Inhibition of acyl-CoA: Cholesterol acyltransferase activity by cyclodepsiptide antibiotics.

Abstract

The effect was studied of the fungal cyclodepsipeptide antibiotics beauvericin and seven distinct enniatins on acyl-CoA: cholesterol acyltransferase (ACAT) activity. In an enzymeassay using rat liver microsomes, all the compounds were found to inhibit ACATactivity. The drug concentration that caused 50%inhibition (IC50 value) of the enzyme activity was determined to be 3.0/jm for beauvericin, indicating that the compoundis one of the most potent ACATinhibitors of microbial origin. Enniatins exhibited much higher IC50 values of 22 to 1 10/xm. More hydrophobic enniatins showed more potent inhibitory activity. Furthermore, the ACATinhibitory activity was evaluated as inhibition of cholesteryl ester formation in a cell assay using J774 macrophages. Calculation of the ratio, CD50 value (the drug concentration causing 50% cell damage)/IC50 value of cholesteryl ester formation, indicated that beauvericin shows the highest specificity. These data indicate that beauvericin is one of the most potent and specific ACATinhibitors of microbial origin.Acyl-CoA: cholesterol acyltransferase (ACAT) [EC 2.3. 1.26], which catalyzes the conversion of cellular cholesterol and long chain fatty acyl-CoA to cholesteryl ester, plays an important role in cholesteryl ester accumulation in atherogenesis1} and in cholesterol absorption from intestines2). Since elevated levels of plasma cholesterol is a well-documented risk factor of atherosclerosis, much attention has been paid to ACATinhibitors for the treatment and prevention of atherosclerosis and hypercholesterolemia.A lot of synthetic ACATinhibitors have been reported having a urea or an amide moiety. Wehave started to find new ACATinhibitors and new lead compounds of microbial origin. During our screening program, fungal strains Fusarium spp. FO-740 and FO-1305 were found to produce ACATinhibitors. The active compounds were identified as beauvericin (Fig. 1) from the former strain and seven components of enniatins (A, Al, B, Bl, D, E and F, Fig. 1) from the latter strain3). All of these cyclodepsipeptides were classified as ionophore antibiotics, most of which were originally reported as antifungal or insecticidal antibiotics produced by Beauveria4' 5\ Paecilomyces6\ Fusarium1' 8) and Polyporus^spp. However, it is not clearly understood whether these biological activities are due to the ionophoric activity.The cyclodepsipeptides were found by the authors to show a new biological activity of ACAT inhibition3*.In this study, we have examined the effect of beauvericin and enniatins on cholesterol

Beauvericin production by the Lepidoptera pathogenic fungus Isaria tenuipes: Analysis of natural specimens, synnemata from cultivation, and mycelia from liquid-media fermentation

“…1 Beauvericin and related fungal cyclooligomer depsipeptides, enniatins, were also reported as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT) 2 and the human immunodeficiency virus type-1 integrase. 3 Beauvericin was first described from an entomopathogenic fungus Beauveria bassiana on the basis of its toxicity to brine shrimp.…”

Novel quinazolinones and enniatins from Fusarium lateritium Nees

“…(antimalarial (16)), and the microbial metabolites tryptanthrin (10, antibiotic (17)), fumiquinazolines A ( l l ) , B (12), and C (13) (cytotoxic agents ( 1 8) The enniatin metabolites are known to exhibit insecticidal (21,22), antibiotic (23), and phytotoxic activities (24), and to also inhibit cholesterol biosynthesis (25). In this work, the antagonistic effect of F .…”

New verticilides, inhibitors of acyl-CoA:cholesterol acyltransferase, produced by Verticillium sp. FKI-2679

“…32 In this sense, verticilides might represent potential leads beyond the pyripyropenes, although their ACAT2 selectivity is insufficient. We previously reported that two types of depsipeptides, beauveriolides and beauvericin, had ACAT inhibitory activity 25,33 and investigated their selectivity toward the two isozymes. Beauveriolides I and III were more selective toward ACAT1, while beauvericin inhibited both ACAT1 and ACAT2.…”

“…One was identified as verticilide (verticilide A1 in this study), which had previously been reported to have insecticidal activity, 20,21 but the others were new compounds, named verticilides A2, A3 and B1 ( Figure 1). They are members of the cyclodepsipeptide family such as beauveriolides, [22][23][24] beauvericin, 25 enniatins 26 and bassianolide. 27 In this study, the taxonomy of the producing strain, fermentation, isolation, structure elucidation and biological properties of verticilides are described.…”