Mechanism of Activation of AMPK by Cordycepin

Simon A. Hawley, Fiona A. Ross, Fiona M. Russell, Abdelmadjid Atrih, Douglas Lamont, D. Grahame Hardie (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Pages (from-to)214-222.e4
Number of pages14
JournalCell Chemical Biology
Volume27
Issue number2
Early online date27 Jan 2020
DOIs
Publication statusPublished - 20 Feb 2020

Keywords

  • 3′-deoxyadenosine
  • AMP-activated protein kinase
  • AMPK
  • cordycepin
  • mechanism
  • metabolism

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