Natural products with architecturally distinct scaffolds remain attractive for the discovery of potential drugs and biological probes. To collect new compounds with privileged skeletons, however, is becoming more challenging. Through various combinations of chemical and biosynthetic approaches, large numbers of structurally interesting and biologically active natural product analogues have been generated to focus on a common scaffold in each case. On the other side, biosynthetic machineries usually accommodate divergent pathways to produce a dazzling array of architecturally distinct skeletons from only a handful of basic building blocks.

Prof. ZENG Ying and Prof. LIU Jikai’ teams at the State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany of Chinese Academy of Sciences investigated how structural diversity is expanded from relatively few fundamental blocks and found it necessary to promote the development of creative approaches for the skeletal diversification of compounds. Therefore, the researchers paid their attention to the basidiomycete fungus Boreostereum vibrans (syn. Stereum vibrans). (Angewandte Chemie International Edition 2013, 52: 2298–2302).

Based on recent elucidation of the biosynthetic pathway for vibralactone, this research demonstrated a divergent pathway to skeletally distinct meroterpenoids in B. vibrans from a common intermediate that has a shikimate-terpenoid origin. Moreover, a FAD-binding monooxygenase VibMO1 was identified that converts prenyl 4-hydroxybenzoate into prenylhydroquinone and is likely involved in the biosynthesis of vibralactone G and other meroterpenoids in B. vibrans. The pathway to 3-substituted γ-butyrolactone such as vibralactone G is distinct in starting from an aryl ring of shikimate origin, which is unusual and the first time such a pathway has been described in natural product chemistry.

This study affords in vivo and in vitro verification of oxidative decarboxylation of prenyl 4-hydroxybenzoate and, subsequent to this, the important discovery of the first genetic and biochemical characterization of a FAD-binding monooxygenase VibMO1 that converts prenyl 4-hydroxybenzoate to prenylhydroquinone and is likely involved in the biosynthesis of meroterpenoids in B. vibrans fungus. 

This identification of VibMO1 will also be informative for the determination of enzymes essential for similar conversion steps in the biosynthesis of yeast coenzyme Q and plant meroterpenoids, where the oxidative decarboxylation of (poly)prenyl hydroxybenzoates to their hydroquinones is understood to occur yet no corresponding genes or enzymes have been described.

This study also demonstrates divergent biosynthetic pathways toward distinct scaffolds from a single precursor. To create skeletal diversification of compounds, further insight into nature’s strategy for expanding structural diversity is needed.

The study has recently been published in Angewandte Chemie International Edition.

This work was supported by the grants from the National Natural Science Foundation of China.