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Decatransin, a novel natural product inhibits co- and posttranslational protein translocation at the Sec61 translocon.

Spiess, Martin and Junne, Tina and Wong Sak Hoi, Joanne and Studer, Christian and Aust, Thomas and Beibel, Martin and Bhullar, Bhupinder and Bruccoleri, Robert and Eichenberger, Juerg and Estoppey, David and Hartmann, Nicole and Knapp, Britta and Krastel, Philipp and Melin, Nicolas and Oakeley, Edward James and Riedl, Ralph and Roma, Guglielmo and Schuierer, Sven and Petersen, Frank and Tallarico, John and Hoepfner, Dominic (2015) Decatransin, a novel natural product inhibits co- and posttranslational protein translocation at the Sec61 translocon. Nature Chemical Biology, 128 (6). pp. 1217-1229. ISSN none

Abstract

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (HUN-7293/cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p/Sec61α1 to confer resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and posttranslationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 homolog. We suggest “decatransin” as the name for this novel decadepsipeptide translocation inhibitor.

Item Type: Article
Keywords: SEC61, endoplasmic reticulum, translocon, co-translational, post-translational, target identification, inhibitor, natural product, depsipeptide, HIP HOP, mutagenesis, genome sequencing
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/20420

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