EFFECTS OF ALTERATION OF STRUCTURE 309 



Although the last three structures do not contribute greatly in terms of 

 molecular species, their dipole moments are high and they counteract the 

 C-Cl moment effectively. A charge of around 0.05 that of an electron charge 

 would be sufficient to account for this reversal if this fractional charge 

 is located on the ortho or 'para positions. Similar resonance forms con- 

 tribute to the over-all moments of nitro-, amino-, and carboxy-substituted 

 benzenes (Wheland, 1955, p. 213). Thus the total dipole moment of a simple 

 molecule and its changes when groups are altered are not simply referable 

 to the groups only; when binding to an enzyme involves such moments, 

 the inhibition will depend upon inductive and resonance effects within 

 the molecules. 



(6) Distance of separation between assumed binding groups. Inhibitors 

 that contain two distinct groups separated by relatively unreactive regions 

 of the molecules, R— X— R, are often assumed to inhibit differently when 

 the size of X is varied due to changes in separation of the groups. An 

 excellent example of such variation in enzyme inhibition may be taken 

 from the study of Blaschko and Himms (1955) on the amine oxidases 

 from various tissues, the results of which are plotted in Fig. 6-21. Com- 

 pounds of the series 



HN NH 



7C^cp— O— (C'H2)„— 0-<p— c/ 



were tested for their ability to inhibit the oxidation of tyramine and in 

 most cases an optimal chain length was found for maximal inhibition. 

 These results might be interpreted as follows: on the enzyme there are 

 two sites capable of reacting with the terminal amidine groups and these 

 sites are a constant distance apart, the degree of inhibition depending on 

 the distance between the amidine groups and how well this corresponds 

 to the enzyme site distance (it was not so interpreted by Blaschko and 

 Himms). This may be so but there are other explanations that are justi- 

 fiable. For example, the — (CHa)^— chain may also interact with the en- 

 zyme surface and the variations in binding attributed to differing disper- 

 sion and steric effects resulting from the change in n. Similar variations are 

 often observed when a hydrocarbon chain length is altered when there is 

 only one possibly reactive group in the molecule. 



(c) Effect of optical isomerism on group effects. The hydrolysis of substi- 

 tuted L-tyrosinamides by a-chymotrypsin is inhibited by the corresponding 

 D-isomers (Manning and Niemann, 1958) and the dissociation constants 

 are shown in Table 6-29. The D-isomers are bound as tightly as the L-isomers 

 but presumably possess a configuration in which the electronic distortion 

 leading to hydrolysis cannot occur. These results illustrate not only the 



