Lysine glutarylation is a protein posttranslational modification regulated by SIRT5

Minjia Tan, Chao Peng, Kristin A. Anderson, Peter Chhoy, Zhongyu Xie, Lunzhi Dai, Jeongsoon Park, Yue Chen, He Huang, Yi Zhang, Jennifer Ro, Gregory R. Wagner, Michelle F. Green, Andreas S. Madsen, Jessica Schmiesing, Brett S. Peterson, Guofeng Xu, Olga R. Ilkayeva, Michael J. Muehlbauer, Thomas BraulkeChris Mühlhausen, Donald S. Backos, Christian A. Olsen, Peter J. McGuire, Scott D. Pletcher, David B. Lombard, Matthew D. Hirschey, Yingming Zhao

Research output: Contribution to journalArticlepeer-review

512 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)605-617
Number of pages13
JournalCell Metabolism
Issue number4
StatePublished - Apr 1 2014

Bibliographical note

Funding Information:
We thank Leonard Guarente for the mouse SIRT5 antibody; we are grateful to Dr. Gozde Colak for critically reading this manuscript; we thank Ailan Guo and Cell Signaling Technology for helpful discussions. This work was supported by NIH grants GM105933, CA160036, and RR020839 (to Y.Z.); and GM101171 and CA177925 (to D.B.L.). Y.Z. is also supported by the Nancy and Leonard Florsheim Family Fund. M.T. is supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China (2012ZX09301001-007), Natural Science Foundation of China (31370814), and Shanghai Pujiang Program (13PJ1410300). M.D.H. and his laboratory are supported by the American Heart Association grants 12SDG8840004 and 12IRG9010008, The Edward Mallinckrodt Jr. Foundation, The Ellison Medical Foundation, the National Institutes of Health (AA022146 and AG045351), and the Duke O’Brien Center for Kidney Research (5P30DK096493-02); M.F.G. is supported by a postdoctoral fellowship from the NIH and NCI training grant to Duke University (CA059365-19). P.C. is supported by an NIH/NIGMS training grant to Duke University Pharmacological Sciences Training Program (5T32GM007105-40). J.S.P. was supported by NIH training grant (AG000114). C.A.O. and his laboratory are supported by the Danish Independent Research Council–Technology and Production Sciences (Sapere Aude grant number 12-132328; A.S.M.), the Danish Independent Research Council–Natural Sciences (Steno grant number 10-080907), the Villum Foundation, and the Carlsberg Foundation. C.A.O. is a Lundbeck Foundation Fellow. C.M. and J.S. are supported by the German Research Foundation (Deutsche Forschungsgemeinschaft grant MU1778/3-1). This work utilized the resources of the Drosophila Aging Core of the Nathan Shock Center of Excellence in the Biology of Aging (NIA, P30-AG-013283). Y.Z. is a shareholder and a member of the scientific advisory board of PTM BioLabs, Co., Ltd. (Chicago).


Dive into the research topics of 'Lysine glutarylation is a protein posttranslational modification regulated by SIRT5'. Together they form a unique fingerprint.

Cite this