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Publication Abstract from PubMed

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-A 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.

Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis.,Newmister SA, Li S, Garcia-Borras M, Sanders JN, Yang S, Lowell AN, Yu F, Smith JL, Williams RM, Houk KN, Sherman DH Nat Chem Biol. 2018 Apr;14(4):345-351. doi: 10.1038/s41589-018-0003-x. Epub 2018 , Mar 12. PMID:29531360^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.