Selectivity of Microbial Acyl-CoA : cholesterol Acyltransferase Inhibitors toward Isozymes

Taichi Ohshiro, Lawrence L. Rudel, Satoshi O_Bold_long.gif"mura, Hiroshi Tomoda

Received: September 12, 2006 / Accepted: December 21, 2006
© Japan Antibiotics Research Association

Abstract The selectivity of microbial inhibitors of acyl-CoA : cholesterol acyltransferase (ACAT) toward the two isozymes, ACAT1 and ACAT2, was assessed in cell-based assays. Purpactin A (IC50 values of ACAT1 vs. IC50 values of ACAT2; 2.5 μM vs. 1.5 μM), terpendole C (10 μM vs. 10 μM), glisoprenin A (4.3 μM vs. 10 μM), spylidone (25 μM vs. 5.0 μM) and synthetic CL-283,546 (0.1 μM vs. 0.09 μM) inhibited ACAT1 and ACAT2 to similar extents. Beauveriolides I (0.6 μM vs. 20 μM) and III (0.9 μM vs. >20 μM) inhibited ACAT1 rather selectively, while pyripyropenes A (>80 μM vs. 0.07 μM), B (48 μM vs. 2.0 μM), C (32 μM vs. 0.36 μM) and D (38 μM vs. 1.5 μM) showed selective inhibition against ACAT2. In particular, pyripyropene A was found to be the most selective ACAT2 inhibitor with a selective index of more than 1,000.

Keywords acyl-CoA : cholesterol acyltransferase, isozyme, microbial inhibitors, lipid droplet accumulation, pyripyropene, beauveriolide, atherosclerosis

H. Tomoda (Corresponding author): School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan, E-mail: tomodah@pharm.kitasato-u.ac.jp
T. Ohshiro, S. O_long.gif"mura: Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
L. L. Rudel: Atherosclerosis Research Program, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA