PXD005896

PXD005896 is an original dataset announced via ProteomeXchange.

Title	SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion
Description	Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control has remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues – methylglutaryl(MG)-, hydroxymethylglutaryl(HMG)-, and 3-methylglutaconyl(MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging. From Anderson et. al. Cell Metabolism, 2017.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:48:49.926.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Paul Grimsrud
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-02-09 02:21:15	ID requested
1	2017-04-05 06:14:13	announced
2	2017-04-10 00:04:21	announced	Updated publication reference for PubMed record(s): 28380376.
⏵ 3	2023-11-14 08:48:51	announced	2023-11-14: Updated project metadata.

Anderson KA, Huynh FK, Fisher-Wellman K, Stuart JD, Peterson BS, Douros JD, Wagner GR, Thompson JW, Madsen AS, Green MF, Sivley RM, Ilkayeva OR, Stevens RD, Backos DS, Capra JA, Olsen CA, Campbell JE, Muoio DM, Grimsrud PA, Hirschey MD, SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metab, 25(4):838-855.e15(2017) [pubmed]

curator keyword: Biological

submitter keyword: Protein acylation, Insulin Secretion, Leucine Metabolism,Sirt4

Matthew D. Hirschey
contact affiliation	Assistant 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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2017/04/PXD005896

PRIDE project URI

• PRIDE
  1. PXD005896
     1. Label: PRIDE project
     2. Name: SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion