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 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.

OTHER RELATED OMICS DATASETS IN: MODEL1109130000 MODEL1909260003 MODEL1909260004 MODEL1703310000 MODEL1909260005 MODEL1909260006 MODEL1311110000 MODEL1311110001

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Paul Grimsrud  

LAB HEAD: Matthew D. Hirschey

PROVIDER: PXD005896 | Pride | 2017-04-05

REPOSITORIES: Pride