MstE from Scytonema sp.

[181]  Moosmann P., Ecker F., Leopold-Messer S., Cahn J. K. B., Dieterich C. L., Groll M., Piel J.
A monodomain class II terpene cyclase assembles complex isoprenoid scaffolds
Nat. Chem., 2020, 12, 968-972 PDF

Class II terpene cyclases, such as oxidosqualene and squalene-hopene cyclases, catalyze some of the most complex polycyclization reactions. They minimally exhibit a β,γ-didomain architecture that has been evolutionarily repurposed in a wide range of terpene-processing enzymes and likely resulted from a fusion of unidentified monodomain proteins. Although single domain class I terpene cyclases have already been identified, single domain class II terpene cyclases have not been previously reported. Here we report high-resolution X-ray structures of a monodomain class II cyclase, merosterolic acid synthase (MstE). With a minimalistic β-domain architecture, this cyanobacterial enzyme is able to construct four rings in cytotoxic meroterpenoids with a sterol-like topology. The structures with bound substrate, product, and inhibitor provide detailed snapshots of a cyclization mechanism largely governed by residues located in a noncanonical enzyme region. Our results complement the few known class II cyclase crystal structures, while also indicating that archaic monodomain cyclases might have already catalyzed complex reaction cascades.