Marine Antifungal Theonellamides Target 3beta-hydroxysterol to Activate Rho1 Signaling

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2010 Jun 15

PMID 20543850

Citations 23

Authors

Shinichi Nishimura

Yuko Arita

Miyuki Honda

Kunihiko Iwamoto

Akihisa Matsuyama

Atsuko Shirai

Hisashi Kawasaki

Hideaki Kakeya

Toshihide Kobayashi

Shigeki Matsunaga

Minoru Yoshida

Affiliations

Soon will be listed here.

Abstract

Linking bioactive compounds to their cellular targets is a central challenge in chemical biology. Here we report the mode of action of theonellamides, bicyclic peptides derived from marine sponges. We generated a chemical-genomic profile of theonellamide F using a collection of fission yeast strains in which each open reading frame (ORF) is expressed under the control of an inducible promoter. Clustering analysis of the Gene Ontology (GO) terms associated with the genes that alter drug sensitivity suggested a mechanistic link between theonellamide and 1,3-beta-D-glucan synthesis. Indeed, theonellamide F induced overproduction of 1,3-beta-D-glucan in a Rho1-dependent manner. Subcellular localization and in vitro binding assays using a fluorescent theonellamide derivative revealed that theonellamides specifically bind to 3beta-hydroxysterols, including ergosterol, and cause membrane damage. The biological activity of theonellamides was alleviated in mutants defective in ergosterol biosynthesis. Theonellamides thus represent a new class of sterol-binding molecules that induce membrane damage and activate Rho1-mediated 1,3-beta-D-glucan synthesis.

Citing Articles

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Theonellamides J and K and 5--Apoa-theopalauamide, Bicyclic Glycopeptides of the Red Sea Sponge .

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