2. Academic Validation
  3. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5

Lysine glutarylation is a protein posttranslational modification regulated by SIRT5

  • Cell Metab. 2014 Apr 1;19(4):605-17. doi: 10.1016/j.cmet.2014.03.014.
Minjia Tan 1,  Chao Peng 2,  Kristin A Anderson 3,  Peter Chhoy 3,  Zhongyu Xie 2,  Lunzhi Dai 2,  Jeongsoon Park 4,  Yue Chen 2,  He Huang 2,  Yi Zhang 1,  Jennifer Ro 5,  Gregory R Wagner 3,  Michelle F Green 3,  Andreas S Madsen 6,  Jessica Schmiesing 7,  Brett S Peterson 3,  Guofeng Xu 2,  Olga R Ilkayeva 3,  Michael J Muehlbauer 3,  Thomas Braulke 7,  Chris Mühlhausen 7,  Donald S Backos 8,  Christian A Olsen 6,  Peter J McGuire 9,  Scott D Pletcher 5,  David B Lombard 4,  Matthew D Hirschey 10,  Yingming Zhao 11
Affiliations

Affiliations

  • 1 The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
  • 2 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
  • 3 Sarah W. Stedman Nutrition and Metabolism Center and Department of Medicine, Duke University Medical Center, Durham, NC 27704, USA.
  • 4 Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5 Department of Molecular and Integrative Physiology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6 Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800 Kongens Lyngby, Denmark.
  • 7 Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 8 Computational Chemistry and Biology Core Facility, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 9 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 10 Sarah W. Stedman Nutrition and Metabolism Center and Department of Medicine, Duke University Medical Center, Durham, NC 27704, USA. Electronic address: matthew.hirschey@duke.edu.
  • 11 The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. Electronic address: yingming.zhao@uchicago.edu.
PMID: 24703693 DOI: 10.1016/j.cmet.2014.03.014
Abstract

We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (Kglu). 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.

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