Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK ß1 isoforms.
Nat Metab
; 2(9): 873-881, 2020 09.
Article
em En
| MEDLINE
| ID: mdl-32719536
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 ß-oxidation2-6. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) ß1-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 ß-subunit. ß1 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 ß1-selective activators and promote LCFA oxidation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acil Coenzima A
/
Regulação Alostérica
/
Proteínas Quinases Ativadas por AMP
Limite:
Animals
Idioma:
En
Revista:
Nat Metab
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Canadá