edoc

Macyranones : structure, biosynthesis, and binding mode of an unprecedented epoxyketone that targets the 20S proteasome

Keller, Lena and Plaza, Alberto and Dubiella, Christian and Groll, Michael and Kaiser, Marcel and Müller, Rolf. (2015) Macyranones : structure, biosynthesis, and binding mode of an unprecedented epoxyketone that targets the 20S proteasome. The journal of the American Chemical Society, Vol. 137, H. 25. pp. 8121-8130.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/dok/A6411211

Downloads: Statistics Overview

Abstract

In our screening efforts to identify unique scaffolds from myxobacteria for the drug discovery process, we used LC-SPE-NMR-MS techniques to isolate six linear peptides, termed macyranone A-F, from Cystobacter fuscus MCy9118. The macyranones are characterized by a rare 2-methylmalonamide moiety and an α-amino ketone fragment including an α',β'-epoxyketone in macyranone A. Gene disruption experiments confirmed the biosynthetic gene cluster of the macyranones as PKS/NRPS hybrid. Detailed in silico and phylogenetic analysis unraveled that the biosynthesis involves two conspicuous amide bond formations accomplished by an amidotransferase and a unique condensation domain. The gene cluster provides further insights into the formation of the powerful epoxyketone residue involving an acyl-CoA dehydrogenase and an unconventional free-standing thioesterase. Macyranone A was found to inhibit the chymotrypsin-like activity of the yeast 20S proteasome with an IC50 of 5.9 nM and the human constitutive proteasome and immunoproteasome with IC50 values of 21 and 15 nM, respectively. The β5 subunit of the 20S proteasome was characterized as target by X-ray crystallography revealing an irreversible binding mode similar to the natural product epoxomicin. The presence of the methylmalonamide residue facilitates the stabilization of macyranone A with the active β5 subunit of the proteasome. Macyranone A exhibits a potent inhibitory effect against the parasites Trypanosoma brucei rhodesiense and Leishmania donovani with IC50 values of 1.55 and 0.22 μM, respectively.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0002-7863
Note:Publication type according to Uni Basel Research Database: Journal article
Related URLs:
Identification Number:
Last Modified:04 Sep 2015 14:30
Deposited On:04 Sep 2015 14:30

Repository Staff Only: item control page