Microbial metabolites affecting lipid biosynthesis

Abstract

Microbial inhibitors for two enzymes involved in lipid metabolism, acyl-CoA:cholesterol acyltransferase (ACAT) and farnesyl-protein transferase (FTase), were screened with assay systems using partially purified enzymes. ACAT inhibitors are expected to work as cholesterol-lowering or anti-atherosclerotic agents, and FTase inhibitors are as anticancer drugs. Three kinds of new ACAT inhibitors were discovered as fungal metabolites; glisoprenins, pyripyropenes and terpendoles. All these inhibitors have a terpene moiety in the structures. Pyripyropenes exhibited very potent ACAT inhibition with nanomolar level of IC50 values and in vivo efficacy in a hamster model. Terpendole D showed high specificity for ACAT inhibition in an intact cell assay using J774 macrophages. A series of new FTase inhibitors, pepticinnamins, were isolated from the culture broth of Streptomyces sp. OH-4652. Pepticinnamin E, composed of five amino acids, showed potent FTase inhibition with an IC50 value of 0.1 µM. The compound inhibited FTase competitively with respect to the substrate ras p21 protein. © 1994 IUPAC