Microbial metabolites affecting lipid biosynt hesis

Microbial inhibitors for two enzymes involved in lipid metabolism, acylCoA:cholesterol acyltransferase (ACAT) and famesyl-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. Pynpyropenes 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 Srreptomyces sp. OH-4652. Pepticinnamin E, composed of five amino acids, showed potent FTase inhibition with an IC50 value of 0.1 pM. The compound inhibited R a s e competitively with respect to the substrate rus p21 protein. Introductio n Our research group has been interested in microbial metabolites affecting lipid biosynthesis and has discovered various useful compounds (1). Many essential products and substrates such as cholesterol, farnesyl pyrophosphate and isopentenyl pyrophosphate are produced via mevalonate biosynthetic pathway. Enzymes involved in the pathway are focused on as potential therapeutic targets for anti-atherosclerotic, antifungal and anticancer drugs. Acyl-CoA:cholesterol acyltransferase (ACAT) and farnesyl-protein transferase Wase) utilize cholesterol and farnesyl pyrophosphate as substrate, respectively, both of which are synthesized via the mevalonate pathway. In this paper, microbial metabolites inhibiting the two enzymes will be described. Inhibitors of ACAT Hypercholesterolemia is a serious risk factor of atherosclerosis developing into coronary heart disease or myocardial infarction. Several therapeutic means have been proposed to lower cholesterol levels in plasma. One successful example is to inhibit de novo cholesterol biosynthesis. Lovastatin and its analogs (pravastatin and simvastatin), potent inhibition of HMG-CoA reductase, the ratelimiting enzyme in the biosynthetic pathway, are now clinically used (2). Another possible therapy is the prevention of the dietary cholesterol absorption. ACAT utilizes long-chain fatty acyl-CoA and cholesterol as substrates to catalize the intracellular formation of cholesteryl ester. ACAT plays important roles in cholesterol metabolism in human body; 1) Dietary cholesterol is absorbed at intestines as cholesteryl ester by the reaction of ACAT, 2) cholesterol in liver supplied by both factors of taking diet and de novo synthesis is acylated by ACAT to be secreted as VLDL, and 3)