MAMMALIAN AMP-ACTIVATED PROTEIN-KINASE SHARES STRUCTURAL AND FUNCTIONAL HOMOLOGY WITH THE CATALYTIC DOMAIN OF YEAST SNF1 PROTEIN-KINASE

The AMP-activated protein kinase is responsible for the regulation of fatty acid synthesis by phosphorylation of acetyl-CoA carboxylase. It may also regulate cholesterol synthesis via phosphorylation and inacti vation of hormone-sensitive lipase and hydroxymethylglutaryl-CoA reduc tase. We have purified the AMP-activated protein kinase 14,000-fold fr om porcine liver. The 63-kDa catalytic subunit co-purifies with two pr oteins of 40 and 38 kDa that may function as subunits. Partial amino a cid sequence of the 63-kDa subunit revealed a striking homology with t he catalytic domain of the yeast protein kinase transcriptional regula tor Snf1 and its plant homologs. The Snf1 (72 kDa) and Snf4 (36 kDa) c omplex was also purified and found to phosphorylate the AMP-activated protein kinase peptide substrate, HMRSAMSGLHLVKRR-amide, but was not a ctivated by AMP. Both Snf1/4 and the AMP-activated protein kinase phos phorylate and inactivate yeast acetyl-CoA carboxylase in vitro. These results indicate that during evolution the catalytic domain sequences of the Snf1 protein kinase subfamily have been exploited in the contro l of mammalian lipid metabolism and raise the possibilities that the A MP-activated protein kinase may have other substrates involved in regu lating gene expression pathways, as well as Snf1 homologs participatin g in the control of lipid metabolism in many eukaryotic organisms.