AMP-activated protein kinase beta-1-containing heterotrimer (AMPK beta-1) (AMPK beta-1)

AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme complex that serves as a central regulator of cellular energy homeostasis [1][2]. The beta-1-containing heterotrimer, characterized by the presence of the PRKAB1 subunit, is primarily expressed in the liver and plays a crucial role in modulating hepatic lipid and glucose metabolism [1][3]. Activation of this specific isoform promotes fatty acid oxidation and inhibits de novo lipogenesis by phosphorylating targets such as acetyl-CoA carboxylase (ACC) [2][4]. This makes the AMPK beta-1 heterotrimer a significant therapeutic target for metabolic diseases, including type 2 diabetes and non-alcoholic steatohepatitis (NASH) [5]. By specifically targeting the beta-1 subunit, drug developers aim to avoid the cardiac hypertrophy associated with the activation of the beta-2 subunit found in heart and skeletal muscle [4][5]. Small molecule activators like PXL770 and PF-06409577 bind to the allosteric drug and metabolite (ADaM) site to enhance the enzyme's activity [4][5]. Consequently, the AMPK beta-1-containing heterotrimer represents a precision medicine approach to treating systemic metabolic dysfunction while minimizing off-target tissue effects [2][5]. Sources: [1] UniProt Consortium. "PRKAB1 - 5'-AMP-activated protein kinase subunit beta-1." UniProtKB - Q9Y478. [2] Hardie, D. G., et al. "AMPK: a nutrient and energy sensor that maintains energy homeostasis." Nature Reviews Molecular Cell Biology (2012). [3] Cool, B., et al. "Identification and characterization of a small molecule AMPK activator that treats steatosis and insulin resistance in obese rodents." Cell Metabolism (2006). [4] Cameron, K. O., et al. "Discovery and Preclinical Characterization of PF-06409577: A Potent and Selective beta-1-Containing AMPK Activator." Journal of Medicinal Chemistry (2016). [5] Bolze, S., et al. "PXL770, a first-in-class direct adenosine monophosphate-activated protein kinase activator, for the treatment of non-alcoholic steatohepatitis." Journal of Hepatology (2019).

Other names

PRKAB1-containing AMPK complexAMPK beta-15'-AMP-activated protein kinase subunit beta-1 heterotrimerAMPK subunit beta-1AMP-activated protein kinase beta-1

Direct allosteric activation by binding to the Allosteric Drug and Metabolite (ADaM) site located at the interface of the alpha-kinase domain and the beta-subunit carbohydrate-binding module, which also protects the complex from dephosphorylation at the Thr172 activation site [2][4].