Mechanistic implications of the inhibition of peptidases by amino aldehydes and bestatin.
alpha-Amino aldehydes and bestatin are found to be effective inhibitors of a cytosolic dipeptidase (rat testicular peptidase C), and a cytosolic tripeptidase (rat kidney peptidase B, EC 3.4.11.4), as well as cytosolic leucine aminopeptidase (pig kidney peptidase S, EC 3.4.11.1). Aldehyde hydrates and bestatin share a resemblance to intermediates that might be formed during direct attack by water on peptide substrates, affording a possible explanation for their tight binding. Alternatively, inhibitors of both kinds might form derivatives of an active site nucleophile, resembling intermediates in a double-displacement mechanism. Exchange experiments with H218O suggest that bestatin is bound intact by leucine aminopeptidase, lending support to the first of these two mechanisms.
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors*; D008297:Male; D010447:Peptide Hydrolases / Q000302:isolation & purification; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors; D051381:Rats; D013737:Testis / Q000201:enzymology
D000447:Aldehydes; D011480:Protease Inhibitors; C046025:alaninal; C035766:leucinal; D011392:Proline; D010447:Peptide Hydrolases; C037529:peptidase C; D000626:Aminopeptidases; D007931:Leucyl Aminopeptidase; C026045:tripeptide aminopeptidase; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C022325:aspartic proteinase A; D016282:Aspartic Acid Endopeptidases; D007930:Leucine; C012211:ubenimex; C046026:prolinal; D000409:Alanine