306 6. IXTERACTIONS OF INHIBITORS WITH ENZYMES 



Classification of the Possible Changes in Molecular Properties 



A fact of major importance that has frequently been neglected is that 

 when a particular group is altered or eliminated or added, the changes 

 in the molecule are not confined to this group. Any change of one part of 

 a molecule generally produces changes either throughout the molecule or 

 at least in those regions adjacent to the changed part. We must therefore 

 primarily divide molecular modifications into those attributable to the 

 group itself and those occurring in the rest of the molecule. The following 

 classification of possible changes may be helpful although it is not exhaus- 

 tive. 



(1) Molexular changes attributable to the modified group itself 



(A) Introduction into the molecule of an ionically charged or dipolar group, 

 or the elimination or modification of such. 



(B) Introduction into the molecule of a group that is chemically reactive with 

 protein groups, or the elimination or modification of such reactivity. 



(C) Alteration of the contour of the molecule at the region of the group, which 

 will either enable the molecule to interact more completely with the en- 

 zyme or sterically to interfere with the interaction. 



(2) Molecular changes induced by the modified group 



(A) Changes in the dissociation constants of acidic or basic groups. 



{B) Changes in the oxidation-reduction potential. 



(C) Changes in the charge distribution or dipole moments throughout the mol- 

 ecule. 



{D) Changes in the solubility of the molecules. 



{E) Changes in the position or freedom of rotation or movement of other groups 



due to steric or electrostatic effects. 

 {F) Changes in stability or reactivity of the molecule. 



Most of the changes observed in molecules resulting from the modifica- 

 tion of a particular group can be attributed to mechanisms which are termed 

 inductive, in which there is a shift in the average electron positions due to 

 the dipole moment of the group; electrostatic, in which the properties of the 

 various regions of the molecule are altered by the electrical field of a charged 

 group; or resonance, in which the electrons of the group are capable of 

 resonating with those in adjacent bonds. These mechanisms are often 

 difficult to distinguish and frequently overlap. Before presenting examples 

 of such changes, let us enumerate some of the ways in which the changes in 

 molecular properties could influence the behavior of an inhibitor in a met- 

 abolic system. For the sake of clarity we may assume that a group has 

 been added to an established inhibitor, I -> I-A, and we inquire into the 



