Title: A Key Motif in the Cholesterol-Dependent Cytolysins Reveals a Large Family of Related Proteins
Authors: Evans, JC
Johnstone, BA
Lawrence, SL
Morton, CJ
Christie, MP
Parker, MW
Tweten, RK
Issue Year: 2020
Series MBIO:
Abstract Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules(1). 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 beta-oxidation(2-6). Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) beta 1-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 alpha-subunit kinase domain and the beta-subunit. beta 1 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 beta 1-selective activators and promote LCFA oxidation.
URI: https://publications.svi.edu.au/publications/7043
Other Identifiers 10.1128/mBio.02351-20
Publication type Article