Chemoenzymatic synthesis of novel cytotoxic epoxyketones using the eponemycin biosynthetic enzyme EpnF Journal Article
| Authors: | Corless, B. C.; Geißen, R.; Prescott, N. A.; David, Y.; Scheinberg, D. A.; Tan, D. S. |
| Article Title: | Chemoenzymatic synthesis of novel cytotoxic epoxyketones using the eponemycin biosynthetic enzyme EpnF |
| Abstract: | Eponemycin is an alpha,beta-epoxyketone naturalproduct thatinhibits the proteasome via covalent interactionof the epoxyketone warhead with catalytic N-terminal threonine residues.The epoxyketone warhead is biosynthesized from a beta-ketoacidsubstrate by EpnF, a recently identified flavin-dependent acyl-CoAdehydrogenase-like enyzme. Herein, we report biochemical characterizationof EpnF kinetics and substrate scope using a series of synthetic beta-ketoacidsubstrates. These studies indicate that epoxide formation likely occursprior to other tailoring reactions in the biosynthetic pathway, andhave led to the identification of novel epoxyketone analogues withpotent anticancer activity. |
| Keywords: | carfilzomib; proteasome inhibitors; epoxomicin; warhead |
| Journal Title: | ACS Chemical Biology |
| Volume: | 18 |
| Issue: | 6 |
| ISSN: | 1554-8929 |
| Publisher: | American Chemical Society |
| Date Published: | 2023-06-16 |
| Start Page: | 1360 |
| End Page: | 1367 |
| Language: | English |
| ACCESSION: | WOS:001010996400001 |
| DOI: | 10.1021/acschembio.3c00080 |
| PROVIDER: | wos |
| PUBMED: | 37172287 |
| PMCID: | PMC10358350 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Derek S. Tan -- Source: Wos |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
-
91Tan -
499Scheinberg -
11Prescott -
5Corless -
3Geissen
Related MSK Work