Stereospecificity of amino acid hydroxamate inhibition of aminopeptidases.
Hydroxamates of amino acids and aliphatic acids are effective inhibitors of Aeromonas proteolytica amino-peptidase (EC 3.4.11.10) and of both the cytosolic (EC 3.4.11.1) and microsomal (EC 3.4.11.2) aminopeptidases of swine kidney. Cytosolic leucine aminopeptidase and the Aeromonas enzyme were inhibited to a greater extent by D isomers than by the L enantiomorphs, manganese-activated kidney cytosolic leucine aminopeptidase being inhibited 10 times more effectively by D-leucine and D-valine hydroxamic acids than by the L isomers. The D isomers of these two compounds inhibited Aeromonas aminopeptidase to an even greater extent with Ki values of 2 X 10(-9) and 5 X 10(-9), respectively, whereas the corresponding L isomers were bound 150 times less tightly. With the Aeromonas enzyme, a comparison of inhibition by racemic mixtures with that of the corresponding L isomers indicated that in all cases the contribution of the D isomer was predominant. Isocaproic hydroxamic acid inhibited this enzyme equally well as L-leucine hydroxamic acid, indicating that the amino group orientation in the D isomer contributes to the binding efficacy. Swine kidney microsomal aminopeptidase was also inhibited by D isomers of leucine and valine hydroxamic acids but in contrast to the other two enzymes, the inhibition was 10-fold less than that observed for the corresponding L isomers. Cytosolic leucine aminopeptidase with either 6 g atoms of zinc per mol or 12 g atoms of zinc per mol was inhibited only slightly by any of the hydroxamic acid compounds; evidently enzyme-bound manganese (or magnesium) is specific for hydroxamate binding to this aminopeptidase.
D000333:Aeromonas / Q000201:enzymology*; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D003600:Cytosol / Q000201:enzymology; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013552:Swine
D000596:Amino Acids; D006877:Hydroxamic Acids; D007931:Leucyl Aminopeptidase