Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis

Newmister, Sean A.; Li, Shasha; Garcia-Borràs, Marc; Sanders, Jacob N.; Yang, Song; Lowell, Andrew N.; Yu, Fengan; Smith, Janet L.; Williams, Robert M.; Houk, K. N.; Sherman, David H.

doi:10.1038/s41589-018-0003-x

Title: Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis

Journal Article · Mon Mar 12 00:00:00 EDT 2018 · Nature Chemical Biology

DOI:https://doi.org/10.1038/s41589-018-0003-x· OSTI ID:1558297

Newmister, Sean A. ^[1]; Li, Shasha ^[1];

^[2]; Sanders, Jacob N. ^[2]; Yang, Song ^[2]; Lowell, Andrew N. ^[1]; Yu, Fengan ^[1]; Smith, Janet L. ^[1]; Williams, Robert M. ^[3]; Houk, K. N. ^[2];

^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of California, Los Angeles, CA (United States)
Colorado State Univ., Fort Collins, CO (United States); Univ. of Colorado Cancer Center, Aurora, CO (United States)

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. In this work, 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: CHE-1700982; CA70375; OCI-1053575

OSTI ID:: 1558297

Journal Information:: Nature Chemical Biology, Vol. 14, Issue 4; ISSN 1552-4450

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 19 works

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