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

Publication date: 4 April 2017
Source:Cell Metabolism, Volume 25, Issue 4
Author(s): Gregory R. Wagner, Dhaval P. Bhatt, Thomas M. O'Connell, J. Will Thompson, Laura G. Dubois, Donald S. Backos, Hao Yang, Grant A. Mitchell, Olga R. Ilkayeva, Robert D. Stevens, Paul A. Grimsrud, Matthew D. Hirschey
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.

Graphical abstract

Teaser

Wagner et al. discover a class of negatively charged acyl-CoA species that are highly reactive metabolites capable of non-enzymatic acylation on a wide range of proteins. They identify the TCA cycle as a pathway commonly regulated by acylation and validate malate dehydrogenase as a key target.


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