Bergstrom J D, Dufresne C, Bills G F, Nallin-Omstead M, Byrne K
Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
Annu Rev Microbiol. 1995;49:607-39. doi: 10.1146/annurev.mi.49.100195.003135.
The zaragozic acids (ZAs), a family of fungal metabolites containing a novel 4,6,7-trihydroxy-2,8-dioxobicyclo[3.2.1]octane-3,4,5-tricarboxylic acid core, were discovered independently by two separate groups screening natural product sources to discover inhibitors of squalene synthase. This family 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 over an extensive taxonomic range of Ascomycotina or their anamorphic states. The zaragozic acids are very potent inhibitors of squalene synthase that inhibit cholesterol synthesis and lower plasma cholesterol levels 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 potential to be developed either as cholesterol lowering agents and/or as antifungal agents.
扎拉戈昔酸（ZAs）是一类真菌代谢产物，其核心为一种新型的4,6,7-三羟基-2,8-二氧代双环[3.2.1]辛烷-3,4,5-三羧酸，由两个独立的小组在筛选天然产物来源以发现角鲨烯合酶抑制剂时分别发现。该类化合物都含有相同的核心，但1-烷基和6-酰基侧链有所不同。扎拉戈昔酸的产生分布在子囊菌纲或其无性型的广泛分类范围内。扎拉戈昔酸是角鲨烯合酶的强效抑制剂，可抑制胆固醇合成并降低灵长类动物的血浆胆固醇水平。它们还抑制真菌麦角固醇的合成，是强效杀真菌化合物。扎拉戈昔酸的生物合成似乎通过烷基柠檬酸中间体进行，并且该家族的新成员已通过定向生物合成产生。这些基于天然产物的角鲨烯合酶强效抑制剂有潜力被开发为降胆固醇药物和/或抗真菌药物。
