Differential inhibition of HMG-CoA synthase and pancreatic lipase by the specific chiral isomers of beta-lactone DU-6622.
A synthetic beta-lactone trans-DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methylcarbonyl)-naphthalen++ +-1-yl]pentanoic acid 1,3-lactone, a mixture of (2R, 3R)- and (2S, 3S)-beta-lactones) was found to inhibit HMG-CoA synthase (IC(50): 0. 15 microM) and pancreatic lipase (IC(50): 120 microM). The effects of the optically pure DU-6622 isomers on the two enzymes were compared. The (2R, 3R)-isomer was shown to be a highly specific inhibitor of HMG-CoA synthase (IC(50): 0.098 microM vs 270 microM for pancreatic lipase), while the (2S, 3S)-isomer markedly increased the specificity of lipase inhibition (IC(50): 27 microM vs 31 microM for HMG-CoA synthase). Furthermore, the (2R, 3R)-isomer strongly inhibited the binding of [(14)C]hymeglusin to HMG-CoA synthase, indicating that the isomer was bound to the same site of the synthase as hymeglusin. The (2R, 3R)-beta-lactone is responsible for the specific inhibition of HMG-CoA synthase, while the (2S, 3S)-beta-lactone is responsible for the inhibition of pancreatic lipase.
Tomoda
H
H
Research Center for Biological Function, Kitasato University, Tokyo, 108-8642, Japan.
Ohbayashi
N
N
Kumagai
H
H
Hashizume
H
H
Sunazuka
T
T
Omura
S
S
D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066298:In Vitro Techniques; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors*; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010179:Pancreas / Q000201:enzymology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
C401845:DU 6622; D004791:Enzyme Inhibitors; D007783:Lactones; D009281:Naphthalenes; D006904:Hydroxymethylglutaryl-CoA Synthase; D008049:Lipase