AMPK activators: mechanisms of action and physiological activities

Abstract

AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Thus, activators of AMPK may have potential as novel therapeutics for these diseases. In this review, we provide a comprehensive summary of both indirect and direct AMPK activators and their modes of action in relation to the structure of AMPK. We discuss the functional differences among isoform-specific AMPK complexes and their significance regarding the development of novel AMPK activators and the potential for combining different AMPK activators in the treatment of human disease.

Figure 1

Functional domains of AMP-activated protein kinase (AMPK) subunits. The mammalian α1/α2 and β1/β2 isoforms are very similar, and their characteristic features are shown. AMPKα subunits: KD, kinase domain containing Thr-172 for the activation by upstream kinases; AID, autoinhibitory domain; two α-RIM, regulatory subunit interacting motifs triggering the conformational changes in response to AMP binding to the AMPKγ subunit; α-CTD, C-terminal domain binding to the β-subunit. AMPKβ subunit: CBM, carbohydrate-binding module, in which Ser108 is important for the action of some direct AMPK activators, such as thienopyridone (A-769662) and salicylate; β-CTD, C-terminal domain containing α-subunit-binding site and immediately followed by the domain for γ-subunit interaction. AMPKγ subunit: three γ-subunit isoforms have variable N-terminal domains (NTDs); four CBS, cystathione-β-synthases domain, which forms two Bateman domains that create four adenosine nucleotide-binding sites (Sites 1–4). Site 2 appears to be always empty and Site 4 to have a tightly bound AMP, whereas Sites 1 and 3 represent the regulatory sites that bind AMP, ADP or ATP in competition.

Figure 2

A summary of the physiological roles of AMP-activated protein kinase (AMPK).