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

SUBMITTER: Anderson KA 

PROVIDER: S-EPMC5444661 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature