Difference between revisions of "AMPK"

Revision as of 21:55, 16 April 2018

AMPK Protein Kinase AMP-Activated Ver. 0.1.

Structure

The structure with regulation sites is presented on Figure 1.

Figure [1]. Molecular regulation of AMPK and LKB1. (a) Modification of the AMPK α1 (top) and α2 (bottom) subunits by phosphorylation/dephosphorylation, ubiquitination, sumoylation and oxidation/reduction. Pathways marked in red indicate α1- or α2-subunit-specific modifications. Numbers of modified amino acids are based on human proteins, and numbers in parenthesis are those reported in the original research (see text for details). (b) Modification of the AMPK β1 (top) and β2 (bottom) subunits by myristoylation, ubiquitination, sumoylation and glycogen binding. Pathways marked in red indicate β1- or β2-subunit-specific modifications. (c) Modification of the AMPK γ-subunit by AMP, ADP or ATP binding. Binding of AMP to CBS1 induces allosteric activation, and binding of AMP or ADP to CBS3 induces T172 phosphorylation. (d) Modification and regulation of LKB1 by phosphorylation, acetylation, ubiquitination, sumoylation and 4HNE adduction. Arrow indicates activation, and bar-headed line indicates inhibition. α/γ-BD, α/γ-subunit-binding domain; AID, autoinhibitory domain; β-BD, β-subunit-binding domain; CBM, carbohydratebinding module; CBS, cystathionine beta-synthase domain; NLS, nuclear localization signal.

Action

AMPK, a fuel sensor and regulator, promotes ATP-producing and inhibits ATP-consuming pathways in various tissues. AMPK is exists as a heterotrimeric complex composed of a catalytic α subunit and regulatory β and γ subunits. The kinase is activated in response to stresses that deplete cellular ATP supplies such as low glucose, hypoxia, ischemia and heat shock. Binding of AMP to the γ subunit allosterically activates the complex, making it a more attractive substrate for its major upstream AMPK kinase, LKB1. As a cellular energy sensor responding to low ATP levels, AMPK activation positively regulates signaling pathways that replenish cellular ATP supplies. For example, activation of AMPK enhances both the transcription and translocation of GLUT4, resulting in an increase in insulin-stimulated glucose uptake. In addition, it also stimulates catabolic processes such as fatty acid oxidation and glycolysis via inhibition of ACC and activation of PFK2. AMPK negatively regulates several proteins central to ATP consuming processes such as TORC2, glycogen synthase, SREBP-1 and TSC2, resulting in the downregulation or inhibition of gluconeogenesis, glycogen, lipid and protein synthesis. Due to its role as a central regulator of both lipid and glucose metabolism, AMPK is considered to be a key therapeutic target for the treatment of obesity, type II diabetes mellitus, and cancer. The AMP-activated protein kinase (AMPK) has an important role in the regulation of cellular energy homeostasis. The enzyme is activated under conditions of low ATP, often caused by a variety of stresses and regulates signaling pathways that increase the supplies of ATP available. (http://www.sinobiological.com/ampk-signaling-pathwawy.html)

Kinetics

Pathways

In general, upstream pathways presented at Figure from [1].

In general, downstream pathways presented at Figure from [1].

AMPK Regulate Multiple Metabolic Processes in Cells.

Figure 3. Substrates of AMPK Regulate Multiple Metabolic Processes in Cells. AMPK is phosphorylated and activated by LKB1 and CAMKK2 in response to stimuli that increase AMP/ADP levels (energy stress) or Ca2+ flux, respectively. Once active, AMPK induces metabolic changes through the phosphorylation of substrates. Some of the best-established metabolic processes regulated by AMPK are shown, together with the relevant substrates [2].

Upstream

Downstream

Isoforms

AMPK is present in only three heterotrimers in human skeletal muscle: α1/β2/γ1, α2/β2/γ1 and α2/β2/γ3. The approximate distribution of the three AMPK heterotrimers can be estimated to be ∼15% α1/β2/γ1,∼65% α2/β2/γ1 and∼20% α2/β2/γ3 [3]. AMPK α2/β2/γ3 heterotrimer is predominantly activated during exercise in human skeletal muscle [3].

Figure [4]. Skeletal muscle AMPK expression and regulation. (a) Molecular regulation of AMPK activity. (b) AMPK expression in human quadriceps and rodent oxidative and glycolytic muscles and their tentative activation profiles during contraction/exercise.

Localisation

Within the individual muscle fibres, α2 AMPK has been reported in both the cytosol and nucleus, while α1 seems expressed exclusively in the cytosol [5].

Activity

AMPK activity associated with the α2/β2/γ3 heterotrimer was strongly correlated to γ3-associated α-Thr-172 AMPK phosphorylation (r2 =0.84, P <0.001) [3]. AMPK phosphorylation (Thr172) and AMPK activity in mammalian muscles are usually strongly positively related. For example, for rat muscle, see figure [6].

Activity regulation

Expression

PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKAA1)

PRKAA2 Protein Kinase AMP-Activated Catalytic Subunit Alpha 2 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKAA2)

PRKAB1 Protein Kinase AMP-Activated Non-Catalytic Subunit Beta 1 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKAB1)

PRKAB2 Protein Kinase AMP-Activated Non-Catalytic Subunit Beta 2 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKAB2)

PRKAG1 Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 1 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKAG1)

PRKAG2 Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKAG2)

PRKAG3 Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 3 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKAG3)

Diseases

References

1. He L, Zhou X, Huang N, Li H, Tian J, Li T, Yao K, Nyachoti CM, Kim SW, and Yin Y. AMPK Regulation of Glucose, Lipid and Protein Metabolism: Mechanisms and Nutritional Significance. Curr Protein Pept Sci. 2017;18(6):562-570. DOI:10.2174/1389203717666160627071125 | PubMed ID:27356941 | HubMed [1]
2. Garcia D and Shaw RJ. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol Cell. 2017 Jun 15;66(6):789-800. DOI:10.1016/j.molcel.2017.05.032 | PubMed ID:28622524 | HubMed [2]
3. Birk JB and Wojtaszewski JF. Predominant alpha2/beta2/gamma3 AMPK activation during exercise in human skeletal muscle. J Physiol. 2006 Dec 15;577(Pt 3):1021-32. DOI:10.1113/jphysiol.2006.120972 | PubMed ID:17038425 | HubMed [3]
4. Jensen TE, Wojtaszewski JF, and Richter EA. AMP-activated protein kinase in contraction regulation of skeletal muscle metabolism: necessary and/or sufficient?. Acta Physiol (Oxf). 2009 May;196(1):155-74. DOI:10.1111/j.1748-1716.2009.01979.x | PubMed ID:19243572 | HubMed [4]
5. Salt I, Celler JW, Hawley SA, Prescott A, Woods A, Carling D, and Hardie DG. AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem J. 1998 Aug 15;334 ( Pt 1)(Pt 1):177-87. DOI:10.1042/bj3340177 | PubMed ID:9693118 | HubMed [5]
6. Park SH, Gammon SR, Knippers JD, Paulsen SR, Rubink DS, and Winder WW. Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. J Appl Physiol (1985). 2002 Jun;92(6):2475-82. DOI:10.1152/japplphysiol.00071.2002 | PubMed ID:12015362 | HubMed [6]