CARBOXYPEPTIDASE, AMINOPEPTIDASES, DIPEPTIDASES 367 



a better inhibitor than L-phenylalanine under the usual conditions, since 

 the NH3+ group of the latter is repelled by the positively charged pep- 

 tidatic site while in the former it does not encounter serious steric in- 

 terference (Fig. 2-9). However, /5-phenylpropionate (hydrocinnamate) is 

 bound more tightly than D-phenylalanine by 2.14 kcal/mole, suggesting 

 that some steric repulsion of the latter analog occurs. iV- Substitution in- 

 creases the repulsion markedly and inhibitory activity is lost. A comparison 

 of the possible orientations of some inhibitors in Fig. 2-9 with the relative 

 binding energies may give some idea of the structural requirements for 

 potent inhibition. It may be noted that benzylmalonate is an effective 

 inhibitor but is somewhat less well bound than /5-phenylpropionate; this is 

 surprising because it might be thought that additional energy would be 

 contributed by interaction of one of the C00~ groups with the peptidatic 

 site. Neither cis- nor <rans-cinnamate inhibits and it was suggested that the 

 double bond restricts the orientation of the ring so that adequate binding 

 cannot occur. The linearity of these molecules may also be a factor, since 

 the active site is probably not flat as is implied by the two-dimensional 

 representations in the figure. 



Competitive inhibition by the following analogs has been demonstrated 

 more recently: 3-indolepropionate, e-aminocaproate, (5-amino-w-valerate 

 (Folk, 1956; Greenbaum and Sherman, 1962), y-aminobutyrate, S-guani- 

 dinovalerate, argininate (Folk and Gladner, 1958), iV-acetyl-L-tyrosine, 

 D-leucinyl-L-tyrosine, glycyl-L-tyrosine, and other dipeptides (Yanari and 

 Mitz, 1957). The inhibition apparently sometimes depends on the substrate 

 used; for example, 3-indolepropionate inhibits the hydrolysis of carbo- 

 benzoxyglycyl-L-phenylalanine but not the hydrolysis of a-iV-benzoyl- 

 glycyl-L-lysine, where s-aminocaproate exhibits just the opposite behavior. 



Relatively little work has been done on analog inhibition of dipepti- 

 dases and aminopeptidases, and it will suffice to mention a few isolated 

 observations. Yeast dipeptidase is inhibited by various amino acids; for 



