Haloketone transition state analog inhibitors of cholesterol esterase.
The cholesterol esterase-catalyzed hydrolysis of p-nitro-phenyl butyrate is reversibly inhibited by four phenyl haloalkyl ketones. Inhibitor potency is greatest for halogenated acetophenones and parallels the extent of hydration of the various ketones in buffered D2O. These results are consistent with an inhibition mechanism wherein haloketones reversibly form hemiketal adducts at the active site that structurally mimic tetrahedral intermediates of the cholesterol esterase catalytic cycle.
Sohl
J
J
Department of Chemistry, University of Iowa, Iowa City 52242.
Sutton
L D
LD
Burton
D J
DJ
Quinn
D M
DM
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002087:Butyrates / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D055598:Chemical Phenomena; D002621:Chemistry; D006219:Halogens / Q000494:pharmacology*; D007659:Ketones / Q000494:pharmacology*; D007700:Kinetics; D010179:Pancreas / Q000201:enzymology*; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*; D013552:Swine
D000098:Acetophenones; D002087:Butyrates; D006219:Halogens; D007659:Ketones; C033592:4-nitrophenyl butyrate; D002265:Carboxylic Ester Hydrolases; D002787:Sterol Esterase