Differential Inhibition of HMG-CoA Synthase and Pancreatic Lipase by the Specific Chiral Isomers of -Lactone DU-6622

Authors: Tomoda H.¹; Ohbayashi N.¹; Kumagai H.¹; Hashizume H.²; Sunazuka T.¹; Omacr mura S.¹

Source: Biochemical and Biophysical Research Communications, Volume 265, Number 2, November 1999 , pp. 536-540(5)

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Abstract:

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 M) and pancreatic lipase (IC₅₀: 120 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 M vs 270 M for pancreatic lipase), while the (2S, 3S)-isomer markedly increased the specificity of lipase inhibition (IC₅₀: 27 M vs 31 M 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)- 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. Copyright 1999 Academic Press.

Language: English

Document Type: Research article

Affiliations: 1: Research Center for Biological Function, Kitasato Institute, Minato-ku, Tokyo, 108-8642, Japan 2: Fuji Chemical Industries Co., Takaoka, Toyama, Japan

Publication date: 1999-11-01