Selectivity of microbial acyl-CoA: cholesterol acyltransferase inhibitors toward isozymes.
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 microM vs. 1.5 microM), terpendole C (10 microM vs. 10 microM), glisoprenin A (4.3 microM vs. 10 microM), spylidone (25 microM vs. 5.0 microM) and synthetic CL-283,546 (0.1 microM vs. 0.09 microM) inhibited ACAT1 and ACAT2 to similar extents. Beauveriolides I (0.6 microM vs. 20 microM) and III (0.9 microM vs. >20 microM) inhibited ACAT1 rather selectively, while pyripyropenes A (>80 microM vs. 0.07 microM), B (48 microM vs. 2.0 microM), C (32 microM vs. 0.36 microM) and D (38 microM vs. 1.5 microM) 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.
Ohshiro
Taichi
T
Kitasato Institute for Life Sciences, Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Rudel
Lawrence L
LL
Omura
Satoshi
S
Tomoda
Hiroshi
H
D000818:Animals; D016466:CHO Cells; D002788:Cholesterol Esters / Q000096:biosynthesis; D006224:Cricetinae; D003412:Cricetulus; D047630:Depsipeptides / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010616:Phenanthrenes / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D000097587:Sterol O-Acyltransferase 2
D002788:Cholesterol Esters; D047630:Depsipeptides; D004224:Diterpenes; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D007527:Isoenzymes; D010616:Phenanthrenes; D010671:Phenylurea Compounds; D011725:Pyridines; D012717:Sesquiterpenes; D013141:Spiro Compounds; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C095518:CL 283,546; C502979:spylidone; C092163:terpendole C; C068086:purpactin A; C077321:glisoprenin A; C082792:pyripyropene A; C013833:beauverolides; C493492:sterol O-acyltransferase 1