TY - JOUR
T1 - Differential inhibition of HMG-CoA synthase and pancreatic lipase by the specific chiral isomers of β-lactone DU-6622
AU - Tomoda, Hiroshi
AU - Ohbayashi, Naomi
AU - Kumagai, Hidetoshi
AU - Hashizume, Hirokazu
AU - Sunazuka, Toshiaki
AU - Omura, Satoshi
N1 - Funding Information:
We are indebted to Dr. T. Aoyagi for a generous supply of ebelactones A and B and esterastin and to Dr. E. K. Weibel for supplying lipstatin. This work was supported by grants from the “Research for the Future” Program of the Japan Society for the Promotion of Science (JSPS-RFTF96I00304), and from the Japan Keirin Association.
PY - 1999/11/19
Y1 - 1999/11/19
N2 - A synthetic β-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)-β-lactones) was found to inhibit HMG-CoA synthase (IC50: 0.15 μM) and pancreatic lipase (IC50: 120 μM). 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 μM vs 270 μM for pancreatic lipase), while the (2S 3S)-isomer markedly increased the specificity of lipase inhibition (IC50: 27 μM vs 31 μM for HMG-CoA synthase). Furthermore, the (2R, 3R)-isomer strongly inhibited the binding of [14C]hymeglusin to HMG-CoA synthase, indicating that the isomer was bound to the same site of the synthase as hymeglusin. The (2R, 3R)-β-lactone is responsible for the specific inhibition of HMG-CoA synthase, while the (2S, 3S)-β-lactone is responsible for the inhibition of pancreatic lipase.
AB - A synthetic β-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)-β-lactones) was found to inhibit HMG-CoA synthase (IC50: 0.15 μM) and pancreatic lipase (IC50: 120 μM). 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 μM vs 270 μM for pancreatic lipase), while the (2S 3S)-isomer markedly increased the specificity of lipase inhibition (IC50: 27 μM vs 31 μM for HMG-CoA synthase). Furthermore, the (2R, 3R)-isomer strongly inhibited the binding of [14C]hymeglusin to HMG-CoA synthase, indicating that the isomer was bound to the same site of the synthase as hymeglusin. The (2R, 3R)-β-lactone is responsible for the specific inhibition of HMG-CoA synthase, while the (2S, 3S)-β-lactone is responsible for the inhibition of pancreatic lipase.
KW - 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase
KW - Enzyme inhibitor
KW - Pancreatic lipase
KW - β-lactone
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U2 - 10.1006/bbrc.1999.1712
DO - 10.1006/bbrc.1999.1712
M3 - Article
C2 - 10558904
AN - SCOPUS:0033585099
SN - 0006-291X
VL - 265
SP - 536
EP - 540
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -