THE CONCEPT OF PACEMAKERS IN METABOLISM 459 



amount needed for their ordinary functioning; fumarase in some cells might 

 be cited as an example. Inhibition of such enzymes will not produce a 

 marked effect on metabolism until their activity has been reduced to the 

 point where they are limiting. The enzymes of the tricarboxylic acid cycle 

 are often given as an illustration of a metabolic system in which the inter- 

 mediates are handled rapidly and readily and little accumulation occurs. 

 However, it has recently been emphasized that this does not apply to all 

 enzymes in the cell and that those enzymes that do limit the rate are the 

 "pacemakers of metabolism" (Krebs, 1957, 1958). According to this con- 

 cept, there are certain key enzymes or reactions that mainly determine 

 the over-all metabolic rates and it is these that are most susceptible to the 

 action of inhibitors. In general, those reactions initiating the degradation 

 of the primary substrates — glucose, amino acids, fatty acids, and oxygen — 

 are the pacemakers, but other pacemaking reactions may occur after a 

 certain amount of degradation has occurred, particularly at branching 

 points which determine the directions of metabolic flow. On this basis 

 Krebs divides inhibitors of respiration into three classes: 



I. Inhibition by interference with utilization of oxygen: cyanide, CO, 

 azide, and sulfide. 



II. Inhibition by interference with utilization of substrate, i.e., by action 

 on the dehydrogenases: malonate and arsenite. 



III. Inhibition by interference with reactions at the branching points 

 of metabolism, diverting metabolism abnormally: agents that may reduce 

 the supply of oxalacetate, such as malonate or ammonium chloride. 



With respect to glycolysis, there are two principal pacemakers, the liexo- 

 kinase and the triose phosphate dehydrogenase, and most inhibitors of 

 glycolysis, such as iodoacetate and glyceraldehyde, act at these loci. A 

 very crucial branching point is often in the systems for the disposition of 

 acetyl-CoA. The number of pathways available for this compound depends 

 upon the type of cell, but in all cells it is a central substance in the utiliza- 

 tion and synthesis of carbohydrate and fatty acids. This is also a vulnerable 

 point for attack by inhibitors and the whole pattern of metabolism may be 

 readily altered by changing the ratios acetyl-CoA/CoA, reduced flavoprotein 

 /oxidized flavoprotein, and DPNH/DPN. According to Krebs, then, these 

 pacemaker reactions are those to which we must turn our attention in 

 considering ways and means of potently inhibiting cellular metabolism. 

 Without denying the importance of this concept, I believe that a too 

 ready acceptance of it may oversimiilify a very complex problem and lead 

 to errors in interpretation. If one jumps to the conclusion that only a few 

 vital reactions or enzymes in the cell are of much importance in the action 

 of inhibitors, that the effects of inhibition can be entirely explained on the 

 basis of these few pacemaker reactions, this conclusion will be quite er- 



