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.
Similar content being viewed by others
Article PDF
References
Roth BD . ACAT inhibitors: Evolution from cholesterol-absorption inhibitors to antiatherosclerotic agents. Drug Disc Today 3: 19–25 ( 1998)
Alegret M, Llaverias G, Silvestre JS . Acyl-coenzyme A : cholesterol acyltransferase inhibitors as hypolipidemic and antiatherosclerotic agents. Methods Find Clin Pharmacol 26: 563–586 ( 2004)
Chang CC, Huh HY, Cadigan KM, Chang TY . Molecular cloning and functional expression of human acyl-coenzyme A : cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J Biol Chem 268: 20747–20755 ( 1993)
Anderson RA, Joyce C, Davis M, Reagan JW, Clark M, Shelness GS, Rudel LL . Identification of a form of acyl-CoA : cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem 273: 26747–26754 ( 1998)
Cases S, Novak S, Zheng YW, Myers HM, Lear SR, Sande E, Welch CB, Lusis AJ, Spencer TA, Krause BR, Erickson SK, Farese RV Jr . ACAT-2, a second mammalian acyl-CoA : cholesterol acyltransferase. Its cloning, expression, and characterization. J Biol Chem 273: 26755–26764 ( 1998)
Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL . Characterization of two human genes encoding acyl coenzyme A : cholesterol acyltransferase-related enzymes. J Biol Chem 273: 26765–26771 ( 1998)
Parini P, Davis M, Lada AT, Erickson SK, Wright TL, Gustafsson U, Sahlin S, Einarsson C, Eriksson M, Angelin B, Tomoda H, Ōmura S, Willingham MC, Rudel LL . ACAT2 is localized to hepatocytes and is the major cholesterol-esterifying enzyme in human liver. Circulation 110: 2017–2023 ( 2004)
Giovannoni MP, Piaz VD, Vergelli C, Barlocco D . Selective ACAT inhibitors as promising antihyperlipidemic, antiathero-sclerotic and anti-Alzheimer drugs. Mini Rev Med Chem 3: 576–584 ( 2003)
Lada AT, Davis M, Kent C, Chapman J, Tomoda H, Ōmura S, Rudel LL . Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. J Lipid Res 45: 378–386 ( 2004)
Ikenoya M, Yoshinaka Y, Kobayashi H, Kawamine K, Shibuya K, Sato F, Sawanobori K, Watanabe T, Miyazaki A . A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels. Atherosclerosis: in press ( 2006)
Ōmura S, Tomoda H, Kim YK, Nishida H, Pyripyropenes highly potent inhibitors of acyl-CoA: cholesterol acyltransferase produced by Aspergillus fumigatus. J Antibiot 46: 1168–1169 ( 1993)
Tomoda H, Kim YK, Nishida H, Masuma R, Ōmura S . Pyripyropenes, novel inhibitors of acyl-CoA : cholesterol acyltransferase produced by Aspergillus fumigatus. I. Production, isolation, and biological properties. J Antibiot 47: 148–153 ( 1994)
Kim YK, Tomoda H, Nishida H, Sunazuka T, Obata R, Ōmura S . Pyripyropenes, novel inhibitors of acyl-CoA : cholesterol acyltransferase produced by Aspergillus fumigatus. II. Structure elucidation of pyripyropenes A, B, C and D. J Antibiot 47: 154–162 ( 1994)
Tomoda H, Nishida H, Masuma R, Cao J, Okuda S, Ōmura S . Purpactins, new inhibitors of acyl-CoA : cholesterol acyltransferase produced by Penicillium purpurogenum. I. Production, isolation and physico-chemical and biological properties. J Antibiot 44: 136–143 ( 1991)
Nishida H, Tomoda H, Cao J, Okuda S, Ōmura S . Purpactins, new inhibitors of acyl-CoA : cholesterol acyltransferase produced by Penicillium purpurogenum. II. Structure elucidation of purpactins A, B and C. J Antibiot 44: 144–151 ( 1991)
Tomoda H, Huang XH, Nishida H, Masuma R, Kim YK, Ōmura S . Glisoprenins, new inhibitors of acyl-CoA : cholesterol acyltransferase produced by Gliocladium sp. FO-1513. I. Production, isolation and physico-chemical and biological properties. J Antibiot 45: 1202–1206 ( 1992)
Nishida H, Huang XH, Tomoda H, Ōmura S . Glisoprenins, new inhibitors of acyl-CoA : cholesterol acyltransferase produced by Gliocladium sp. FO-1513. II. Structure elucidation of glisoprenins A and B. J Antibiot 45: 1669–1676 ( 1992)
Ghosh I, Kishi Y, Tomoda H, Ōmura S . Guse of achiral praseodymium shift reagent in predicting the complete stereostructure of glisoprenin A. Org Lett 6: 4719–4722 ( 2004)
Huang XH, Tomoda H, Nishida H, Masuma R, Ōmura S . Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. I. Production, isolation and biological properties. J Antibiot 48: 1–4 ( 1995)
Huang XH, Nishida H, Tomoda H, Tabata N, Shiomi K, Yang DJ, Takayanagi H, Ōmura S . Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. II. Structure elucidation of terpendoles A, B, C and D. J Antibiot 48: 5–11 ( 1995)
Tomoda H, Tabata N, Yang DJ, Takayanagi H, Ōmura S . Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. III. Production, isolation and structure elucidation of new components. J Antibiot 48: 793–804 ( 1995)
Namatame I, Tomoda H, Si S, Yamaguchi Y, Masuma R, Ōmura S . Beauveriolides, specific inhibitors of lipid droplet formation in mouse macrophages, produced by Beauveria sp. FO-6979. J Antibiot 52: 1–6 ( 1999)
Namatame I, Tomoda H, Tabata N, Si S, Ōmura S . Structure elucidation of fungal beauveriolide III, a novel inhibitor of lipid droplet formation in mouse macrophages. J Antibiot 52: 7–12 ( 1999)
Matsuda D, Namatame I, Tomoda H, Kobayashi S, Zocher R, Kleinkauf H, Ōmura S . New beauveriolide produced by amino acid-supplemented fermentation of Beauveria sp. FO-6979. J Antibiot 57: 1–9 ( 2004)
Mochizuki K, Ohmori K, Tamura H, Shizuri H, Nishiyama S, Miyoshi E, Yamamura S . The structures of bioactive cyclodepsipeptides, beauveriolides I and II, metabolites of entomopathogenic fungi Beauveria sp. Bull Chem Soc Jpn 66: 3041–3046 ( 1993)
Tomoda H, Namatame I, Si S, Kawaguchi K, Masuma R, Namikoshi M, Ōmura S . Phenochalasins, inhibitors of lipid droplet formation in mouse macrophages, produced by Phomopsis sp. FT-0211. J Antibiot 52: 851–856 ( 1999)
Tomoda H, Namatame I, Tabata N, Kawaguchi K, Si S, Ōmura S . Structure elucidation of fungal phenochalasins, novel inhibitors of lipid droplet formation in mouse macrophages. J Antibiot 52: 857–861 ( 1999)
Koyama N, Nagahiro T, Yamaguchi Y, Ohshiro T, Masuma R, Tomoda H, Ōmura S . Spylidone, a novel inhibitor of lipid droplet accumulation in mouse macrophages produced by Phoma sp. FKI-1840. J Antibiot 58: 338–345 ( 2005)
Uchida R, Kim YP, Namatame I, Tomoda H, Ōmura S . Sespendole, a new inhibitor of lipid droplet synthesis in macrophages, produced by Pseudobotrytis terrestris FKA-25. J Antibiot 59: 93–97 ( 2006)
Namatame I, Tomoda H, Matsuda D, Tabata N, Kobayashi S, Ōmura S . K97-0239A and B, new inhibitors of macrophage foam cell formation, produced by Streptomyces sp. K97-0239. Proc Japan Acad B 78: 45–50 ( 2002)
Namatame I, Tomoda H, Ishibashi S, Ōmura S . Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages. Proc Natl Acad Sci USA 101: 737–742 ( 2004)
Chem Eng News 18: 15 ( 2004)
Namatame I, Tomoda H, Arai H, Inoue K, Ōmura S . Complete inhibition of mouse macrophage-derived foam cell formation by triacsin C. J Biochem 25: 319–327 ( 1999)
Bligh EG, Dyer W . A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37: 911–917 ( 1959)
Field FJ, Cooper AD, Erickson SK . Regulation of rabbit intestinal acyl coenzyme A-cholesterol acyltransferase in vivo and in vitro. Gastroenterology 83: 873–880 ( 1982)
Cho KH, An S, Lee WS, Paik YK, Kim YK, Jeong TS . Mass-production of human ACAT-1 and ACAT-2 to screen isoform-specific inhibitor: a different substrate specificity and inhibitory regulation. Biochem Biophys Res Commun 309: 864–872 ( 2003)
Tomoda H, Namatame I, Ōmura S . Microbial metabolites with inhibitory activity against lipid metabolism. Proc Japan Acad B 78: 217–240 ( 2002)
Kouri K, Lemmens M, Gruber RL . Beauvericin-induced channenls in ventricular myocytes and liposomes. Biochim Biophys Acta 1609: 203–210 ( 2003)
Jow GM, Chou CJ, Chen BF, Tsai JH . Beauvericin induces cytotoxic effects in human acute lympoblastic leukemia cells through cytochrome c release, caspase 3 activation: the causative role of calcium. Cancer Lett 216: 165–173 ( 2004)
Fukuda T, Arai M, Yamaguchi Y, Masuma R, Tomoda H, Ōmura S . New beauvericins, potentiators of antifungal miconazole activity, produced by Beauveria sp. FKI-1366. I. Taxonomy, fermentation, isolation and biological properties, J Antibiot 57: 110–116 ( 2004)
Lin S, Cheng D, Liu MS, Chen J, Chang TY . Human acyl-CoA : cholesterol acyltransferase-1 in the endoplasmic reticulum contains seven transmembarane domains. J Biol Chem 274: 23276–23285 ( 1999)
Joyce CW, Shelness GS, Davis MA, Lee RG, Skinner K, Anderson RA, Rudel LL . ACAT1 and ACAT2 membrane topology segregates a serine residue essential for activity to opposite sides of the endoplasmic reticulum membrane. Mol Biol Cell 11: 3675–3687 ( 2000)
Guo ZY, Lin S, Heinen JA, Chang CC, Chang TY . The active site His-460 of Human acyl-coenzyme A : cholesterol acyltransferase 1 resides in a hitherto undisclosed transmembrane domain. J Biol Chem 280: 37814–37826 ( 2005)
Lin S, Lu X, Chang CC, Chang TY . Human acyl-coenzyme A : cholesterol acyltransferase expressed in Chinese hamuster ovary cells: Membrane topology and active site location. Mol Biol Cell 14: 2447–2460 ( 2003)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ohshiro, T., Rudel, L., Ōmura, S. et al. Selectivity of Microbial Acyl-CoA : cholesterol Acyltransferase Inhibitors toward Isozymes. J Antibiot 60, 43–51 (2007). https://doi.org/10.1038/ja.2007.6
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ja.2007.6
Keywords
This article is cited by
-
Exploration of marine natural resources in Indonesia and development of efficient strategies for the production of microbial halogenated metabolites
Journal of Natural Medicines (2022)
-
Voluhemins, new inhibitors of sterol O-acyltransferase, produced by Volutella citrinella BF-0440
The Journal of Antibiotics (2020)
-
Helvamide, a new inhibitor of sterol O-acyltransferase produced by the fungus Aspergillus nidulans BF-0142
The Journal of Antibiotics (2019)
-
Tremorgenic and neurotoxic paspaline-derived indole-diterpenes: biosynthetic diversity, threats and applications
Applied Microbiology and Biotechnology (2019)
-
Celludinones, new inhibitors of sterol O-acyltransferase, produced by Talaromyces cellulolyticus BF-0307
The Journal of Antibiotics (2018)