atio and activate the pathway. AMPK activation by AMP is not completely understood; the current model states that binding of AMP to the gamma subunit leads to conformational changes that allosterically activate AMPK and render phosphorylated-Thr172 unavailable for inhibitory dephosphorylation. ATP antagonizes the effect of AMP; both AMP and ATP bind in a mutually exclusive manner to the Bateman (CBS) domains of the gamma subunit. There are four tandem repeats of CBS number 1-4; site 2 is empty, site 4 has a bound AMP molecule, sites 1 and 3 are the regulatory sites that competitively bind AMP, ADP or ATP. Binding of AMP to site 1 is believed to confer allosteric activation while binding of AMP or ADP to site 3 is thought to protect threonine 172 from dephosphorylation. The upstream kinase, known as Lkb1, is a complex of one catalytic and two regulatory subunits; Lkb1 is believed to be 'constitutively active'. In certain cell types, Thr172 can be phosphorylated by calmodulin-dependent protein kinase kinases (CAmKK), in turn activated by calcium/calmodulin. A well known role of AMPK is in the regulation of lipid metabolism; it stimulates fatty acids oxidation and inhibits their synthesis. Phosphorylation by AMPK inhibits acetyl-CoA carboxylase (ACC) and results in reduced levels of malonyl-CoA product. Malonyl CoA is a substrate in the de novo synthesis of fatty acids and fatty acids elongation. Importantly, it is also an inhibitor of the carnitine palmitoyl transferase I, required for the transfer of primed cytosolic fatty acids into the mitochondrion where they can undergo degradative beta-oxidation. AMPK inhibits mTOR signaling pathway by activating Tsc2 and downstream of Tsc2 by inhibiting Raptor component of mTOR complex 1 [note that this effect is opposite to Tsc2 phosphorylation and inactivation by PI3K-Akt signaling downstream of insulin]. AMPK is also involved in promoting glucose uptake and utilization and integrates adipokynes and hormonal signals in both the hypothalamus and the periphery with potential impact on energy expenditure. A target of AMPK is TBC1D1, a protein related to TBC1D4, the Rab protein GAP involved in glucose uptake in insulin sensitive tissues. Rabs are small monomeric G-proteins involved in vesicular transport; they are activated by GTP exchange factors (GEFs) and inactivated by GTPase activator proteins (GAPs). Due to its roles in fuel regulation, the AMPK pathway is regarded as a potential therapeutic target for Diabetes Mellitus type 2 (T2D), obesity and metabolic syndrome. Drugs used in the treatment of insulin resistance and diabetes can activate AMPK. For instance, metformin - an antihyperglycemic drug used in the first-line treatment of T2D activates AMPK signaling, albeit indirectly. The primary target of metformin is the complex I of the respiratory chain; lowering of the proton gradient and reduction of the proton-driven synthesis of ATP will lead to a change in the AMP:ATP ratio.To see the ontology report for Gviewer, annotations and download, click here ...(less)