Journal
CHEMISTRY & BIOLOGY
Volume 15, Issue 11, Pages 1220-1230Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2008.10.005
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Funding
- Australian Research Council
- National Health and Medical Research Council
- Danish Research Council of Health and Diseases
- National Heart Foundation
- NHMRC Senior Research
- ARC Federation
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The AMP-activated protein kinase (AMPK) is an alpha beta gamma heterotrimer that plays a pivotal role in regulating cellular and whole-body metabolism. Activation of AMPK reverses many of the metabolic defects associated with obesity and type 2 diabetes, and therefore AMPK is considered a promising target for drugs to treat these diseases. Recently, the thienopyriclone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the beta subunit carbohydrate-binding module and residues from the gamma subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the 01 subunit. Our findings highlight the regulatory role played by the beta subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator.
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