SIMM Identifies Novel Protein Post-translational Modification in Metabolic Disease

Jul 18, 2014     Email"> PrintText Size

Targeting PTM pathways is a hot and promising therapeutic approach in new drug development. Recently, a novel protein post-translational modification, lysine glutarylation (Kglu), was first discovered by the international collaboration works led by scientists from SIMM, University of Chicago and Duke University. This study provided a new potential strategy for the treatment of metabolic diseases. 

Glutaric acidemia type I disease is a genetic deficient disease. Currently, there is no effective treatment and specific drugs due to the limited understanding of relevant molecular mechanism. In this study, researchers identified the Kglu as a new type of protein modification in vivo and confirmed Kglu is ubiquitous, widely presented in living organisms.  

This article also demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase and majority of lysine glutarylated proteins are related to diverse metabolic pathways, such as metabolic enzymes and mitochondrial proteins. Particularly, this study identified carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and revealed that CPS1 is a substrate of SIRT5 for deglutarylation. Further study suggested that Kglu was significantly increased in liver mitochondria of mouse with glutaric academia compared to normal mouse. 

This study provided novel insight of the mechanism of glutaric acidemia type I disease and implied SIRT5 as a novel intervention target of this metabolic disease. This research has been published as an article in Cell Metabolism (2014, 19, 605–617).