赖氨酸谷氨酰化是 SIRT5 调控的新型蛋白翻译后修饰

We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (K-glu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191 proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and increases our understanding of the deacylase SIRT5.

Tan, MJ et al. (2014). Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5. CELL METABOLISM. doi:10.1016/j.cmet.2014.03.014