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SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.

Cell metabolism | Apr 4, 2017

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.

Pubmed ID: 28380376 RIS Download

Mesh terms: Amidohydrolases | Amino Acid Sequence | Animals | Carbon-Carbon Ligases | Glucose | HEK293 Cells | Homeostasis | Humans | Insulin | Insulin Resistance | Leucine | Lysine | Metabolic Flux Analysis | Mice, Inbred C57BL | Mice, Knockout | Mitochondrial Proteins | Models, Molecular | Phylogeny | Sirtuins

Data used in this publication

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Associated grants

  • Agency: NCI NIH HHS, Id: T32 CA059365
  • Agency: NIDDK NIH HHS, Id: F32 DK105665
  • Agency: NIA NIH HHS, Id: R56 AG052568
  • Agency: NIDDK NIH HHS, Id: T32 DK007012
  • Agency: NEI NIH HHS, Id: T32 EY021453
  • Agency: NIDDK NIH HHS, Id: R24 DK085610
  • Agency: NIDDK NIH HHS, Id: R01 DK089312
  • Agency: NIA NIH HHS, Id: R01 AG045351
  • Agency: NCATS NIH HHS, Id: UL1 TR001082
  • Agency: NIA NIH HHS, Id: P30 AG028716
  • Agency: NIGMS NIH HHS, Id: T32 GM007105

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