biostudies-literature00470Newmister SANIDDK NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHS345-351https://www.ebi.ac.uk/biostudies/studies/S-EPMC5880276biostudies-literatureUnknown14(4)Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These complex metabolites are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps: a rare Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution. Here we report the structure of HpiC1, a Stig cyclase that catalyzes the formation of 12-epi-hapalindole U in vitro. The 1.5-Å structure revealed a dimeric assembly with two calcium ions per monomer and with the active sites located at the distal ends of the protein dimer. Mutational analysis and computational methods uncovered key residues for an acid-catalyzed [3,3]-sigmatropic rearrangement, as well as specific determinants that control the position of terminal electrophilic aromatic substitution, leading to a switch from hapalindole to fischerindole alkaloids.Nature chemical biologyStructural basis of the Cope rearrangement and cyclization in hapalindole biogenesis.PMC5880276S10 OD020011F32 GM122218R01 DK042303R35 GM118101S10 OD012289R01 CA070375Garcia-Borras MSanders JNLi SWilliams RMSmith JLYu FLowell ANHouk KNNewmister SAYang SSherman DH47falseStructural basis of the Cope rearrangement and cyclization in hapalindole biogenesis.Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These complex metabolites are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps: a rare Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution. Here we report the structure of HpiC1, a Stig cyclase that catalyzes the formation of 12-epi-hapalindole U in vitro. The 1.5-Å structure revealed a dimeric assembly with two calcium ions per monomer and with the active sites located at the distal ends of the protein dimer. Mutational analysis and computational methods uncovered key residues for an acid-catalyzed [3,3]-sigmatropic rearrangement, as well as specific determinants that control the position of terminal electrophilic aromatic substitution, leading to a switch from hapalindole to fischerindole alkaloids.2018-01-01T00:00:00Z2018 Apr2024-11-07T06:39:59.675Z2019-06-06T19:15:51ZS-EPMC58802762953136010.1038/s41589-018-0003-x