bioRxiv Biochemistry
bioRxiv Biochemistry
5 years ago

Structural basis of the Cope rearrangement and C-C bond-forming cascade in hapalindole/fischerindole biogenesis

Garcia-Borras, Sanders, Li, Newmister, J. N., K. N., S., F., J. L., Houk, D. H., Smith, Lowell, R. M., A. N., S. A., Yu, Yang, Sherman, Williams, M.
Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These polycyclic scaffolds are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps, including 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 reveals a dimeric assembly with two calcium ions per monomer and 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 and specific determinants that control the position of terminal electrophilic aromatic substitution leading to a switch from hapalindole to fischerindole alkaloids.

Publisher URL: http://biorxiv.org/cgi/content/short/173674v1

DOI: 10.1101/173674

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