Mechanisms of cyclic ether formation in fungal natural product biosynthesis

Natural products biosynthesized by filamentous fungi exhibit complex structures and exciting biological activities. Cyclic and multicyclic ethers are formed prevalently in biosynthesis of polyketides, terpenes and alkaloids, often through unexplored mechanisms. For example, aurovertin is a powerful ATP-synthase inhibitor and contains a 2,6-dioxabicyclo[3.2.1]octane ring that is derived from a polyene precursor; while the penigequinolone/asperquinolone alkaloids contain cyclic ethers derived from novel cyclizations of a C10 terpene precursor.  We have investigated the biosynthetic pathways of these natural products in detail and have mapped the enzymes and mechanisms of ether formation.  In aurovertin biosynthesis, we showed that the iterative functions of a flavin-dependent monooxygenase and a hydrolase are responsible for oxidative formation of the bicyclooctane ring. We demonstrated that a tetrahydrofuranyl polyene is the first stable intermediate in the transformation, which can undergo epoxidation and anti-Baldwin 6-endo-tet ring opening.  In the quinolone alkaloid pathways, we uncovered a new class of epoxide opening enzymes that have sequence homology to CrtC, which has not been implicated in epoxide rearrangement previously.  The corresponding enzyme from Pen and Asp pathways catalyzes semipinacol and 3-exo-tet rearrangements, respectively, both of which are new to epoxide enzymology.  Results from these biosynthetic investigations will be discussed in this talk.