Abstract
Five known fungal metabolites, aurasperone A, aurasperone D, averufanin, flavasperone and sterigmatocystin, were isolated from the culture broths of Aspergillus species as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) in the cell-based assay using ACAT1- and ACAT2-expressing CHO cells. These compounds share a similar polycyclic skeleton. Among them, flavasperone and sterigmatocystin, having an angular skeleton, showed selective inhibition toward ACAT2 isozyme, while the others having a linear one had no selectivity in inhibition.
Similar content being viewed by others
Article PDF
References
Roth BD . ACAT inhibitors: Evolution from cholesterolabsorption inhibitors to antiatherosclerotic agents. Drug Discov 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)
Meiner VL, Cases S, Myers HM, Sande ER, Bellosta S, Schambelan M, Pitas RE, McGuire J, Herz J, Farese RV Jr. Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc Natl Acad Sci USA 93: 14041–14046 ( 1996)
Yagyu H, Kitamine T, Osuga J, Tozawa R, Chen Z, Kaji Y, Oka T, Perrey S, Tamura Y, Ohashi K, Okazaki H, Yahagi N, Shionoiri F, Iizuka Y, Harada K, Shimano H, Yamashita H, Gotoda T, Yamada N, and Ishibashi S . Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia. J Biol Chem 275: 21324–21330 ( 2000)
Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, Farese RV Jr. Resistance to dietinduced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 6: 1341–1347 ( 2000)
Giovannoni MP, Piaz VD, Vergelli C, Barlocco D . Selective ACAT inhibitors as promising antihyperlipidemic, antiatherosclerotic 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 191: 290–297 ( 2007)
Ohshiro T, Rudel LL, Ōmura S, Tomoda H . Selectivity of microbial acyl-CoA:cholesterol acyltransferase inhibitors toward isozymes. J Antibiot 60: 43–51 ( 2007)
Tomoda H, Ōmura S . Potential therapeutics for obesity and atherosclerosis: inhibitors of neutral lipid metabolism from microorganisms. Pharmacol Ther 115: 375–389 ( 2007)
Tanaka H, Wang PL, Yamada O, Tamura T . Yellow pigments of Aspergillus niger and Asp. awamori. I. Isolation of aurasperone A and related pigments. Agric Biol Chem 30: 107–113 ( 1966)
Campos FR, Barison A, Daolio C, Ferreira AG, Rodrigues-Fo E. Complete 1H- and 13C-NMR assignments of aurasperone A and fonsecinone A, two bis-naphthopyrones produced by Aspergillus aculeatus. Magn Reson Chem 43: 962–965 ( 2005)
Ghosal S, Biswas K, Chakrabarti DK . Toxic naphtho- gpyrones from Aspergillus niger. J Agric Food Chem 27: 1347–1351 ( 1979)
Lund NA, Robertson A, Whalley WB . The Chemistry of Fungi. Part XXI. Asperxanthone and a Preliminary Examination of Aspergillin. J Chem Soc: 2434–2439 ( 1953)
Gorst-Allman CP, Steyn PS, Rabie CJ . Structural elucidation of the nigerones, four new naphthopyrones from cultures of Aspergillus niger. J Chem Soc Perkin Trans 1: 2474–2479 ( 1980)
Donkersloot JA, Mateles RI, Yang SS . Isolation of averufin from a mutant of Aspergillus parasiticus impaired in aflatoxin biosynthesis. Biochem Biophys Res Commun 47: 1051–1055 ( 1972)
Hatsuda Y, Kuyama S . Studies on the metabolic products of Aspergillus versicolor. J Agr Chem 28: 989–991 ( 1954)
Pachler KGR, Steyn PS, Vleggaar R, Wessels PL, Scott DB . Carbon-13 nuclear magnetic resonance assighnments and biosynthesis of aflatoxin B1 and sterigmatocystin. J Chem Soc Perkin Trans I: 1182–1189 ( 1976)
Hatano T, Uebayashi H, Ito H, Shiota S, Tsuchiya T, Yoshida T . Phenolic constituents of Cassia seeds and antibacterial effect of some naphthalenes and anthraquinones on methicillin-resistant Staphylococcus aureus. Chem Pharm Bull 47: 1121–1127 ( 1998)
Steyn SP . The biosynthesis of polyketide-derived mycotoxins. Pure Appl Chem 52: 189–204 ( 1979)
Henry MK, Townsend AC . ordering the reductive and cytochrome P450 oxidative steps in demethylsterigmatocystin formation yields general insights into the biosynthesis of aflatoxin and related fungal metabolites. J Am Chem Soc 127: 3724–3733 ( 2005)
Das A, Davis MA, Tomoda H, Ōmura S, Rudel LL . Identification of the interaction site within acyl Coenzyme A (CoA):cholesterol acyltransferase-2 (ACAT2) for the isoform-specific inhibitor pyripyropene A. J Biol Chem 283: 10453–10460 ( 2008)
Song YC, Li H, Ye YH, Shan CY, Yang YM, Tan RX . Endophytic naphthopyrone metabolites are co-inhibitors of xanthine oxidase, SW1116 cell and some microbial growths. FEMS Microbiol Lett 241: 67–72 ( 2004)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sakai, K., Ohte, S., Ohshiro, T. et al. Selective Inhibition of Acyl-CoA:cholesterol Acyltransferase 2 Isozyme by Flavasperone and Sterigmatocystin from Aspergillus Species. J Antibiot 61, 568–572 (2008). https://doi.org/10.1038/ja.2008.76
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ja.2008.76
Keywords
This article is cited by
-
Aspergillus Carneus metabolite Averufanin induced cell cycle arrest and apoptotic cell death on cancer cell lines via inducing DNA damage
Scientific Reports (2023)
-
Pseudopyronine B, an inhibitor of sterol O-acyltransferase, produced by Pseudomonas sp. BYK11209
The Journal of Antibiotics (2017)
-
Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens
Scientific Reports (2016)
-
Induced production of 6,9-dibromoflavasperone, a new radical scavenging naphthopyranone in the marine-mudflat-derived fungus Aspergillus niger
Archives of Pharmacal Research (2016)
-
Identification of potential ACAT-2 selective inhibitors using pharmacophore, SVM and SVR from Chinese herbs
Molecular Diversity (2016)