Article open access publication

Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5

Cell Metabolism, Elsevier, ISSN 1550-4131

Volume 19, 4, 2014

DOI:10.1016/j.cmet.2014.03.014, Dimensions: pub.1038263394, PMC: PMC4108075, PMID: 24703693,



  1. (1) Shanghai Institute of Materia Medica, grid.419093.6
  2. (2) Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
  3. (3) Duke University Hospital, grid.189509.c
  4. (4) University of Michigan, grid.214458.e
  5. (5) Technical University of Denmark, grid.5170.3, DTU
  6. (6) University Medical Center Hamburg-Eppendorf, grid.13648.38
  7. (7) University of Colorado Anschutz Medical Campus, grid.430503.1
  8. (8) National Human Genome Research Institute, grid.280128.1


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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Times Cited: 348

Field Citation Ratio (FCR): 43.11

Relative Citation ratio (RCR): 13.48

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