44 1. MALONATE 



active center may not be smoothly curved as shown, and we shall soon 

 examine evidence that it is not. 



The problem of the interactions of di-ionic substances with receptor 

 groups has been recently treated by Schueler (1960, p. 448) and on the basis 

 of statistical calculations he has concluded, "The most dramatic alteration 

 in activity should occur upon approaching that agent in the series which 

 possesses a length distribution just capable of overlapping the negative- 

 charge spacing in the receptor, and this should be followed by a relatively 

 slow rate of loss in activity with respect to increasing length" (he is assum- 

 ing a positively charged drug). In view of what has just been said above, 

 there is some doubt if predictions like this can be made with confidence. 

 The large distances between the interacting charged groups make it very 

 difficult to assign receptor configuration and much will depend on the over 

 all configuration of the protein surface. Other factors, such as distortion of 

 long-chain molecules, interactions of regions between the end charged 

 groups the surface, and possible steric repulsions, must be considered. 



Inasmuch as little accurate information on the intercationic distance can 

 be obtained from Kj and K^. values alone, let us now turn to more profitable 

 considerations of the topography of the active center. There is evidence 

 from several lines that the active center is not a flat or slightly convex 

 surface. In the first place, alkylsuccinates are bound to the enzyme very 

 poorly; methylsuccinate is oxidized at 23% the rate for succinate, and 

 ethylsuccinate at 18% the rate for succinate, while higher members are 

 neither oxidized nor are they inhibitory (Franke, 1944 a). In the second 

 place, as we have already seen, alkylmalonates are very poor inhibitors. 

 Indeed, even the introduction of a hydroxyl group (tartronate) reduces the 

 inhibition markedly. These observations indicate a rather close fit for 

 malonate and succinate at the active center, additional groups giving rise 

 to steric repulsion, as frequently reported for antigen-antibody reactions. 

 In the third place, fumarate is bound fairly well while maleate is not, indi- 

 cating again some steric repulsion since the intercarboxylate distances 

 alone would certainly allow predictions that maleate would be bound more 

 tightly. All molecules that bind appreciably to succinate dehydrogenase 

 seem to be simple linear substances, or substances capable of assuming a 

 linear configuration. All of this evidence points to a slit or tubular structure 

 for the active center, such that compounds with added groups or rigid non- 

 linear molecules cannot enter. Such a situation is pictured in Fig. 1-8 in 

 two dimensions. This is not to be construed as an attempt to represent 

 the actual configuration but merely to show the steric barriers impeding 

 attachment of larger or nonlinear molecules. Glutarate and adipate could 

 not fit well, not because of unsatisfactory intercarboxylate distances, but 

 because of the bulkiness of the longer hydrocarbon chains. Fumarate is 

 able to bind because its configuration is much like that of succinate in the 



