermediate products generally do not accumulate shows 

 that the substrates of the intermediary enzymes are removed 

 as rapidly as they are formed. The average half-life of the 

 acids of the tricarboxylic acid cycle in a rapidly respiring 

 tissue is of the order of a few seconds (Krebs, 1954). Thus the 

 amount of enzyme in the tissue is sufficient to deal with the 

 intermediate as soon as it arises ; in other words, the amount 

 of available substrate is the factor limiting the rate at which 

 many intermediary steps proceed. Hence a partial destruc- 

 tion of an enzyme does not necessarily upset cell metabolism. 



It is obvious, however, that this cannot apply to all steps 

 of metabolism. There are some reactions, small in number by 

 comparison, where the rates depend on factors other than the 

 amounts of enzyme or substrate. These are the " pacemakers " 

 of metabolism (Krebs, 1956). 



The pacemaker reactions are the steps of metabolism which 

 are especially vulnerable to extraneous agents, because any 

 decrease in activity is liable to show itself in a diminished 

 overall rate of metabolism. Pacemakers are therefore the 

 enzyme systems towards which the study of the effect of 

 extraneous agents should be primarily directed. I would like 

 to elaborate these considerations on some examples, taken 

 mainly from the field of energy transformations. 



Effects of extraneous agents on anaerobic glycolysis 



The anaerobic glycolysis is known to involve some twelve 

 separate steps. The factors which control the overall rate of 

 glycolysis and adjust the rate to the physiological energy 

 requirements are by no means fully known but there are two 

 steps which have been identified as pacemakers. The first is 

 the hexokinase reaction (LePage, 1950) which probably 

 initiates all major metabolic reactions of glucose, such as the 



