Enzymes that convert linear molecules into cyclic ones greatly enhance the diversity of natural products. But the way they developed this ability evolutionarily is not fully understood. Researchers have now identified a possible scenario: a set of amino acid substitutions that “unlock” cyclization in an enzyme that normally produces only linear products. The findings could aid the production of new and existing natural-product-based compounds for a range of drug, flavor, and fragrance applications. Terpene synthases (TPSs) produce both linear terpenes and cyclic terpenes, such as the malaria treatment artemisinin, isolated from wormwood plants. Working with wormwood enzymes, Paul E. O’Maille of the John Innes Centre, in Norwich, England, and coworkers generated a library of some 27,000 mutated TPSs by transferring amino acid sequences from a cyclizing TPS into a TPS that produces only linear terpenes (Nat. Commun. 2015, DOI: 10.1038/ncomms7143). The study revealed that one predominant mutation and several secondary mutations form a residue network that can activate, suppress, or reactivate cyclization activity in the linear enzyme. Similar mutations also controlled cyclization in a TPS from another plant, suggesting that the residue network may be a conserved element in the evolution of cyclization.