title: Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont.
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.
authors: 1] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, CREST, Tokyo, Japan. [3].
authors: Toshiyuki
authors: T
authors: Wakimoto
authors: 1] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, CREST, Tokyo, Japan. [3].
authors: Yoko
authors: Y
authors: Egami
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors: Yu
authors: Y
authors: Nakashima
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors: Yukihiko
authors: Y
authors: Wakimoto
authors: 1] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, CREST, Tokyo, Japan.
authors: Takahiro
authors: T
authors: Mori
authors: 1] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, CREST, Tokyo, Japan.
authors: Takayoshi
authors: T
authors: Awakawa
authors: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
authors: Takuya
authors: T
authors: Ito
authors: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
authors: Hiromichi
authors: H
authors: Kenmoku
authors: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
authors: Yoshinori
authors: Y
authors: Asakawa
authors: Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors: Jörn
authors: J
authors: Piel
authors: 1] Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, CREST, Tokyo, Japan.
authors: Ikuro
authors: I
authors: Abe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D011756:Diphosphates / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D008387:Marine Toxins; D054892:Metagenome; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D010755:Organophosphates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D048630:Polyketide Synthases / Q000235:genetics; D011161:Porifera / Q000382:microbiology* / Q000502:physiology; D012336:RNA, Ribosomal, 16S; D013559:Symbiosis
chemical_list: D000970:Antineoplastic Agents; D011756:Diphosphates; D008387:Marine Toxins; D010755:Organophosphates; D010080:Oxazoles; D012336:RNA, Ribosomal, 16S; C107241:diphosphoric acid; D048630:Polyketide Synthases; C059041:calyculin A; D010770:Phosphotransferases