Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont
Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont
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DOI：
10.1038/nchembio.1573
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发表时间：
2014-08-01
影响因子：
14.8
通讯作者：
Abe, Ikuro
中科院分区：
文献类型：
--
作者：
Wakimoto, Toshiyuki;Egami, Yoko;Abe, Ikuro
日本海绵Discodermia花萼含有一种主要的细胞毒性化合物calyculin a，它对蛋白磷酸酶1和2A具有选择性抑制作用。长期以来，它一直被用作评估可逆蛋白磷酸化调控的细胞内信号转导的化学工具。我们描述了用宏基因组挖掘方法鉴定花青素A的生物合成基因簇。单细胞分析表明，该基因簇起源于共生细菌“Candidatus Entotheonella”sp.。该基因簇编码的磷酸转移酶使calyculin A失活，产生新发现的二磷酸，这实际上是生物合成的最终产物。二磷酸曾被忽视，因为在海绵组织破坏的反应中发生了酶解去磷酸化。据我们所知，我们的工作提供了calyculin A生物合成过程的第一个证据，以及一个显著的磷酸化-去磷酸化机制来调节毒性，这表明在所有最原始的多细胞动物中激活了化学防御。
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.