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Updated: Feb 13, 2026

Study of Phagolysosome Biogenesis in Live Macrophages
Published on: March 10, 2014
Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis
Sean A Newmister1, Shasha Li1,2, Marc Garcia-Borràs3
1Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Abstract:
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.
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