Reactive Acyl-CoA Species Modify Proteins and Induce Carbon Stress

Abstract

In recent years, our understanding of the scope and diversity of protein post-translational modifications (PTMs) has rapidly expanded. In particular, mitochondrial proteins are decorated with an array of acyl groups that can occur non-enzymatically. Interestingly, these modifying chemical moieties are often associated with intermediary metabolites from core metabolic pathways. In this Review, we describe biochemical reactions and biological mechanisms that activate carbon metabolites for protein PTM. We explore the emerging links between the intrinsic reactivity of metabolites, non-enzymatic protein acylation, and possible signaling roles for this system. Finally, we propose a model of 'carbon stress', similar to oxidative stress, as an effective way to conceptualize the relationship between widespread protein acylation, nutrient sensing, and metabolic homeostasis.

Keywords: carbon stress; metabolism; oxidative stress; post-translational modifications; reactive acyl-CoA species; reactive oxygen species.

Fig. 1

Ancient reactive metabolites predicted to be biochemical precursors of modern biochemistry, including: 1,3-bisphosphoglycerate (1,3-BPG), Acetyl-phosphate (Acetyl-P), Acetyl-Sulfide, Adenosine Triphosphate, Carbamoyl-phosphate (Carbamoyl-P), Carbonyl-Sulfide, Carboxy-phosphate (Carboxy-P), Cyanide, Glucose-1-phosphate (Glucose-1P), Glucose-6-phosphate (Glucose-6P), Metal-Sulfide, Methyl-Sulfide, Phosphoenolpyruvate (PEP); stylized using standard Corey-Pauling-Koltun (CPK) coloring convention: black, carbon; red, oxygen; blue, nitrogen, yellow, sulfur; purple, phosphorus; gray, metal; thin lines, single bond; medium lines, double bond; thick line, triple bond; hydrogens omitted for clarity

Fig. 2

Modern reactive metabolites. A. Coenzyme A structure depicted using standard CPK coloring convention (see Fig. 1 for key), hydrogens omitted for clarity; B. Prototypical mechanism by which an acyl-CoA synthase enzyme activates fatty acids into fatty acyl-CoAs; C. Reactive acyl-CoA species known or predicted to modify proteins, with corresponding rates of spontaneous hydrolysis as one indicator of reactivity of each acyl group from CoA at room temperature [8].

Fig. 3

RACS and ROS could have similar signaling roles and damaging consequences. Protein oxidation is known to alter protein-protein interactions, inactive proteins, and in some settings, cause irreversible damage. Similarly, protein acylation can alter protein-protein interactions, reduce enzyme activity, cause protein damage, and modify proteins outside of the pathway where the acyl-species was generated. In each case, the system would be predicted to have an appropriate cellular response.