A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.
Cell Metab
; 25(4): 823-837.e8, 2017 Apr 04.
Article
em En
| MEDLINE
| ID: mdl-28380375
ABSTRACT
The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive intermediates that non-enzymatically modify proteins. Based on this mechanism, we predicted, validated, and characterized a protein modification 3-hydroxy-3-methylglutaryl(HMG)-lysine. In a model of altered HMG-CoA metabolism, we found evidence of two additional protein modifications 3-methylglutaconyl(MGc)-lysine and 3-methylglutaryl(MG)-lysine. Using quantitative proteomics, we compared the "acylomes" of two reactive acyl-CoA species, namely HMG-CoA and glutaryl-CoA, which are generated in different pathways. We found proteins that are uniquely modified by each reactive metabolite, as well as common proteins and pathways. We identified the tricarboxylic acid cycle as a pathway commonly regulated by acylation and validated malate dehydrogenase as a key target. These data uncover a fundamental relationship between reactive acyl-CoA species and proteins and define a new regulatory paradigm in metabolism.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Acil Coenzima A
/
Proteínas
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cell Metab
Assunto da revista:
METABOLISMO
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos