Targeting AMPK: From Ancient Drugs to New Small-Molecule Activators.
The AMP-activated protein kinase (AMPK) is an evolutionary conserved and ubiquitously expressed serine/threonine kinase mainly acting as a key regulator of cellular energy homeostasis. AMPK is a heterotrimeric protein complex, consisting of a catalytic α subunit and two regulatory β and γ subunits, whose activity is tightly regulated by changes in adenine nucleotides and several posttranslational modifications. Once activated in response to energy deficit, AMPK concomitantly inhibits ATP-consuming anabolic processes and promotes ATP-generating catabolic pathways via direct phosphorylation of multiple downstream effectors, leading to restoration of cellular energy balance. A growing number of energy/nutrient-independent functions of AMPK are also regularly reported, progressively expanding its role to regulation of non-metabolic cellular processes. Historically, AMPK as a therapeutic target has attracted much of interest due to its potential impact on metabolic disorders, such as obesity and type 2 diabetes, but has also recently received considerable renewed attention in the framework of cancer studies, highlighting the persistent need for selective, reversible, potent, and tissue-specific activators. In this chapter, we review the most recent advances in the understanding of the mechanism(s) of action of the current portfolio of AMPK activators, including plant-derived natural compounds and newly discovered small-molecule agonists directly targeting various AMPK subunits.
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. b.g.a.guigas@lumc.nl.|Department of Parasitology, Leiden University Medical Center, 9600, Postzone L40-Q, 2300 RC, Leiden, The Netherlands. b.g.a.guigas@lumc.nl.
Bruno
B
Guigas
INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
Benoit
B
Viollet
D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D020156:Salicylic Acid / Q000627:therapeutic use; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000627:therapeutic use; D013267:Stilbenes / Q000627:therapeutic use
D007004:Hypoglycemic Agents; D021122:Protein Subunits; D054852:Small Molecule Libraries; D013267:Stilbenes; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D020156:Salicylic Acid; D000077185:Resveratrol
991; A-769662; AMPK; Compound-13; Metformin; Salicylate