DISCOVERY, BIOSYNTHESIS, AND MECHANISM OF ACTION OF THE ZARAGOZIC ACIDS - POTENT INHIBITORS OF SQUALENE SYNTHASE

The zaragozic acids (ZAs), a family of fungal metabolites containing a novel -2,8-dioxobicyclo[3.2.1]octane-3,4,5-tricarboxylic acid core, w ere discovered independently by two separate groups screening natural product sources to discover inhibitors of squalene synthase. This fami ly of compounds all contain the same core but differ in their 1-alkyl and their 6-acyl side chains. Production of the ZAs is distributed ove r an extensive taxonomic range of Ascomycotina or their anamorphic sta tes. The zaragozic acids are very potent inhibitors of squalene syntha se that inhibit cholesterol synthesis and lower plasma cholesterol lev els in primates. They also inhibit fungal ergosterol synthesis and are potent fungicidal compounds. The biosynthesis of the zaragozic acids appears to proceed through alkyl citrate intermediates and new members of the family have been produced through directed biosynthesis. These potent natural product based inhibitors of squalene synthase have pot ential to be developed either as cholesterol lowering agents and/or as antifungal agents.