Metabolic Inhibitors of O-GlcNAc Transferase That Act In Vivo Implicate Decreased O-GlcNAc Levels in Leptin-Mediated Nutrient Sensing

Angewandte Chemie
Tai-Wei LiuDavid J Vocadlo

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. Herein, 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. We show that of these inhibitors, 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 the transcription factor Sp1 and the satiety-inducing hormone leptin, thus revealing a link between decreased O-GlcNAc levels and nutrient sensing in peripheral tissues of mammals.

References

Jul 28, 1995·Science·M A PelleymounterF Collins
May 1, 1997·Molecular and Cellular Biology·I Han, J E Kudlow
Jul 24, 2002·Proceedings of the National Academy of Sciences of the United States of America·Donald A McClainJohn A Hanover
Jul 23, 2003·Proceedings of the National Academy of Sciences of the United States of America·David J VocadloCarolyn R Bertozzi
Oct 20, 2005·Journal of the American Chemical Society·Benjamin J GrossSuzanne Walker
Jan 25, 2011·Nature Chemical Biology·Tracey M GlosterDavid J Vocadlo
Nov 16, 2011·Nature Chemical Biology·Jiaoyang JiangSuzanne Walker
Nov 30, 2013·Pharmacology & Therapeutics·Sujith Dassanayaka, Steven P Jones
Jan 18, 2015·The Journal of Biological Chemistry·Chithra KeembiyehettyJohn A Hanover
Mar 10, 2015·ACS Chemical Biology·Rodrigo F Ortiz-MeozSuzanne Walker
Mar 17, 2015·Nature Chemical Biology·Yanping ZhuDavid J Vocadlo
Apr 29, 2015·Proceedings of the National Academy of Sciences of the United States of America·Partha S BanerjeeGerald W Hart
Oct 22, 2015·Chembiochem : a European Journal of Chemical Biology·Wei LinXing Chen
Jan 13, 2016·Angewandte Chemie·Franziska DollValentin Wittmann
Feb 11, 2016·Biochemical Society Transactions·Riccardo TrapannoneDaan M F van Aalten
Mar 19, 2016·Science·Olof LagerlöfRichard L Huganir
Apr 14, 2016·Glycobiology·Chin Fen TeoLance Wells
Jun 28, 2016·Journal of Molecular Biology·Christina M FerrerMauricio J Reginato
Sep 23, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Peder J LundMark M Davis
Jul 1, 2017·The EMBO Journal·Po-Han ChenJen-Tsan Chi

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Citations

Oct 18, 2019·Traffic·Sadia RahmaniCostin N Antonescu
Dec 25, 2019·The Journal of Cell Biology·Alexander Buffone, Valerie M Weaver
May 15, 2020·Chembiochem : a European Journal of Chemical Biology·Eun Ju Kim
Jul 6, 2019·BMC Biology·Neha M AkellaMauricio J Reginato
May 1, 2020·Journal of Biomedical Science·Yi-Hsuan ChangKuo-I Lin
Mar 25, 2020·Chemistry : a European Journal·Arielis EstevezJiaoyang Jiang
Oct 28, 2020·Chemistry : a European Journal·Yukishige ItoYoichi Takeda
Jan 9, 2021·Chemical Reviews·Junfeng MaGerald W Hart
Feb 4, 2021·Current Opinion in Structural Biology·Matthew G AlteenDavid J Vocadlo
Jan 31, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Israel Olapeju BolanleTimothy M Palmer
Jan 13, 2021·Current Opinion in Structural Biology·Aaron T BalanaMatthew R Pratt
Jul 31, 2020·Physiological Reviews·John C ChathamAdam R Wende
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Cyril BalsollierMarko Anderluh
Jan 22, 2021·Molecular Cancer Research : MCR·Harri M ItkonenIan G Mills
May 19, 2021·Current Protocols·Kamau FahieNatasha E Zachara
Jul 24, 2021·The Biochemical Journal·Aaron T Balana, Matthew R Pratt
Aug 3, 2021·Chemical Society Reviews·Abhijit SahaAlberto Fernández-Tejada
Oct 5, 2021·Circulation Research·Sarah E BasehoreAlisa Morss Clyne
Dec 23, 2021·Nature Chemical Biology·Charlie Fehl, John A Hanover

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Methods Mentioned

BETA
electrophoresis
ELISA
glycosylation

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