Lipid metabolism inhibitors of microbial origin.

Abstract

Thiotetromycin is isolated from Streptomyces sp. OM-674 discovered in the course of the screening for antibacterial antibiotics. The antibiotic was found to be a specific inhibitor of type II fatty acid synthase. In order to search acyl-CoA synthetase inhibitors, a kind of yeast, Candida lipolytica, was utilized as test organism for the primary screening. Four structurally related compounds named triacsin were isolated from Streptomyces sp. SK-1894 as a specific inhibitor of acyl-CoA synthetase I of C. lipolytica. Further biochemical studies revealed that triacsins inhibit acyl-CoA synthetases from widely different sources. The inhibition is competitive with respect to long chain fatty acids. The common N-hydroxytriazene moiety of triacsins is essential for inhibition. To discover inhibitors of mevalonate biosynthesis, Vero cells were used as test organism for the screening. A beta-lactone 1233A(F-244) isolated from Scopulariopsis sp. F-244 was demonstrated to inhibit mevalonate biosynthesis with assays using cell and enzyme systems. Further studies demonstrated that the compound inhibits 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase specifically and irreversibly. The geometry of the (2R, 3R)-beta-lactone ring in the structure is essential for specific inhibition against the enzyme.