Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Fingerprints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK.
Cell Chem Biol. 2020 Feb 20;27(2):214-222.e4. doi: 10.1016/j.chembiol.2020.01.004. Epub 2020 Jan 27.
Cordycepin (3'-deoxyadenosine) is a major bioactive agent in Cordyceps militaris, a fungus used in traditional Chinese medicine. It has been proposed to have many beneficial metabolic effects by activating AMP-activated protein kinase (AMPK), but the mechanism of activation remained uncertain. We report that cordycepin enters cells via adenosine transporters and is converted by cellular metabolism into mono-, di-, and triphosphates, which at high cordycepin concentrations can almost replace cellular adenine nucleotides. AMPK activation by cordycepin in intact cells correlates with the content of cordycepin monophosphate and not other cordycepin or adenine nucleotides. Genetic knockout of AMPK sensitizes cells to the cytotoxic effects of cordycepin. In cell-free assays, cordycepin monophosphate mimics all three effects of AMP on AMPK, while activation in cells is blocked by a γ-subunit mutation that prevents activation by AMP. Thus, cordycepin is a pro-drug that activates AMPK by being converted by cellular metabolism into the AMP analog cordycepin monophosphate.
蛹虫草中的主要生物活性成分是虫草素（3'-脱氧腺苷），这是一种传统中药中使用的真菌。虫草素通过激活 AMP 激活的蛋白激酶（AMPK），被认为具有许多有益的代谢作用，但激活机制仍不清楚。我们的研究报告表明，虫草素通过腺苷转运蛋白进入细胞，并在细胞代谢过程中转化为单、二、三磷酸酯，在高浓度的虫草素条件下，这些磷酸酯几乎可以替代细胞内的腺嘌呤核苷酸。完整细胞中虫草素激活 AMPK 与虫草素单磷酸酯的含量相关，而与其他虫草素或腺嘌呤核苷酸无关。AMPK 的基因敲除使细胞对虫草素的细胞毒性作用更加敏感。在无细胞的测定中，虫草素单磷酸酯模拟了 AMP 对 AMPK 的所有三种作用，而细胞内的激活则被一种阻止 AMP 激活的γ亚基突变所阻断。因此，虫草素是一种前体药物，可通过细胞代谢转化为 AMP 类似物虫草素单磷酸酯来激活 AMPK。
