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Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359
Univ Bonn, Inst Pharmazeut Biol, Bonn, Germany.
Univ Bonn, Inst Pharmazeut Biol, Bonn, Germany.
] Eidgenoss Tech Hsch ETH Zurich, Inst Mikrobiol, Zurich, Switzerland.
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2018 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 57, no 3, p. 836-840Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 57, no 3, p. 836-840
Keywords [en]
FR900359, G proteins, biosynthesis, heterologous expression, natural products
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-342249DOI: 10.1002/anie.201707996PubMedID: 29194875OAI: oai:DiVA.org:uu-342249DiVA, id: diva2:1183913
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-03-14Bibliographically approved

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Attwood, Misty M.

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