Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis

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

doi:10.1038/s41589-018-0003-x

Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis

Nat Chem Biol. 2018 Apr;14(4):345-351. doi: 10.1038/s41589-018-0003-x. Epub 2018 Mar 12.

Authors

Sean A Newmister¹, Shasha Li^{1

2}, Marc Garcia-Borràs³, Jacob N Sanders³, Song Yang³, Andrew N Lowell¹, Fengan Yu¹, Janet L Smith^{1

4}, Robert M Williams^{5

6}, K N Houk⁷, David H Sherman^{8

9

10

11}

Affiliations

¹ Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
² Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
³ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Chemistry, Colorado State University, Fort Collins, CO, USA. robert.williams@colostate.edu.
⁶ University of Colorado Cancer Center, Aurora, CO, USA. robert.williams@colostate.edu.
⁷ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA. houk@chem.ucla.edu.
⁸ Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.
⁹ Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.
¹⁰ Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.
¹¹ Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids / chemistry*
Calcium / chemistry
Catalysis
Catalytic Domain
Cloning, Molecular
Cyanobacteria / enzymology*
Cyclization
DNA Mutational Analysis
Dimerization
Indole Alkaloids / chemistry
Indoles / chemistry*
Ions
Molecular Conformation
Molecular Dynamics Simulation
Molecular Structure
Protein Binding
Quantum Theory
Recombinant Proteins / chemistry
Stereoisomerism

Substances

Alkaloids
Indole Alkaloids
Indoles
Ions
Recombinant Proteins
fischerindole
hapalindole U
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding