VARIATION OF INTRACELLULAR INHIBITION WITH pH 733 



will consist of two major portions, on the acid side of the piC^ the action of 

 HI will be represented and on the alkaline side the action of I~, these being 

 connected near the pK^. Since the anion will often exert much less effect, 

 its part of the curve will be higher than the HI portion. This cannot explain 

 the leveling off of the majority of the experimental curves because this 

 occurs several units above the \)K^, whereas the effect of I~ would be near 

 maximal one unit above the pi^^. 



(C) The membrane is somewhat permeable to the anion. Whether or not 

 this will produce a change in the alkaline side of the curve, it will alter the 

 acid portion because (I)^ will not rise as high as if the anion were trapped 

 in the cell. The lower the pH^, the smaller is (I)^, the more readily will 

 the anion escape from the cell and the lower will be its equilibrium con- 

 centration within the cell. 



(D) The permeability to the anion becomes appreciable only at high pHg. 

 If the anion could penetrate into the cells progressively better at higher 

 pHo's, a lower concentration of the inhibitor would be required and the 

 slope of the right-hand portion of the curve would decrease. There would 

 seem to be no evidence for such a phenomenon and, in fact, one would 

 predict that the permeability to anions might well decrease at higher pH^'s 

 because the membrane would become charged more negatively. 



{E) Intracellular inhibition varies ivith pH ^. In the calculations above, 

 it was assumed that the effect of the anion within the cell was independent 

 of pHj. How^ever, from what has been discussed earlier in the chapter, it 

 is likely that a fall in pH^ will modify the inhibition, first increasing it 

 (due to a greater net positive charge on the enzyme or active center) and 

 then decreasing it (due to the reduction in the concentration of I~). We 

 are concerned with the former effect and this may cause a dropping off 

 of the low pH portion of the curve. 



{F) Lowering of pHi by buffer penetration leads to altered metabolism. 

 When the external medium contains buffers, the buffers in the undissociated 

 form may penetrate into the cell when the pH^ is lowered and cause an 

 acidification of the cell. This may in turn so alter the metabolism that its 

 sensitivity to the inhibitor will change. In other words, the sensitivity of 

 the metabolic systems to the inhibitor will vary with pH^ independently 

 of the presence of the inhibitor. This may lead to deflections of the low pH 

 portion of the curve either upwards or downwards, depending on whether 

 the metabolism has been made less or more sensitive to the inhibitor. 



(G) Change of pH^^ produces a change, other than ionization, in the inhibitor. 

 Various properties of the inhibitor may be changed when the pH is altered 

 from the normal physiological range. The inhibitor may be made more or 



