Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids

The formation of C-C bonds in an enantioselective fashion to create complex polycyclic scaffolds in the hapalindole-and fischerindole-type alkaloids from Stigonematales cyanobacteria represents a compelling and urgent challenge in adapting microbial biosynthesis as a catalytic platform in drug development. Here we determine the biochemical basis for tri- and tetracyclic core formation in these secondary metabolites, involving a new class of cyclases that catalyze a complex cyclization cascade.