ACTION ON VARIOUS MULTIENZYME SYSTEMS 501 



and E3 respectively, and if is the inhibition of C formation. It is interesting 



that this is one of the few situations where the individual inhibitions 



are additive, i.e., i, + i, = i, . The inhibition of two or more pathwavs 

 1 3 1,3 



leading to a final product has been termed "concurrent blocking" (Skipper 

 et al., 1954). This procedure does frequently offer a means of inhibiting the 

 over-all reaction more potently than with either inhibitor alone, especially 

 when it is not possible for some reason to increase the concentration of a 

 single inhibitor sufficiently to produce the required degree of block. 



Multiple inhibition of divergent chains (Eq. 7-25) presents no special 

 problems that have not already been discussed, except for the possibility 

 that a second inhibitor acting on Eg might antagonize the depression of C 

 formation produced by an inhibitor acting on E2 by diverting more of B 

 to C. The response of a polylinear system (Eq. 7-30) to multiple inhibition 

 will follow the same rules as for convergent chains and it is in such systems 

 that the use of a second inhibitor will often depress a resistant phase of 

 metabolism. The effects of two inhibitors on a .steady-state cyclic system 

 (Eq. 7-35) are complex but the behavior can be treated in general terms. 

 The conservation of intermediates prevents marked changes in their in- 

 dividual concentrations and thus a cycle is usually more inhibitable than a 

 monolinear chain. AVhen E^ is inhibited, the rise in (A) allows the inhi- 

 bition to be partially antagonized; if E3 is inhibited in addition, this tends 

 to prevent the rise in (A) and the over-all inhibition is augemented. How- 

 ever, two inhibitors will not depress the formation of product additively 

 in most cases and potentiation will not be observed. Another situation is 

 that where a measured jiroduct is produced at each step of the cycle (or 

 at certain steps, as COg is produced in the tricarboxylic acid cycle). The 

 reduction in the rate of formation of this product will depend on the site 

 of inhibition in the cycle; the additional inhibition produced by a second 

 inhibitor will also depend on where it acts relative to the first inhibitor. 

 Finally, in cycles where the sum of the concentrations of intermediates is 

 not necessarily constant, of which the tricarboxylic acid cycle is an exam- 

 ple, inhibition may lead to a disappearance of intermediates (especially 

 if these intermediates participate in other extracyclic reactions) with sub- 

 sequent reduction in the incorporation of substrate, leading to a progres- 

 sive deterioration. In such cases, two inhibitors might have a final effect 

 out of all proportion to their individual inhibitions. 



Simple regenerative systems (Eq. 7-39) would not be very sensitive to 

 two inhibitors. As has been pointed out, such a system is potently inhi- 

 bited only when the action is on that reaction which is potentially the 

 slowest and thus further inhibition on the other reaction would not be pre- 

 dicted to increase the inhibition to a great extent. If the reactions are ini- 

 tially of comparable potential rates, inhibition of one will progressively 

 make the other reaction less .sensitive to inhibition. 



