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Chem Biol. 2014 May 22;21(5):619-27. doi: 10.1016/j.chembiol.2014.03.006. Epub 2014 Apr 17.

Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling.

Author information

1
Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia. Electronic address: jscott@svi.edu.au.
2
Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia.
3
Divisions of Endocrinology and Metabolism, Department of Medicine, and Division of Biochemistry and Biomedical Sciences, Department of Pediatrics, McMaster University, 1200 Main Street W., Hamilton, ON L8N 3Z5, Canada.
4
Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy VIC 3065, Australia. Electronic address: joakhill@svi.edu.au.

Abstract

The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis, making it a therapeutic target for metabolic diseases such as type 2 diabetes and obesity. AMPK signaling is triggered by phosphorylation on the AMPK α subunit activation loop Thr172 by upstream kinases. Dephosphorylated, naive AMPK is thought to be catalytically inactive and insensitive to allosteric regulation by AMP and direct AMPK-activating drugs such as A-769662. Here we show that A-769662 activates AMPK independently of α-Thr172 phosphorylation, provided β-Ser108 is phosphorylated. Although neither A-769662 nor AMP individually stimulate the activity of dephosphorylated AMPK, together they stimulate >1,000-fold, bypassing the requirement for β-Ser108 phosphorylation. Consequently A-769662 and AMP together activate naive AMPK entirely allosterically and independently of upstream kinase signaling. These findings have important implications for development of AMPK-targeting therapeutics and point to possible combinatorial therapeutic strategies based on AMP and AMPK drugs.

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PMID:
24746562
DOI:
10.1016/j.chembiol.2014.03.006
[Indexed for MEDLINE]
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