title: SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.
abstract: 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 have 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.
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Anderson
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Frank K
authors.initials: FK
authors.lastname: Huynh
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Fisher-Wellman
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: J Darren
authors.initials: JD
authors.lastname: Stuart
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Peterson
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Douros
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wagner
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Duke Proteomics and Metabolomics Shared Resource, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.affiliation: Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Madsen
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Biological Sciences, Department of Biomedical Informatics, Vanderbilt Genetics Institute, Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: R Michael
authors.initials: RM
authors.lastname: Sivley
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Computational Chemistry and Biology Core Facility, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Backos
authors.affiliation: Department of Biological Sciences, Department of Biomedical Informatics, Vanderbilt Genetics Institute, Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Capra
authors.affiliation: Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Olsen
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grimsrud
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: matthew.hirschey@duke.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007930:Leucine / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D064688:Metabolic Flux Analysis; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010802:Phylogeny; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007328:Insulin; D024101:Mitochondrial Proteins; D000581:Amidohydrolases; C514813:SIRT4 protein, mouse; D037761:Sirtuins; D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase; D007930:Leucine; D005947:Glucose; D008239:Lysine
keywords: branched-chain amino acids; deacylase; insulin secretion; leucine; mitochondria; sirtuin 4