96 H. A. Krebs 



rate of oxygen consumption is determined, and at those where, 

 after a partial degradation, more than one pathway is open; 

 in other words, where the pathways of metabohsm can branch. 

 Before I discuss the effect of inhibitors on the different 

 types of pacemaker reactions, I must make reference to the 

 mechanism by which the rate of oxygen consumption is con- 

 trolled. One of the decisive factors is the rate at which hydro- 

 gen atoms or electrons travel from reduced DPN, via flavo- 

 protein and cytochrome c, to molecular oxygen. Unless the 

 catalysts of the electron carrier chain are in the oxidized 

 form the substrates cannot be attacked. Further, the trans- 

 port of electrons under physiological conditions is coupled 

 with the synthesis of ATP from ADP and orthophosphate 

 ( ' ' oxidative phosphorylation " ) : ' 



DPNH2 + 4O2 \ r DPN + H2O 



ADP + P j "^ \ ATP 



This coupling appears to be obligatory. Hence the rate of 

 oxygen consumption reaches a maximum value only if ADP 

 and orthophosphate are present above certain critical con- 

 centrations and it falls when the concentration of the phos- 

 phates falls below the critical level. In most tissues the physio- 

 logical concentrations of ADP and P are generally below the 

 critical level. The rate of oxygen consumption therefore 

 depends on the rate at which ATP is split in the tissue to ADP 

 and P, i.e. on the rate at which energy is spent. It is thus 

 evident that the component reactions of oxidative phos- 

 phorylation are pacemakers. 



The following examples show, for the case of cell respiration, 

 that extraneous agents interfere with pacemakers rather than 

 with other intermediary steps of metabolism. Inhibitors of 

 respiration fall into three main classes, according to the type 

 of pacemaker which they inhibit. Substances of Class I 

 inhibit rate of oxygen consumption because they interfere 

 with electron transport. Class II interferes with the initiating 

 reaction of respiration and therefore affects the type of 

 substrate which is oxidized. Class III interferes with the 



