Bifunctional assembly-line terpenoid synthases catalyze a specific sequence of chemical reactions starting with simple 5-carbon precursors, and ending with 20- or 25-carbon polycyclic natural products that contain multiple fused rings and stereocenters. Many such terpenoids exhibit useful biological properties, e.g., as anti-cancer, anti-inflammatory, or antibacterial agents. Terpenoid synthase reaction sequences are among the most complex carbon-carbon bond forming reactions in nature, since approximately two-thirds of the carbon atoms in the substrates undergo changes in bonding and/or hybridization during a single, precisely controlled reaction sequence. For example, the diterpenoid fusicocca-2,10(14)-diene, is precursor to fusicoccin A, a C<sub>20</sub> glucoside containing a tricyclic 5-8-5 ring system that blocks proliferation and migration of glioblastoma cells and has potential as a cancer chemotherapeutic agent. Fusicoccadiene synthase in <i>Phomopsis amygdali</i> (PaFS) catalyzes the first committed step of fusicoccin A biosynthesis and establishes the structure and stereochemistry of the hydrocarbon skeleton. Oligomerization of PaFS likely confers an “agglomeration effect,” in which substrate is channeled by proximity between active sites of consecutive reactions. We present here the cryo-EM structure of the PaFS tetramer, the first structure of an intact assembly-line terpenoid synthase. These studies uncover the structural basis of substrate channeling between active sites and the molecular basis of cooperativity measured in enzymological studies. The studies discussed herein will directly inform biosynthesis of pharmaceutically relevant terpenoids.

Investigating substrate channeling and cooperativity in assembly-line terpenoid biosynthesis

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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