COMPARISON OF HALOGEN ATED ACIDS 271 



esters. In addition, some of the other halogenated alkylating agents will 

 be mentioned. 



lodoacetate and lodoacetamide 



Goddard (1935) introduced iodoacetamide as a more penetrable alkylat- 

 ing agent of the iodoacetate type, and attributed the differences he observed 

 in the responses to these two inhibitors of Neurospora ascospores to a greater 

 penetration of the iodoacetamide, although this evidence is inconclusive 

 since the potencies of action within the cells might be different. The im- 

 portant differences in general reactivity may be summarized as follows: 

 iodoacetamide reacts more rapidly than iodoacetate with SH groups 

 (around 1.9 times as fast at pH 7.1 and 4 times as fast at pH 6.1) (Smythe; 

 1936), whereas iodoacetate usually reacts more rapidly than iodoacetamide 

 with amino groups (Table 1-2). Following reaction with proteins or enzymes, 

 iodoacetate introduces negatively charged groups ( — CHjCOO-), while iodo- 

 acetamide introduces neutral groups ( — CHgCONHg), and this might be 

 quite important in the effects produced. If enzyme SH groups are involved 

 in the inhibition, one might expect iodoacetamide to inhibit more rapidly 

 and perhaps more potently than iodoacetate, and this is usually observed 

 (Table 1-41). As far as I know, no direct comparison of the relative actions 

 on 3-PGDH has yet been reported, which is unfortunate since it might 

 help to understand the differences in the inhibition of the EM pathway. 



When cellular systems are considered there is in addition to these fac- 

 tors the matter of relative penetrations into the cells and the resultant 

 intracellular concentration. The potency of iodoacetate should vary mark- 

 edly with the pH, except as membrane structure is altered (the pZ,, of 

 iodoacetamide is far too low for protonation in any usable pH range). 

 Theoretically one would expect iodoacetamide to be much more potent 

 than iodoacetate at pH 7 or above and, from the results on isolated enzymes, 

 would not predict iodoacetate ever to be much more effective than iodoacet- 

 amide even at low pH's. However, these predictions are not borne out, and in 

 several cases iodoacetate is the more potent, even around neutrality (Table 

 1-42). Indeed, with respect to the inhibition of glycolysis and respiration, 

 iodoacetate appears to be generally more effective. The inhibition of photo- 

 synthesis, on the other hand, follows the theory quite closely, although at 

 low pH's iodoacetate is often a good deal more potent than iodoacetamide, 

 which may be due to the fact that when the external pH is much below the 

 intracellular pH, the concentration of iodoacetate inside the cells can be 

 greater than outside (see page 1-714). Stannard (1937) long ago suggested 

 that the actions of iodoacetate and iodoacetamide are in some way different, 

 particularly because they have quite different effects on the R.Q. of muscle. 

 Furthermore, iodoacetate causes an increase in the muscle excitability, 

 followed by a fall during contracture, whereas iodoacetamide does not alter 

 the excitability until rigor occurs (Stannard, 1938 b). Lehninger (1951) found 



