Regulation of lipid metabolism by the AMP-activated protein kinase.

The AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade which plays an important role in the regulation of many different aspects of lipid metabolism [1,2]. AMPK is activated 50to 100-fold by phosphorylation by an upstream protein kinase, AMPK kinase (AMPKK) [3]. The key regulators of the AMPK cascade currently appear to be S’-AMP and ATP. AMP activates the system through no less than four mechanisms [4-61: (1) direct allosteric activation (up to 5-fold); (2) binding to AMPK, making it a better substrate for AMPKK; (3) binding to AMPK, making it a worse substrate for the inactivating phosphatase, protein phosphatase-2C; and (4) allosteric activation of AMPKK. High levels of ATP antagonize effects (1) and (3) of AMP [4,6], and also antagonize the effect of AMP on phosphorylation of AMPK by AMPKK [3], although in this case it is not yet clear whether the effect is to oppose mechanism (2) or (4), or both. Multiple isoforms of AMPK have been identified