Releasing potential power of terpene synthases by a robust precursor supply platform

Approximately 76,000 discovered makes terpenoids the largest family of natural products in nature with widespread applications. The wide-spectrum of structural diversity of the terpenoids were largely due to the variable skeletons generated by terpene synthases. The number of terpene skeletons found in nature, however, were so much more than those conceivably generated from known terpene synthases and the limited characterized terpene synthases also make no chance for some useful terpenoids overproduction in microbe. Here, we first demonstrated that the promiscuous synthases in vivo can produce more variable terpenoid products by converting precursors of different lengths (C 10 , C 15 , C 20 , C 25 ). This discovery was prompted by the development of an efficient in vivo platform by combining the two promiscuous terpene synthases and three prenyltransferases to generate 50 terpenoids, at least 3 ring systems of which were completely new. Furthermore, protein engineering was further integrated to enhance product diversity. Clearly, the work is expected to dramatically reshape the terpenoid research by widening the flexibility of the terpene synthases for the fresh discovery or creation of the new terpenoid compounds by skeleton reframing.