TY - JOUR
T1 - Thienopyridone Drugs Are Selective Activators of AMP-Activated Protein Kinase β1-Containing Complexes
AU - Scott, John W.
AU - van Denderen, Bryce J.W.
AU - Jorgensen, Sebastian B.
AU - Honeyman, Jane E.
AU - Steinberg, Gregory R.
AU - Oakhill, Jonathan S.
AU - Iseli, Tristan J.
AU - Koay, Ann
AU - Gooley, Paul R.
AU - Stapleton, David
AU - Kemp, Bruce E.
N1 - Funding Information:
This study was supported by grants from the Australian Research Council (B.E.K.), National Health and Medical Research Council (B.E.K., G.R.S.), Danish Research Council of Health and Diseases (S.B.J.), and National Heart Foundation (B.E.K.). G.R.S. is an NHMRC Senior Research Fellow and B.E.K. is an ARC Federation Fellow.
PY - 2008/11/24
Y1 - 2008/11/24
N2 - The AMP-activated protein kinase (AMPK) is an αβγ 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 thienopyridone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the β subunit carbohydrate-binding module and residues from the γ subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the β1 subunit. Our findings highlight the regulatory role played by the β subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator.
AB - The AMP-activated protein kinase (AMPK) is an αβγ 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 thienopyridone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the β subunit carbohydrate-binding module and residues from the γ subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the β1 subunit. Our findings highlight the regulatory role played by the β subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator.
KW - CHEMBIO
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=56049112796&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2008.10.005
DO - 10.1016/j.chembiol.2008.10.005
M3 - Article
C2 - 19022182
AN - SCOPUS:56049112796
SN - 1074-5521
VL - 15
SP - 1220
EP - 1230
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 11
ER -