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Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing

Research output: Contribution to journalArticle

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Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing. / Liu, Ta-wei; Zandberg, Wesley F.; Gloster, Tracey M.; Deng, Lehua; Murray, Kelsey D; Shan, Xiaoyang; Vocadlo, David Jaro.

In: Angewandte Chemie International Edition, Vol. 57, No. 26, 25.06.2018, p. 7644-7648.

Research output: Contribution to journalArticle

Harvard

Liu, T, Zandberg, WF, Gloster, TM, Deng, L, Murray, KD, Shan, X & Vocadlo, DJ 2018, 'Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing', Angewandte Chemie International Edition, vol. 57, no. 26, pp. 7644-7648. https://doi.org/10.1002/anie.201803254

APA

Liu, T., Zandberg, W. F., Gloster, T. M., Deng, L., Murray, K. D., Shan, X., & Vocadlo, D. J. (2018). Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing. Angewandte Chemie International Edition, 57(26), 7644-7648. https://doi.org/10.1002/anie.201803254

Vancouver

Liu T, Zandberg WF, Gloster TM, Deng L, Murray KD, Shan X et al. Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing. Angewandte Chemie International Edition. 2018 Jun 25;57(26):7644-7648. https://doi.org/10.1002/anie.201803254

Author

Liu, Ta-wei ; Zandberg, Wesley F. ; Gloster, Tracey M. ; Deng, Lehua ; Murray, Kelsey D ; Shan, Xiaoyang ; Vocadlo, David Jaro. / Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing. In: Angewandte Chemie International Edition. 2018 ; Vol. 57, No. 26. pp. 7644-7648.

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@article{6ec7b15eca854797ae734bdec7c5c82c,
title = "Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing",
abstract = "O‐linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N‐acetylglucosamine (O‐GlcNAc) residues is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Here we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5‐thiosugar analogues of N‐acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N‐acetylglucosamine‐6‐phosphate de‐N‐acetylase (NAGA) to generate a common OGT inhibitor within cells. Of these inhibitors, we show that 2‐deoxy‐2‐N‐hexanamide‐5‐thio‐D‐glucopyranoside (5SGlcNHex) acts in vivo to induce dose‐ and time‐dependent decreases in O‐GlcNAc levels in various tissues. Decreased O‐GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of transcription factor Sp1 and the satiety‐inducing hormone leptin ‐ revealing a link between decreased O‐GlcNAc levels and nutrient sensing in peripheral tissues of mammals.",
keywords = "Glycoprotein, Thiosugar, Nucleotide sugars, Leptin, Nutrient sensing",
author = "Ta-wei Liu and Zandberg, {Wesley F.} and Gloster, {Tracey M.} and Lehua Deng and Murray, {Kelsey D} and Xiaoyang Shan and Vocadlo, {David Jaro}",
note = "This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (NSERC). D.J.V. is a scholar of the Michael Smith Foundation of Health Research (MSFHR) and a Tier II Canada Research Chair in Chemical Glycobiology. T.M.G. was supported by a Sir Henry Wellcome postdoctoral fellowship (WT082572) and a Research Career Development Fellowship from the Wellcome Trust (WT095828).",
year = "2018",
month = "6",
day = "25",
doi = "10.1002/anie.201803254",
language = "English",
volume = "57",
pages = "7644--7648",
journal = "Angewandte Chemie International Edition",
issn = "1433-7851",
publisher = "John Wiley & Sons, Ltd.",
number = "26",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Metabolic inhibitors of O-GlcNAc transferase (OGT) that act in vivo implicate decreased O-GlcNAc levels in leptin-mediated nutrient sensing

AU - Liu, Ta-wei

AU - Zandberg, Wesley F.

AU - Gloster, Tracey M.

AU - Deng, Lehua

AU - Murray, Kelsey D

AU - Shan, Xiaoyang

AU - Vocadlo, David Jaro

N1 - This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (NSERC). D.J.V. is a scholar of the Michael Smith Foundation of Health Research (MSFHR) and a Tier II Canada Research Chair in Chemical Glycobiology. T.M.G. was supported by a Sir Henry Wellcome postdoctoral fellowship (WT082572) and a Research Career Development Fellowship from the Wellcome Trust (WT095828).

PY - 2018/6/25

Y1 - 2018/6/25

N2 - O‐linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N‐acetylglucosamine (O‐GlcNAc) residues is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Here we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5‐thiosugar analogues of N‐acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N‐acetylglucosamine‐6‐phosphate de‐N‐acetylase (NAGA) to generate a common OGT inhibitor within cells. Of these inhibitors, we show that 2‐deoxy‐2‐N‐hexanamide‐5‐thio‐D‐glucopyranoside (5SGlcNHex) acts in vivo to induce dose‐ and time‐dependent decreases in O‐GlcNAc levels in various tissues. Decreased O‐GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of transcription factor Sp1 and the satiety‐inducing hormone leptin ‐ revealing a link between decreased O‐GlcNAc levels and nutrient sensing in peripheral tissues of mammals.

AB - O‐linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N‐acetylglucosamine (O‐GlcNAc) residues is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Here we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5‐thiosugar analogues of N‐acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N‐acetylglucosamine‐6‐phosphate de‐N‐acetylase (NAGA) to generate a common OGT inhibitor within cells. Of these inhibitors, we show that 2‐deoxy‐2‐N‐hexanamide‐5‐thio‐D‐glucopyranoside (5SGlcNHex) acts in vivo to induce dose‐ and time‐dependent decreases in O‐GlcNAc levels in various tissues. Decreased O‐GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of transcription factor Sp1 and the satiety‐inducing hormone leptin ‐ revealing a link between decreased O‐GlcNAc levels and nutrient sensing in peripheral tissues of mammals.

KW - Glycoprotein

KW - Thiosugar

KW - Nucleotide sugars

KW - Leptin

KW - Nutrient sensing

UR - https://europepmc.org/articles/PMC6055616

U2 - 10.1002/anie.201803254

DO - 10.1002/anie.201803254

M3 - Article

VL - 57

SP - 7644

EP - 7648

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

SN - 1433-7851

IS - 26

ER -

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