Cyclic nucleotides are the most diversified category of second messengers and are found in all organisms modulating diverse pathways. While cAMP and cGMP have been studied over 50 years, cyclic di‐nucleotide signaling in eukaryotes emerged only recently with the anti‐viral molecule 2´3´cGAMP. Recent breakthrough discoveries have revealed not only the astonishing chemical diversity of cyclic nucleotides but also surprisingly deep‐rooted evolutionary origins of cyclic oligo‐nucleotide signaling pathways and structural conservation of the proteins involved in their synthesis and signaling. Here we discuss how enzyme‐centered approaches have paved the way for the identification of several cyclic nucleotide signals, focusing on the advantages and challenges associated with deciphering the activation mechanisms of such enzymes.

中文翻译：

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以酶为中心的方法如何推进环状寡核苷酸的研究

环核苷酸是最多样化的第二信使类别，存在于调节不同途径的所有生物体中。虽然 cAMP 和 cGMP 的研究已超过 50 年，但真核生物中的环状二核苷酸信号传导直到最近才随着抗病毒分子 2´3´cGAMP 的出现而出现。最近的突破性发现不仅揭示了环核苷酸惊人的化学多样性，而且还揭示了环状寡核苷酸信号传导途径根深蒂固的进化起源以及参与其合成和信号传导的蛋白质的结构保守性。在这里，我们讨论以酶为中心的方法如何为识别几种环核苷酸信号铺平道路，重点讨论与破译此类酶的激活机制相关的优势和挑战。