Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family

doi:10.1074/jbc.M706543200

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Papers In Press, published online ahead of print August 29, 2007
J. Biol. Chem, 10.1074/jbc.M706543200
Submitted on August 7, 2007
Revised on August 29, 2007
Accepted on August 29, 2007

Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family

Matthew J. Sanders, Zahabia S. Ali, Bronwyn D. Hegarty, Richard Heath, Michael A. Snowden, and David Carling

Cellular Stress Group, MRC Clinical Sciences Centre, London W12 0NN

Corresponding Author: dcarling{at}csc.mrc.ac.uk

AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis. Activation of AMPK in peripheral tissues has been shown to alleviate the symptoms of metabolic diseases, such as type 2 diabetes, and consequently AMPK is a target for treatment of these diseases. Recently, a small molecule activator (A-769662) of AMPK was identified that had beneficial effects on metabolism in ob/ob mice. Here we show that A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on threonine 172 (T172), similar to the effects of AMP. A-769662 activates AMPK harbouring a mutation in the subunit that abolishes activation by AMP. An AMPK complex lacking the glycogen binding domain of the ß subunit abolishes the allosteric effect of A-769662, but not allosteric activation by AMP. Moreover, mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the ß1 subunit, almost completely abolishes activation of AMPK by A-769662 in cells and in vitro, whilst only partially reducing activation by AMP. Based on our results we propose a model for activation of AMPK by A-769662. Importantly, this model may provide clues for understanding the mechanism by which AMP leads to activation of AMPK, which in turn may help in the identification of other AMPK activators.

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