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Wagner et al. Cell Metabolism, April 2017.

Mitochondria and Metabolism Journal Club (June 2017).

Presented by: Arianne Caudal, graduate PhD student in the Tian Lab.

Succinyl-CoA is an efficient acylating agent

Post-translational modifications to protein side chains can affect enzyme catalysis and protein-protein interactions. In this study, Wagner et al. illustrate that succinyl-CoA is a highly reactive metabolite that easily modifies lysines on Bovine Serum Albumin. More so, Succinyl-CoA out-competes other metabolites in a pH-independent manner as shown by Western Blot and LC-MS. It was determined by 1H-NMR that Succinyl-CoA undergoes intramolecular catalysis to form a highly reactive cyclic anhydride intermediate that allows for non-enzymatic modification to lysines.

HMG-CoA and Glutaryl-CoA are post-translational acylating agents

Using combinatorial approaches to profile succinyl-CoA, the authors demonstrate that HMG-CoA and Glutaryl-CoA – which also have 4 carbons and a carboxylic acid – undergo intramolecular catalysis to generate a high-energy intermediate which can modify proteins in a pH independent manner in vitro. To dissect the physiological importance of HMGylation in vivo, a mouse model of hydoxy-methylglutaryl-CoA lyase (HMGCL) deficiency was employed. In these mice, authors demonstrate that increased protein lysine HMGylation is a physiologically relevant occurance. Using a similar approach, authors also define a glutarylome in a glutaryl-CoA dehydrogenase (GCDH) knock out mouse. Using quantitative proteomics, authors reveal an interesting overlap between the mitochondrial HMGylome and glutarylome, hypothesizing that some pathways are susceptible to specific acyl modifications (lysine metabolism), while others (leucine degradation/ketogenesis) are commonly modified regardless of reactive acyl-CoA.

Acylation in TCA enzymes

The enzymes in the citric acid cycle are greatly affected by post-translational modification. Here, authors illustrate that these enzymes are also differentially HMGylated and glutarylated and this may affect flux through this pathway. Specifically, HMGylation at malate dehydrogenase (MDH2) at K296 and K335 result in decreased activity in vitro. These novel findings shed light on the intricacies of post-translational modifications, as MDH2 is also known to be acetylated. It appears that lysine modifications may converge in vivo to play regulatory roles. The convergence of these lysine modifications on enzymes raises many questions. Are certain modifications playing a larger regulatory role than others? Under which cellular conditions does differential modification occur? Are modifications necessary for function? Which deacylase is responsible for removal of these modifications?