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J. Biol. Chem., Vol. 282, Issue 45, 32539-32548, November 9, 2007

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Defining the Mechanism of Activation of AMP-activated Protein Kinase by the Small Molecule A-769662, a Member of the Thienopyridone Family^*

Matthew J. Sanders¹, Zahabia S. Ali², Bronwyn D. Hegarty³, Richard Heath⁴, Michael A. Snowden, and David Carling⁵

From the Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Imperial College, DuCane Road, London W12 0NN and Screening and Compound Profiling, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, United Kingdom

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 Thr-172, similar to the effects of AMP. A-769662 activates AMPK harboring a mutation in the subunit that abolishes activation by AMP. An AMPK complex lacking the glycogen binding domain of the subunit abolishes the allosteric effect of A-769662 but not the allosteric activation by AMP. Moreover, mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the 1 subunit, almost completely abolishes activation of AMPK by A-769662 in cells and in vitro, while 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.

Received for publication, August 7, 2007 , and in revised form, August 29, 2007.

^* This work was supported in part by the Medical Research Council UK and the European Commission Grants LSHM-CT-2004-005272 and LSH-CT-2005-518181. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Biotechnology and Biological Sciences Research Council-Collaborative Awards in Science and Engineering Ph.D. studentship.

² Recipient of a Medical Research Council Ph.D. studentship.

³ Present address: Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, New South Wales 2021, Australia.

⁴ Present address: Medical Research Council National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

⁵ To whom correspondence should be addressed. Tel.: 44-2083834313; Fax: 44-2083838514; E-mail: dcarling{at}csc.mrc.ac.uk.

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