The Structure and Regulation of AMPK:

AMPK contains three subunits: a, b, and g. The g subunit is variable. The a subunit is responsible for the catalytic activity of the protein - transferring a phosphate from ATP to another protein to activate or inactivate it. The g and b subunits are important for regulation of the protein - AMPK is allosterically activated by AMP, and inhibited by creatine phosphate. AMPK is generally active in a low energy environment and inactive in a high energy environment. Shown to the right is a cartoon figure of the structure of AMPK. The a and g subunits are joined by AMP, and Threonine 172 is phosphorylated when the enzyme is active. Muscle contraction (exercise) has also been shown to increase AMPK activity.

The Function and Regulation of Acetyl CoA Carboxylase:

ACC catalyzes the conversion of acetyl CoA to malonyl CoA for fatty acid biosynthesis. This enzyme is allosterically activated by citrate (and intermediate of the TCA cycle), and inactivated when phosphorylated. This enzyme can be phosphorylated by AMPK in muscle (it can also be phosphorylated by cAMP dependent protein kinase in other areas of the body).  It is interesting to note that ACC has only been known previously as an enzyme that is involved in fatty acid biosynthesis.  Why then is it present in muscle, where fatty acids aren't usually synthesized?  It could be because ACC is needed for this pathway, to regulate the oxidation of fats as well.

Integration of Activities and another Possible Role for AMPK:

Shown in the figure to the left is a summary of the relationship between ACC, AMPK, and Malonyl CoA: Active AMPK phosphorylates ACC and inactivates it. Thus the equilibrium between Malonyl CoA and Acetyl CoA is shifted toward the top of the figure. Interestingly, it is hypothesized that AMPK may play yet another role in control of fatty acid oxidation. Malonyl CoA decarboxylase (MCD) is responsible for degrading Malonyl CoA to Acetyl CoA. It is possible that AMPK is responsible for phosphorylating MCD, and thus even further reducing the concentration of Malonyl CoA in the cytoplasm. To read more about this, take a trip on this link, or head over to reference 3.

Results That Support the Role of AMPK in this Pathway:

Figure 12: An a-subunit that is catalytically inactive was used to block the activity of AMPK (Ad-DN). Without AMPK activity, Leptin is inable to produce (indirectly) phospho-ACC, as compared to the large amount of phospho-ACC produced with the addition of leptin to Ad-Null (full AMPK activity). This indicates that AMPK is the key mediator of the pathway.