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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. / Anderson, Kristin A; Huynh, Frank K; Fisher-Wellman, Kelsey; Stuart, J Darren; Peterson, Brett S; Douros, Jonathan D; Wagner, Gregory R; Thompson, J Will; Madsen, Andreas S; Green, Michelle F; Sivley, R Michael; Ilkayeva, Olga R; Stevens, Robert D; Backos, Donald S; Capra, John A; Olsen, Christian A; Campbell, Jonathan E; Muoio, Deborah M; Grimsrud, Paul A; Hirschey, Matthew D.

In: Cell Metabolism, Vol. 25, No. 4, 04.04.2017, p. 838-855.e15.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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 2017, 'SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion', Cell Metabolism, vol. 25, no. 4, pp. 838-855.e15. https://doi.org/10.1016/j.cmet.2017.03.003

APA

Anderson, K. A., Huynh, F. K., Fisher-Wellman, K., Stuart, J. D., Peterson, B. S., Douros, J. D., Wagner, G. R., Thompson, J. W., Madsen, A. S., Green, M. F., Sivley, R. M., Ilkayeva, O. R., Stevens, R. D., Backos, D. S., Capra, J. A., Olsen, C. A., Campbell, J. E., Muoio, D. M., Grimsrud, P. A., & Hirschey, M. D. (2017). SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metabolism, 25(4), 838-855.e15. https://doi.org/10.1016/j.cmet.2017.03.003

Vancouver

Anderson KA, Huynh FK, Fisher-Wellman K, Stuart JD, Peterson BS, Douros JD et al. SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metabolism. 2017 Apr 4;25(4):838-855.e15. https://doi.org/10.1016/j.cmet.2017.03.003

Author

Anderson, Kristin A ; Huynh, Frank K ; Fisher-Wellman, Kelsey ; Stuart, J Darren ; Peterson, Brett S ; Douros, Jonathan D ; Wagner, Gregory R ; Thompson, J Will ; Madsen, Andreas S ; Green, Michelle F ; Sivley, R Michael ; Ilkayeva, Olga R ; Stevens, Robert D ; Backos, Donald S ; Capra, John A ; Olsen, Christian A ; Campbell, Jonathan E ; Muoio, Deborah M ; Grimsrud, Paul A ; Hirschey, Matthew D. / SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. In: Cell Metabolism. 2017 ; Vol. 25, No. 4. pp. 838-855.e15.

Bibtex

@article{30de541697324d3b8c3da28bf2c9ef6e,
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.",
keywords = "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, Journal Article",
author = "Anderson, {Kristin A} and Huynh, {Frank K} and Kelsey Fisher-Wellman and Stuart, {J Darren} and Peterson, {Brett S} and Douros, {Jonathan D} and Wagner, {Gregory R} and Thompson, {J Will} and Madsen, {Andreas S} and Green, {Michelle F} and Sivley, {R Michael} and Ilkayeva, {Olga R} and Stevens, {Robert D} and Backos, {Donald S} and Capra, {John A} and Olsen, {Christian A} and Campbell, {Jonathan E} and Muoio, {Deborah M} and Grimsrud, {Paul A} and Hirschey, {Matthew D}",
note = "Copyright {\textcopyright} 2017 Elsevier Inc. All rights reserved.",
year = "2017",
month = apr,
day = "4",
doi = "10.1016/j.cmet.2017.03.003",
language = "English",
volume = "25",
pages = "838--855.e15",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

AU - Anderson, Kristin A

AU - Huynh, Frank K

AU - Fisher-Wellman, Kelsey

AU - Stuart, J Darren

AU - Peterson, Brett S

AU - Douros, Jonathan D

AU - Wagner, Gregory R

AU - Thompson, J Will

AU - Madsen, Andreas S

AU - Green, Michelle F

AU - Sivley, R Michael

AU - Ilkayeva, Olga R

AU - Stevens, Robert D

AU - Backos, Donald S

AU - Capra, John A

AU - Olsen, Christian A

AU - Campbell, Jonathan E

AU - Muoio, Deborah M

AU - Grimsrud, Paul A

AU - Hirschey, Matthew D

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/4/4

Y1 - 2017/4/4

N2 - 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.

AB - 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.

KW - Amidohydrolases

KW - Amino Acid Sequence

KW - Animals

KW - Carbon-Carbon Ligases

KW - Glucose

KW - HEK293 Cells

KW - Homeostasis

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Leucine

KW - Lysine

KW - Metabolic Flux Analysis

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mitochondrial Proteins

KW - Models, Molecular

KW - Phylogeny

KW - Sirtuins

KW - Journal Article

U2 - 10.1016/j.cmet.2017.03.003

DO - 10.1016/j.cmet.2017.03.003

M3 - Journal article

C2 - 28380376

VL - 25

SP - 838-855.e15

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 4

ER -

ID: 184203288