Differential inhibition of HMG-CoA synthase and pancreatic lipase by the specific chiral isomers of β-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 (IC50: 0.15 mu M) and pancreatic lipase (IC50: 120 mu M). 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 (IC50: 0.098 mu M vs 270 mu M for pancreatic lipase), while the (2S, 3S)-isomer markedly increased the specificity of lipase inhibition (IC50: 27 mu M vs 31 mu M for HMG-CoA synthase). Furthermore, the (2R, 3R)-isomer strongly inhibited the binding of [C-14]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, SS)-beta-lactone is responsible for the inhibition of pancreatic lipase. (C) 1999 Academic Press.