Abstract

Terpene cyclases catalyze the most complex chemical reactions in biology, in that more than half of the carbon atoms in the isoprenoid substrate undergo changes in bonding or hybridization during a typical cyclization cascade. Although the substrate pool for these enzymes is limited to just a handful of linear isoprenoids, more than 100,000 terpenoid natural products have been identified to date. X-ray crystal structures reveal that three principal catalytic modules are at the roots of this exquisite chemodiversity. Most recently, cryo-EM structures of bifunctional terpene synthases show how prenyltransferases generate linear isoprenoids that are utilized as cyclase substrates in massive oligomeric assemblies. Substrate channelling ensures efficient carbon management in some, but not all, of these systems. The structure of a bifunctional terpene cyclase-phosphatase chimera further shows how isoprenoid cyclization is combined with a downstream tailoring activity in a newly identified class of bifunctional terpene synthases.