Differential inhibition of HMG-CoA synthase and pancreatic lipase by the specific chiral isomers of β-lactone DU-6622

Hiroshi Tomoda, Naomi Ohbayashi, Hidetoshi Kumagai, Hirokazu Hashizume, Toshiaki Sunazuka, Satoshi Omura

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)536-540
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume265
Issue number2
DOIs
StatePublished - Nov 19 1999

Keywords

  • 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase
  • Enzyme inhibitor
  • Pancreatic lipase
  • β-lactone

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Differential inhibition of HMG-CoA synthase and pancreatic lipase by the specific chiral isomers of β-lactone DU-6622'. Together they form a unique fingerprint.

  • Cite this