Structure and Regulation of AMPK.
AMP-activated protein kinase is a family of heterotrimeric serine/threonine protein kinases that come in twelve different flavors. They serve an essential function in all eukaryotes of conserving cellular energy levels. AMPK complexes are regulated by changes in cellular AMP:ATP or ADP:ATP ratios and by a number of neutraceuticals and some of the widely-used diabetes medications such as metformin and thiazolinonediones. Moreover, biochemical activities of AMPK are tightly regulated by phosphorylation or dephosphorylation by upstream kinases and phosphatases respectively. Efforts are underway in many pharmaceutical companies to discover direct AMPK activators for the treatment of cardiovascular and metabolic diseases such as diabetes, non-alcoholic steatohepatitis (NASH) and diabetic nephropathy. Many advances have been made in the AMPK structural biology arena over the last few years that are beginning to provide detailed molecular insights into the overall topology of these fascinating enzymes and how binding of small molecules elicit subtle conformational changes leading to their activation and protection from dephosphorylation. In the brief review below on AMPK structure and function, we have focused on the recent crystallographic results especially on specific molecular interactions of direct synthetic AMPK activators which lead to biased activation of a sub-family of AMPK isoforms.
Pfizer Worldwide Research and Development, Pfizer Inc, Eastern Point Road, Groton, CT, 06340, USA. ravi.g.kurumbail@pfizer.com.
Ravi G
RG
Kurumbail
Pfizer Worldwide Research and Development, Pfizer Inc, Eastern Point Road, Groton, CT, 06340, USA.
Matthew F
MF
Calabrese
D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000737:chemistry / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D007004:Hypoglycemic Agents; D021122:Protein Subunits; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases
AMPK; Allostery; Crystallography; Enzyme activators; X-ray