Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms
Journal article
Stephen L. Pinkosky, John Scott, Eric M. Desjardins, Brennan Smith, Emily A. Day, Rebecca J. Ford, Christopher G. Langendorf, Naomi Ling, Tracy L. Nero, Kim Loh, Sandra Galic, Ashfaqul Hoque, William Smiles, Kevin R. W. Ngoei, Michael W. Parker, Yan Yan, Karsten Melcher, Bruce Kemp, Jon Oakhill and Gregory R. Steinberg. (2020). Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nature Metabolism. 2(9), pp. 873-881. https://doi.org/10.1038/s42255-020-0245-2
Authors | Stephen L. Pinkosky, John Scott, Eric M. Desjardins, Brennan Smith, Emily A. Day, Rebecca J. Ford, Christopher G. Langendorf, Naomi Ling, Tracy L. Nero, Kim Loh, Sandra Galic, Ashfaqul Hoque, William Smiles, Kevin R. W. Ngoei, Michael W. Parker, Yan Yan, Karsten Melcher, Bruce Kemp, Jon Oakhill and Gregory R. Steinberg |
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Abstract | Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules1. LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation2,3,4,5,6. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1–containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. Thus, LCFA-CoA metabolites act as direct endogenous AMPK β1–selective activators and promote LCFA oxidation. |
Year | 2020 |
Journal | Nature Metabolism |
Journal citation | 2 (9), pp. 873-881 |
Publisher | Nature Publishing Group - Macmillan Publishers |
ISSN | 2522-5812 |
Digital Object Identifier (DOI) | https://doi.org/10.1038/s42255-020-0245-2 |
Scopus EID | 2-s2.0-85088600360 |
Publisher's version | File Access Level Controlled |
Publication process dates | |
Deposited | 19 Apr 2021 |
https://acuresearchbank.acu.edu.au/item/8vx46/long-chain-fatty-acyl-coa-esters-regulate-metabolism-via-allosteric-control-of-ampk-1-isoforms
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