0000000000113632
AUTHOR
G. Leyhausen
Cell Surface-Bound Leucine Aminopeptidase: Target of the Immunomodulator Bestatin
The study of low molecular weight enzyme inhibitors of microbial origin was initiated by Umezawa in 1965 (see Umezawa 1972). Since the discovery of an inhibitor of tyrosine hydroxylase, nearly 50 inhibitors of various enzymes have been found by him; their structures were elucidated and most of the compounds were chemically synthesized (Umezawa 1982). Among them one inhibitor of both aminopeptidase B and the ectoenzyme, leucine aminopeptidase was found in 1976 and was termed bestatin (Fig. 1), [(2S,3R)-3-amino-2-hydroxy 4-phenyl-butanoyl]-(S)-leucine (Umezawa et al. 1976).
Identification and properties of the cell membrane bound leucine aminopeptidase interacting with the potential immunostimulant and chemotherapeutic agent bestatin.
Bestatin was found to be a competitive inhibitor (with respect to the Leu-NA substrate) not only of the isolated microsomal and cytosolic leucine aminopeptidases (Leu-APm and Leu-APc) but also of the aminopeptidases (APs) present in membrane preparations (from mouse liver) and on the cell surface of L5178Y cells. Kinetic parameters indicate that cellular AP is identical to Leu-APm. To rule out the possibility that AP-B is involved in the inhibition reactions, comparable studies with amastatin were performed. Electrophoretical studies revealed the solubilized cell membrane bound AP to co-migrate with Leu-APm in polyacrylamide gels. The activity of the separated membrane AP was inhibited by b…