Catalysis by human leukocyte elastase. Aminolysis of acyl-enzymes by amino acid amides and peptides

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Abstract
Acyl-enzymes of human leukocyte elastase (HLE) were generated in situ during the hydrolysis of peptide thiobenzyl esters and served as substrates for aminolysis by a variety of amino acid amides and short peptide nucleophiles. For amino acid amides, there is a positive correlation between nucleophilic reactivity toward N-methoxysuccinyl (MeOSuc)-Ala-Ala-Pro-Val-HLE and the hydrophobicity of the side chain. For peptides, nucleophilicity toward MeOSuc-Ala-Ala-Pro-Val-HLE decreases dramatically with increasing chain length. Combined, these results suggest that (i) substrate specificity for the P1'' residue may be more dependent on side chain hydrophobicity than on specific, structural features of the side chain and (ii) there may be no important binding interactions available past S1''. Kinetic parameters were also determined for the nucleophilic reactions of PheNH2 and TyrNH2 with MeOSuc-Pro-Val-HLE, MeO-Suc-Ala-Pro-Val-HLE, MeOSuc-Ala-Ala-Pro-Val-HLE, and MeOSuc-Ala-Ala-Pro-Ala-HLE. Reactivity of these acyl-enzymes toward nucleophilic attack displays no dependence on peptide chain lengths but does not increase significantly for the substrate with Ala at P1. This same correlation between reactivity and acyl-enzyme structure is also seen for nucleophilic attack by water.

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