Control of Stereoselectivity in Diverse Hapalindole Metabolites Is Mediated by Cofactor Induced Combinatorial Pairing of Stig Cyclases

The stereospecific polycyclic core formation of hapalindoles and fischerindoles is controlled by the Stig cyclases through a three-step cascade involving Cope rearrangement, 6-exo-trig cyclization and a final electrophilic aromatic substitution. Here we report a comprehensive study of all currently annotated Stig cyclases, and reveal that these proteins can assemble into heteromeric complexes induced by Ca²⁺ to cooperatively control the stereochemistry of hapalindole natural products.