Unusual cyclization mechanism of Streptomyces terpene cyclases

Terpenoids have been an important resource for biologically active compounds because of their structural diversity. The complexity of the terpenoid skeleton is generated by the condensation of C₅ isoprene units and subsequent cyclization. In this presentation, I will share with you cyclization mechanism of two terpene cyclases that involved in the biosynthesis of terpenoids, lavanducyanin produced by Streptomyces sp. CL190 and cyclooctatin produced by Streptomyces melanosporofaciens MI614-43F2.

Lavanducyanin is a structurally unique phenazine compound with a cyclolavandulyl carbon skeleton attached through N-5 of a phenazine nucleus. Recently, we identified an unprecedented terpene cyclase that synthesizes the cyclolavandulyl skeleton. Notably, the enzyme, a single-domain protein that consists of only 217 amino acids, catalyzed both condensation and cyclization to form the cyclolavandulyl structure. We propose a likely reaction mechanism for this unusual terpene cyclase.

Cyclooctatin is a diterpene having a unique tricyclic C₂₀ skeleton characterized by a 5-8-5 fused ring system. Recently, we cloned and characterized the cyclooctatin biosynthetic cotB gene cluster. CotB2 catalyzes the cyclization of C₂₀ geranylgeranyl diphosphate to produce cyclooctat-9-en-7-ol, a tricyclic diterpene alcohol intermediate in cyclooctatin biosynthesis. We propose a mechanism of the one-pot biosynthesis of the unusual tricyclic fused ring structure, based on the combined isotopic labeling results. The mechanism involves an unusual carbon−carbon bond rearrangement in catalysis.