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Nat Chem Biol. 2014 Aug;10(8):648-55. doi: 10.1038/nchembio.1573. Epub 2014 Jun 29.

Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont.

Author information

1
1] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, CREST, Tokyo, Japan. [3].
2
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
3
1] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, CREST, Tokyo, Japan.
4
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
5
Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.

Abstract

The Japanese marine sponge Discodermia calyx contains a major cytotoxic compound, calyculin A, which exhibits selective inhibition of protein phosphatases 1 and 2A. It has long been used as a chemical tool to evaluate intracellular signal transduction regulated by reversible protein phosphorylation. We describe the identification of the biosynthetic gene cluster of calyculin A by a metagenome mining approach. Single-cell analysis revealed that the gene cluster originates in the symbiont bacterium 'Candidatus Entotheonella' sp. A phosphotransferase encoded in the gene cluster deactivated calyculin A to produce a newly discovered diphosphate, which was actually the biosynthetic end product. The diphosphate had been previously overlooked because of the enzymatic dephosphorylation that occurred in response to sponge tissue disruption. Our work presents what is to our knowledge the first evidence for the biosynthetic process of calyculin A along with a notable phosphorylation-dephosphorylation mechanism to regulate toxicity, suggesting activated chemical defense in the most primitive of all multicellular animals.

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PMID:
24974231
DOI:
10.1038/nchembio.1573
[Indexed for MEDLINE]

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