PXD018156

PXD018156 is an original dataset announced via ProteomeXchange.

Title	Deglutarylation of GCDH by SIRT5 controls lysine metabolism in mice
Description	A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be non-enzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways. To better understand the biology of protein glutarylation, we studied the relationship between enzymes within the lysine/tryptophan catabolic pathways, protein glutarylation, and regulation by the deglutarylating enzyme Sirtuin 5 (SIRT5). Here, we identify glutarylation of the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH). We show increased GCDH glutarylation when glutaryl-CoA production is stimulated by lysine catabolism. Our data reveal glutarylation of GCDH impacts its function, ultimately decreasing lysine oxidation. We then demonstrate the ability of SIRT5 to deglutarylate GCDH, restoring its enzymatic activity. Finally, metabolomic and bioinformatic data indicate a novel role for SIRT5 in regulation of amino acid metabolism. Together, these data suggest a model whereby a feedback loop exists within the lysine/tryptophan oxidation pathway, in which glutaryl-CoA is produced, in turn inhibiting GCDH function. This inhibition is relieved by SIRT5 deacylation activity.
HostingRepository	PRIDE
AnnounceDate	2022-02-22
AnnouncementXML	Submission_2022-02-22_13:23:27.899.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Paul Grimsrud
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-23 16:50:44	ID requested
⏵ 1	2022-02-22 13:23:28	announced

Bhatt DP, Mills CA, Anderson KA, Henriques BJ, Lucas TG, Francisco S, Liu J, Ilkayeva OR, Adams AE, Kulkarni SR, Backos DS, Major MB, Grimsrud PA, Gomes CM, Hirschey MD, Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice. J Biol Chem, 298(4):101723(2022) [pubmed]

submitter keyword: GCDH, acylation, Sirt5, mitochondria, sirtuins

Matthew Hirschey
contact affiliation	Matthew Hirschey, PhD Associate Professor Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition Department of Pharmacology and Cancer Biology Duke University Medical Center
contact email	matthew.hirschey@duke.edu
lab head
Paul Grimsrud
contact affiliation	Duke Molecular Physiology Institute
contact email	paul.grimsrud@duke.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD018156
     1. Label: PRIDE project
     2. Name: Deglutarylation of GCDH by SIRT5 controls lysine metabolism in mice