International Journal of Molecular Sciences Review Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds Fabiola Marín-Aguilar 1, Luis E. Pavillard 1, Francesca Giampieri 2, Pedro Bullón 1 and Mario D. Cordero 1,* 1 Research Laboratory, Oral Medicine Department, University of Sevilla, Sevilla 41009, Spain; [email protected] (F.M.-A.); [email protected] (L.E.P.); [email protected] (P.B.) 2 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche—Sez. Biochimica, Università Politecnica delle Marche, Ancona 60100, Italy; [email protected] * Correspondence: [email protected]; Tel.: +34-954-481-120; Fax: +34-954-486-784 Academic Editor: Rosa M. Lamuela-Raventós Received: 17 November 2016; Accepted: 23 January 2017; Published: 29 January 2017 Abstract: Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor which is activated by increases in adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio and/or adenosine diphosphate (ADP)/ATP ratio, and increases different metabolic pathways such as fatty acid oxidation, glucose transport and mitochondrial biogenesis. In this sense, AMPK maintains cellular energy homeostasis by induction of catabolism and inhibition of ATP-consuming biosynthetic pathways to preserve ATP levels. Several studies indicate a reduction of AMPK sensitivity to cellular stress during aging and this could impair the downstream signaling and the maintenance of the cellular energy balance and the stress resistance. However, several diseases have been related with an AMPK dysfunction. Alterations in AMPK signaling decrease mitochondrial biogenesis, increase cellular stress and induce inflammation, which are typical events of the aging process and have been associated to several pathological processes. In this sense, in the last few years AMPK has been identified as a very interesting target and different nutraceutical compounds are being studied for an interesting potential effect on AMPK induction. In this review, we will evaluate the interaction of the different nutraceutical compounds to induce the AMPK phosphorylation and the applications in diseases such as cancer, type II diabetes, neurodegenerative diseases or cardiovascular diseases. Keywords: adenosine monophosphate-activated protein kinase (AMPK); nutraceutical compounds; cancer; type II diabetes; neurodegenerative diseases; cardiovascular diseases 1. Introduction Adenosine monophosphate-activated protein kinase (AMPK), is a heterotrimeric protein kinase consisting of an alpha (α) catalytic subunit in combination with scaffolding beta (β) and regulatory gamma (γ) subunits (Figure1). These subunits, encoded by seven genes: Protein Kinase AMP-Activated Catalytic Subunit α1 (PRKAA1), Protein Kinase AMP-Activated Catalytic Subunit α2 (PRKAA2), Protein Kinase AMP-Activated Non-Catalytic Subunit β1 (PRKAB1), Protein Kinase AMP-Activated Non-Catalytic Subunit β2 (PRKAB2), Protein Kinase AMP-Activated Non-Catalytic Subunit γ1 (PRKAG1), Protein Kinase AMP-Activated Non-Catalytic Subunit γ2 (PRKAG2), Protein Kinase AMP-Activated Non-Catalytic Subunit γ3 (PRKAG3) can theoretically combine to form twelve different possible isoforms that may differ in tissue-specific expression and activation. AMPK is known as the fuel of the cell, working to ensure that adenosine triphosphate (ATP) levels are maintained under energetic stress situations such as exercise, starvation, hypoxia or rapid cell growth [1]. Int. J. Mol. Sci. 2017, 18, 288; doi:10.3390/ijms18020288 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 288 2 of 24 Int. J. Mol. Sci. 2017, 18, 288 2 of 24 The co-expression of the three different subunits (α,, β, and γ) of AMPK is absolutely necessary to generate a a functionally functionally active active protein. protein. The The ββ-subunit-subunit is isthe the smallest smallest am amongong the the three three and and serves serves as asa scaffold a scaffold for for anchoring anchoring α αandand γγ-subunits-subunits by by its its C-terminal C-terminal module, module, conforming conforming the the “AMPK regulatory core”. The carbohydrate-bindingcarbohydrate-binding module (CBM) of the β-subunits sits above the protein kinase module of the α-subunit. The The interface interface between between both both creates creates a a novel allosteric binding site, recently described as the “ADaM" (allosteric drug and metabolite) site, binding some of the known synthetic AMPK activators [[1].1]. The The catalytic catalytic domain domain on on the α-subunit (Thr172) is followed by an auto-inhibitory domaindomain (AID) (AID) and and regulatory regulatory interacting interacting motifs motifs (α-RIMS), (α-RIMS), which are which flexible are regulatory flexible segmentsregulatory triggering segments conformational triggering conformational changes in response changes to in adenosine response monophosphate to adenosine monophosphate (AMP) binding to(AMP) the AMPK bindingγ-subunit. to the AMPKγ-subunits γ-subunit. contain γ-subunits four tandem contain cystathionine four tandemβ synthase cystathionine domains β synthase (CBS´s), whichdomains are (CBS´s), known which as bateman are known domains. as batemanγ1, γ2 and domains.γ3 contain γ1, γ four2 and potential γ3 contain nucleotide four potential binding nucleotide binding sites, mainly CBS1 and CBS3, known to bind AMP, adenosine diphosphate sites, mainly CBS1 and CBS3, known to bind AMP, adenosine diphosphate (ADP) or ATP, inducing a (ADP) or ATP, inducing a conformational switch that allosterically activates AMPK as well as conformational switch that allosterically activates AMPK as well as protecting pTr172 in α- subunits protecting pTr172 in α- subunits from dephophosrylation by phosphatases [2]. from dephophosrylation by phosphatases [2]. Thr-172 P N Catalytic domain AID β-binding C AMPKα subunits: α-1, α-2 domain α-RIM Ser-108 P N Glycogen interacting α-γ binding domain C AMPKβ subunits: β-1, β-2 domain ATP/ADP/AMP AMPKγ subunits: γ1, γ2, γ3 Site 1 Site 2 Site 3 Site 4 β-binding N CBS1 CBS2 CBS3 CBS4 C γ-1 domain N β-binding CBS1 CBS2 CBS3 CBS4 C γ-2 domain N β-binding CBS1 CBS2 CBS3 CBS4 C γ-3 domain Figure 1. Diagram of the adenosine monophosphate-activated protein kinase (AMPK) domain structure. Figure 1. Diagram of the adenosine monophosphate-activated protein kinase (AMPK) domain Two α subunits, two β and three γ subunits have been described to date. The α-subunit is conformed structure. Two α subunits, two β and three γ subunits have been described to date. The α-subunit is by a catalytic domain containing Thr172 kinase for the activation by upstream kinases, Liver Kinase conformed by a catalytic domain containing Thr172 kinase for the activation by upstream kinases, B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKb), an auto-inhibitory Liver Kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKb), an domain (AID), two regulatory interacting motifs (α-RIMs), and a C-terminal domain that firmly binds to auto-inhibitory domain (AID), two regulatory interacting motifs (α-RIMs), and a C-terminal domain β and γ subunits. The β-subunit contains a N-terminal domain rich in glycine, a carbohydrate binding that firmly binds to β and γ subunits. The β-subunit contains a N-terminal domain rich in glycine, a module (CBM) containing Ser108, important for some direct activators of AMPK, and a C-terminal carbohydrate binding module (CBM) containing Ser108, important for some direct activators of domain that attaches to α and γ subunits. The γ-subunit consist of three γ isoforms and variable length AMPK, and a C-terminal domain that attaches to α and γ subunits. The γ-subunit consist of three γ N-terminal domains and four cystathionine β-synthase domains (CBS) forming bateman domains isoforms and variable length N-terminal domains and four cystathionine β-synthase domains (CBS) that create adenosine monophosphate (AMP)/ adenosine diphosphate (ADP)/adenosine triphosphate forming bateman domains that create adenosine monophosphate (AMP)/ adenosine diphosphate (ATP) binding sites. All amino acid numbers refer to human AMPK sequences. (ADP)/adenosine triphosphate (ATP) binding sites. All amino acid numbers refer to human AMPK sequences. 1.1. Mechanism of AMPK Activation 1.1. MechanismAs discussed of AMPK above, Activation AMPK is regulated both allosterically and by post-translational modifications. ThereAs are discussed different well-definedabove, AMPK mechanisms is regulated of AMPKboth activationallosterically by whichand by several post-translational small drugs havemodifications. been developed There are to inducedifferent AMPK well-defined phosphorylation. mechanisms The of AMPK direct phosphorylationactivation by which at a several kinase α site,small fordrugs example, have been Thr172 developed of the to -subunitinduce AMPK by upstream phosphorylation. kinases LiverThe direct Kinase phosphorylation B1 (LKB1) and at 2+ β β Caa kinase/calmodulin-dependent site, for example, Thr172 protein of kinase-the α-subunit(CaMKKb) by upstream or, Ser108 kinases of the Liver-subunit, Kinase is theB1 (LKB1) mechanism and Ca2+/calmodulin-dependent protein kinase-β (CaMKKb) or, Ser108 of the β-subunit, is the Int. J. Mol. Sci. 2017, 18, 288 3 of 24 used by salicylate and A769662. Another small-molecule allosteric activator of AMPK is compound 2, C2 (5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid). It is thought that C2 activates both AMPK α1 and α2 isoforms by binding to the γ-subunit. This is