A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Sunday, February 2, 2020
Cyclization Reaction-Based Turn-on Probe for Covalent Labeling of Target Proteins
Simon A. Hawley, Fiona A. Ross, Fiona M. Russell, Abdelmadjid Atrih, Douglas J. Lamont, D. Grahame Hardie
Cell Chem. Biol. 2020
DOI: https://doi.org/10.1016/j.chembiol.2020.01.006
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.
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Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation
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Guanghui Tang , Wei Wang , Chengjun Zhu , Huisi Huang , Peng Chen , Xuan Wang , Manyi Xu , Jie Sun , Chong-Jing Zhang , Qicai Xiao ...