454 9. INHIBITION IN CELLS AND TISSUES 



concerned with. When (Ig) = the enzyme will be inhibited by I^ to a cer- 

 tain degree, and when (Ig) is very high the rate will be zero. To determine 

 if a maximum in the rate curve occurs as (Ig) is increased, the derivative 

 dvjdil^) may be determined; it is simpler to take the derivative of the 

 denominator of Eq. 9-10 and equate it to zero since a minimum in this 

 denominator implies a maximum in the rate. 



ihhna. = V K,K,,a,),IK, - K,, (9-13) 



where 0-2)max i^ the inhibitor concentration giving the maximal rate. If 

 K<^{l-i)tJK^ is greater than ^^2' (^'dynax will have a positive value. Thus 

 the possibility of stimulation depends on the concentration of the original 

 inhibitor, the relative affinities of the two inhibitors for the enzyme and 

 the dissociation constant of the I^Ig complex. When these factors are 

 favorable, a plot of Eq. 9-10 will show a biphasic effect as (Ig) is increased. 

 The relationships may be a great deal more complex, however, if the initial 

 inhibitor is a metal ion that can function both as an activator and inhibitor, 

 as Mg++ and Ca++ with ATPase. 



II. Alteration of metabolic fow in multienzyme systems. Some examples 

 of this mechanism have already been discussed in Chapter 7. It is usually 

 exhibited in divergent or polylinear chains when one pathway is inhibited. 

 The over-all flow rate may not be altered but the activity in a particular 

 pathway may be increased. Thus the appearance of stimulation will depend 

 on what aspect of the total system one is examining. For example, a 

 branched chain of the following type: 



, C ^ O, 

 A ^ B ^ 



\d 



where B can either be oxidized or enter into the synthesis of D, will, upon 

 inhibition of B-> C, appear to be inhibited if oxygen uptake is being meas- 

 ured, to be stimulated if synthesis of D is determined, or to be unaffected 

 if utilization of A is the criterion of rate. This mechanism is actually a di- 

 version of metabolism rather than a true stimulation, but nevertheless it 

 manifests itself as stimulation and in most cases it is difficult to distin- 

 guish it from a direct effect. Electron transport systems apparently have 

 phosphorylating and nonphosphorylating pathways and a shift from one 

 to the other, brought about by specific inhibition, could increase or de- 

 crease the rate of formation of ATP and all the reactions dependent upon 

 ATP. The inhibition of cytochrome oxidase with cyanide increases the di- 

 version of hydrogen atoms to methylene blue or other acceptor dyes; 

 without knowledge of the situation here, one might conclude that cyanide 

 stimulated the oxidation of the substrate. These examples show that care 



