Functional Plasticity of a Viral Terpene Synthase, OILTS, that Shows Non–Specific Metal Cofactor Binding and Metal–Dependent Biosynthesis

Abstract OILTS is a viral class I terpene synthase found from the giant virus Orpheovirus IHUMI–LCC2. It exhibits a unique structure and demonstrates high plasticity to metal cofactors, allowing it to biosynthesize different cyclic terpene frameworks. Notably, while OILTS produces only (+)‐germacrene D–4–ol with the most common cofactor, Mg 2+ , it also biosynthesizes a different cyclic terpene, (+)‐cubebol, with Mn 2+ , Co 2+ , or Ni 2+ , presenting a rare instance of cofactor‐dependent enzyme catalysis. This is the first report of (+)‐cubebol biosynthesis, to our knowledge. In addition, OILTS can uptake Zn 2+ as a cofactor, which is uncommon among ordinary terpene synthases. These findings suggest that OILTS′s functional plasticity may benefit the virus in diverse host environments, highlighting potential evolutionary implications.