438 9. INHIBITION IN CELLS AND TISSUES 



where S is the normal substrate, P its product, X the precursor, and I the 

 inhibitor formed. When I inhibits E (a form of product inhibition actually), 

 both reactions will, of course, be depressed, and progressively so as (I) in- 

 creases. The development of the inhibition is thus slowed relative to the 

 situation in which the inhibition is on another enzyme. However, a steady 

 state will not be reached unless X is limited or I diffuses away. If the inhi- 

 bition is on a succeeding enzyme in a sequence: 



El E^ 



S -> Pi -> P, 



Ej E2 



X ^ I ^ Y 



that is, where I inhibits Eg, the kinetics are different than in the previous 

 case. The rate of formation of Pg will be progressively depressed as (I) 

 rises. The level of (I), as in any monolinear chain, will depend on the re- 

 lative rates of X ^^ I and I -> Y; if the latter is rapid, (I) may reach only 

 low levels and inhibition on Eg will be small. However, inasmuch as I 

 slows down its own disappearance, its concentration will slowly rise and 

 the inhibition will become greater and greater. If step I ^ Y does not 

 occur and I accumulates, the formation of Pg is progressively depressed 

 but (Pj) may rise. If X is limited in amount, after it has been used up the 

 inhibition on the formation of P2 will be the same as if one had added I 

 in the initial concentration of X, providing the inhibitor can gain access 

 to the enzyme. In the case of fluoroacetate added in small amounts, the 

 inhibition will reach a constant level when the i^recursor has been utilized, 

 but the inhibition will not be the same as if an equivalent concentration 

 of fluorocitrate were added, because fluorocitrate cannot penetrate readily 

 to the mitochondrial aconitase. 



This example illustrates one of the interesting aspects of lethal synthesis. 

 If an inhibitor is incapable of entering a cell, or any region of a cell, a pre- 

 cursor that can penetrate will allow the inhibition to be exerted. The 

 useful group of inhibitors comprising the phosphorylated substrate and 

 coenzyme analogs is usually unable to penetrate into the cell, but the non- 

 phosphorylated precursors may enter and be phosphorylated. 



Inhibition of Transport Systems in the Membrane 



The substrate for an intracellular reaction may be obtained from outside 

 the cell and its uptake regulated or limited by the activity of certain 

 proteins or enzymes in the plasma membrane. Two general situations may 

 be recognized. The transport may be active and involve energy derived 

 metabolically, in which case the uptake rate will depend on a number of 

 enzymes as well as the specific transport mechanisms. On the other hand, 



