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Angew Chem Int Ed Engl. 2018 Jan 15;57(3):836-840. doi: 10.1002/anie.201707996. Epub 2017 Dec 20.

Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359.

Author information

1
Institut für Pharmazeutische Biologie, Universität Bonn, Nussallee 6, 53115, Bonn, Germany.
2
Institut für Mikrobiologie, Eidgenössische Technische Hochschule (ETH) Zürich, Vladimir-Prelog Weg 4, 8093, Zürich, Switzerland.
3
Institute for Integrative Biology of the Cell, UMR9198, CNRS, Université Paris-Sud, CEA, Avenue de la Terrasse, Gif-sur-Yvette, 91198, France.
4
PharmaCenter Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie I, Universität Bonn, An der Immenburg 4, 53121, Bonn, Germany.
5
Institut für Physiologie I, Medizinische Fakultät, Universität Bonn, Life&Brain Center, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
6
Institut für Pflanzen- und Mikrobiologie, Universität Zürich, Zollikerstr. 107, 8008, Zürich, Switzerland.
7
Pflanzenwissenschaften (IBG-2) Forschungszentrum Jülich, Wilhelm-Johnen-Str., 52428, Jülich, Germany.
8
Department of Neuroscience, Biomedical Center, Uppsala University, 751 24, Uppsala, Sweden.
9
Bioproduction Research Institute AIST Hokkaido, Tsukisamu-higashi 2-17-2-1, Sapporo, 062-8517, Japan.
10
Institut für Insektenbiotechnologie, Universität Gießen, Heinrich-Buff-Ring 26-32, 35392, Gießen, Germany.
11
Department of Biochemistry and Microbiology, University of Gent, K.L. Ledeganckstraat 35, L9, 9000, Gent, Belgium.

Abstract

The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq-related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC-1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time.

KEYWORDS:

FR900359; G proteins; biosynthesis; heterologous expression; natural products

PMID:
29194875
DOI:
10.1002/anie.201707996

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