title: Inhibition of aminopeptidases by aminophosphonates.
abstract: More than 30 aminophosphonates were synthesized to probe how the structural changes introduced into the phosphonic acid analogue of leucine, a potent inhibitor of cytosolic leucine aminopeptidase (Giannousis & Bartlett, 1987), affect their ability to inhibit cytosolic (EC 3.4.11.1) and microsomal (EC 3.4.11.2) aminopeptidases. Although most of the compounds studied were found to exert only a modest competitive inhibitory effect, nearly every modification of the structure of the phosphonic acid analogue of leucine was reflected in a marked difference in the affinities of these compounds for the two enzymes. [1-Amino-2-(N-alkylamino)ethyl]phosphonic acids are effective inhibitors of the microsomal enzyme, acting in a time-dependent manner. Kinetic data obtained for these inhibitors correspond to the mechanism for a biphasic slow-binding inhibition process: E + I in equilibrium E* in equilibrium E*I, in which the slow initial isomerization of the enzyme is followed by the fast formation of enzyme-inhibitor complex. The most effective inhibitor of this type was [1-amino-2-(N-cyclohexylamino)ethyl]phosphonic acid, which has a Ki value of 0.87 microM toward the microsomal aminopeptidase--a value that can be considered as equipotent with bestatin and with leucinal and hydroxamic acids, the strongest known nonpeptide inhibitors of this enzyme.
authors.affiliation: Institute of Organic and Physical Chemistry, Technical University of Wrocław, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Lejczak
authors.forename: P
authors.initials: P
authors.lastname: Kafarski
authors.forename: J
authors.initials: J
authors.lastname: Zygmunt
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D018826:CD13 Antigens; D003600:Cytosol / Q000201:enzymology; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors; D008861:Microsomes / Q000201:enzymology; D008956:Models, Chemical; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D009943:Organophosphorus Compounds; D000626:Aminopeptidases; D007931:Leucyl Aminopeptidase; D018826:CD13 Antigens