EFFECTS OF ENZYME OR METABOLIC RATE 859 



but the inhibition will be diminished. In general, however, enzymes in 

 zone A will be inhibited to the same degrees, whatever the rates as influenced 

 by a variety of factors. 



Multienzyme Systems 



The situation here becomes very complex because of the great number of 

 possibilities as to the ways in which the rates may be changed and as to 

 the mechanisms by which the inhibitors can act. Therefore discussion will 

 be limited to specific cases. In simple irreversible monolinear chains, such 

 as A->B->C-^D, the over-all rate is determined by the first reaction 

 and will increase with the concentration of A up to saturation of E^. Inhi- 

 bition of an enzyme later in the sequence will depress the formation of 

 product only if the F,,, of the inhibited step is reduced below the rate of 

 the first step, or if the intermediate that is the substrate for the inhibited 

 enzyme cannot rise in concentration sufficiently to maintain a steady state 

 (see Chapter 7). The greater the concentration of A and the more rapid the 

 uninhibited rate, the easier will it be for an inhibitor to reduce the Vj„ 

 of the inhibited enzyme below t\. This is seen in Eq. 7-6 where the over-all 

 inhibition in the formation of the product depends on (A). 



The opportunities for the inhibition to be aff"ected by the rate are in- 

 creased in branched chains. A convergent system, such as shown in Eq. 

 7-22, will be inhibited by an action on E^ or Eg to a degree depending on the 

 fractions of the flow that pass through reactions 1 and 3. For example, if 

 an inhibitor acts on Eg, an increase in (A) will increase the fraction of 

 the rate that is resistant to the inhibitor and hence will decrease the in- 

 hibition while increasing the rate of formation of C. Such relationships 

 are readily treated and they are mentioned only to emphasize that similar 

 phenomena may occur in cellular metabolism. 



One may also generalize that any change in the rates in complicated 

 multienzyme systems that leads to a shift in limiting reactions is very 

 apt to alter the degree of response to an inhibitor, since the sensitivity 

 of the over-all rate to an inhibitor will depend on whether it acts on an 

 enzyme that is limiting. Thus the uncoupling of oxidative phosphorylation 

 may modify the inhibition on electron transport or respiratory systems. 



Cellular Metabolism and Function 



The factor of inhibitor-sensitive and inhibitor-resistant fractions in 

 most metabolic systems is very important in connection with the effect 

 of over-all rate on inhibition because the response will depend on whether 

 the fractions remain relatively the same when the total rate changes. If 

 the inhibitor-stable metabolism is always a constant fraction of the total 

 metabolism, whatever the over-all rate, the inhibition will be independent 



