Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Enzyme Inhibition by Hydroamination: Design and Mechanism of a Hybrid Carmaphycin-Syringolin Enone Proteasome Inhibitor

Full text
Author(s):
Trivella, Daniela B. B. [1] ; Pereira, Alban R. [2] ; Stein, Martin L. [3] ; Kasai, Yusuke [4] ; Byrum, Tara [5] ; Valeriote, Frederick A. [6] ; Tantillo, Dean J. [7] ; Groll, Michael [8] ; Gerwick, William H. [9] ; Moore, Bradley S. [10]
Total Authors: 10
Affiliation:
[1] Univ Calif San Diego. Scripps Inst Oceanog
[2] Univ Calif San Diego. Scripps Inst Oceanog
[3] Tech Univ Munich. Ctr Integrated Prot Sci
[4] Univ Calif San Diego. Scripps Inst Oceanog
[5] Univ Calif San Diego. Scripps Inst Oceanog
[6] Henry Ford Hlth Syst. Dept Internal Med
[7] Univ Calif Davis. Dept Chem
[8] Tech Univ Munich. Ctr Integrated Prot Sci
[9] Univ Calif San Diego. Scripps Inst Oceanog
[10] Univ Calif San Diego. Scripps Inst Oceanog
Total Affiliations: 10
Document type: Journal article
Source: CHEMISTRY & BIOLOGY; v. 21, n. 6, p. 782-791, JUN 19 2014.
Web of Science Citations: 12
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. (AU)

FAPESP's process: 11/21358-5 - Screening of (bio)synthetic organic compounds with biological targets against cancer
Grantee:Daniela Barretto Barbosa Trivella
Support Opportunities: Scholarships abroad - Research Internship - Post-doctor