A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wagner, GR; Bhatt, DP; O'Connell, TM; Thompson, JW; Dubois, LG; Backos, DS; Yang, H; Mitchell, GA; Ilkayeva, OR; Stevens, RD; Grimsrud, PA; Hirschey, MD

Published Date

  • April 4, 2017

Published In

Volume / Issue

  • 25 / 4

Start / End Page

  • 823 - 837.e8

PubMed ID

  • 28380375

Pubmed Central ID

  • PMC5399522

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2017.03.006


  • eng

Conference Location

  • United States