THE CONCEPT OF PACEMAKERS IX METABOLISM 



461 



It is ijossible to cite many examples of metabolic inhibition in which 

 the primary reaction affected is not a pacemaker. The inhibition of glycol- 

 ysis and respiration by fluoride acting on enolase has been mentioned. A 

 good example is the very potent inhibition induced by fluoroacetate, inas- 

 much as aconitase would certainly not be considered a limiting enzyme in 

 respiration. Also, respiration can be readily inhibited by substances acting 

 on enzymes other than cytochrome oxidase or the dehydrogenases in the 

 electron transport pathways; antimycin A. dimercaprol, and certain 

 naphthoquinones all act on some intermediate transfer. Reasons such as 

 those presented above and experimental evidence of this nature do not 

 by any means invalidate the basic concept but only suggest caution in 

 its application. 



Fig. 9-.5. Possible sites for metabolic control in ascites tumor cells. (1) control of 

 respiration by ADP concentration. (2) control of ATP utilization in endogenous 

 processes by ATP concentration. (3) control of glucose phosphorylation by the ATP 

 level. (4) reservoir of ATP formed in mitochondrial oxidations not readily available 

 for glucose phosphorylation. (5) control of glycolytic or oxidative phosphorylation 

 by the inorganic phosphate level. (6) control of glycolytic phosphorylation by the ADP 

 level. (7) control of glycolytic phosphorylation by the substrate (hexose diphosphate) 

 level. (From Chance and He.ss, 1959). 



Another concept of great importance, and related closely to the eluci- 

 dation of pacemaker reactions, is that of certain controlling processes in 

 the cell. In any complex metabolic system, there are specific loci where 

 various influences can readily control the over-all rate. This has been 

 expressed particularly clearly by Chance and Hess (1959) whose spectro- 

 scopic studies of glucose utilization by ascites tumor cells have provided 

 several such loci. Figure 9-5, showing possible controlling points for this 

 particular type of cell, summarizes their conclusions. It is very interesting 

 to work out the effects of inhibition at various sites in such a scheme and 



