Enzyme inhibition by hydroamination: Design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor

TitleEnzyme inhibition by hydroamination: Design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor
Publication TypeJournal Article
Year of Publication2014
AuthorsTrivella D.BB, Pereira A.R, Stein M.L, Kasai Y., Byrum T., Valeriote F.A, Tantillo D.J, Groll M., Gerwick WH, Moore BS
JournalChemistry & Biology
Volume21
Pagination782-791
Date Published2014/06
Type of ArticleArticle
ISBN Number1074-5521
Accession NumberWOS:000338507700011
Keywords20s proteasome; crystal-structure; cyclic; depsipeptides; epoxomicin; functionals; marine cyanobacterium; noncovalent interactions; performance; protein-degradation; resolution
Abstract

Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and alpha,beta-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.

DOI10.1016/j.chembiol.2014.04.010
Short TitleChem. Biol.
Integrated Research Themes: 
Student Publication: 
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