Inhibitors of a rat brain enkephalin aminopeptidase.
Eight protease inhibitors of microbiological origin were examined as potential inhibitors of a homogeneous rat brain enkephalin aminopeptidase. Bestatin [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine and analogs of bestatin having basic, acid, and other neutral amino acids substituted for the Leu residue exhibited inhibition constants ranging from 3.3 X 10(-5) to 8.3 X 10(-8) M. The best inhibitor had a positively charged amino acid (Lys) substituted for Leu. A series of phenylalanyl dipeptides were examined as substrates with the aminopeptidase. The amino acid residue on the carboxyl side of the peptide bond undergoing cleavage was varied systematically in the dipeptides to include neutral, acidic, and basic residues. Again, a positively charged amino acid (Arg) adjacent to the bond undergoing scission was kinetically preferred. These results may be used to design highly specific inhibitors of the enkephalin aminopeptidase.
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D011480:Protease Inhibitors; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D007930:Leucine; C012211:ubenimex