Enzyme inhibitors aspartic proteinase

The mutation of the hydroxyl group positioned in R-configuration at the C(3) atom of the central statine (rSta) residue of the inhibitor gives rise to AAGbind of -0.51 kcal/mol, which is very close to the experimental value of -0.8 kcal/mol. It may be noted here that the starting configuration of the inhibitor in the enzyme-inhibitor complex is the same as that of pepstatin. The crystal structure of rhizopus pepsin or any other aspartic proteinase... 

The mechanism of the aspartic proteinases involves two essential catalytic aspartate residues. There is some controversy in the literature as to whether the mechanism involves an acyl en me intermediate or an amino enzyme intermediate (4). However, there is no direct evidence for either intermediate so additional studies with inhibitors and pseudosubstrates along with crystallographic analysis will ultimately be required to resolve these questions. 

If the main-chain hydrogen bonding of substrates is conserved among aspartic proteinases, how are the differences in specificities achieved Table 1 defines the enzyme residues that line the specificity pockets for both mouse and human renin. In modeling exercises (e.g., Reference 4) it was assumed that specificities derive from differences in the sizes of the residues in the specificity pockets (Sn) and their ability to complement the corresponding side chains at positions Pn in the substrate/inhibitor. A detailed analysis now shows that this simple assumption only partly accounts for the steric basis of specificity. 

Today it is generally assumed that all enzymes inactivated by these inhibitors share a common catalytic mechanism. The terms "aspartate proteinases" or "carboxyl proteinases" have been suggested for these enzymes. Not all proteinases with low pH-optimum belong to this group. For instance, proteinases from Aspergillus niger (12) and Scytalidium lignicolum (13) are insensitive to these inhibitors. We shall limit this discussion to acidic proteinases with aspartic acid residues in the active site. The term "aspartate proteinases" (14) in the same manner as serine proteinases is used. 

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