萜类是数量和结构多样性最为庞大天然产物家族，由于它们可以高效精确调控生理机能，因而成为药物研发的源泉。真菌可以产生丰富的萜类，相较其他物种，真菌拥有独特的萜类生物合成机制，因此对于真菌来源的萜类天然产物的生物合成研究是发现新颖合成机制的有效途径。Quadranes倍半萜天然产物家族具有优异的抗肿瘤活性，然而其新颖而复杂的三环骨架结构的化学合成却极具挑战性，这严重阻碍了对于quadranes倍半萜类似物的构建，进而影响了其药学开发前景。Quadranes家族的其中一个成员terrecyclic acid由土曲霉产生，项目申请人将在阐明其生物合成途径及特殊骨架结构形成和后修饰的酶学机制的基础上，通过对萜类环化酶改造，获得新型倍半萜骨架。

Terpenes comprise the most structurally diversified members among all families of natural products. Due to the ability to precisely regulate the cellular processes, they have become a major source for developing new human therapeutics. Filamentus fungi are prolific producers of terpenes. Compare to other species, fungi employ unique machinery to form terpenoids. Therefore investigating fungal terpene biosynthesis is an effective approach to discover novel biosynthetic enzymology. Quadranes sesquiterpenoid family have exceptional anti-cancer activity, however, chemical synthesis of its tricyclic ring bearing scaffold to make analogs is challenging, which further impedes developing quadranes into new drugs. Terrecyclic acid, a member of quadranes family, is produced by Aspergillus terreus. In this proposal, we plan to elucidate the biosynthetic pathway and enzymology of the formation of the unique scaffold of terrecyclic acid, which is followed by protein engineering of the sesquiterpene cyclase to obtain new sesquiterpene scaffolds.