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

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
Cell Metab. 2017 25 (4): 838-855.e15

PMID: 28380376 · PMCID: PMC5444661 · DOI:10.1016/j.cmet.2017.03.003

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.

Copyright © 2017 Elsevier Inc. All rights reserved.

MeSH Terms (20)

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

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