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

Liu, Chun‐Jen; Zandberg, Wesley F.; Gloster, T.M.; Deng, Liwei; Murray, Kelsey; Shan, Xiaoyang; Vocadlo, David J.

doi:10.1002/anie.201803254

Cited by 56 publications

(60 citation statements)

References 37 publications

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“…The development of potent and selective OGT or OGA inhibitors may thus possess potential for the treatment of diseases that show abnormal O-GlcNAcylation. Indeed, several OGT or OGA inhibitors have been developed [103,[160][161][162]. OGA inhibitors have recently entered early clinical trials for the treatment of Progressive Supranuclear Palsy [163] as O-GlcNAcylation of Tau blocks the pathological effects of phosphorylation and aggregation of Tau [76].…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation and its role in the immune system

2020

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O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is a type of glycosylation that occurs when a monosaccharide, O-GlcNAc, is added onto serine or threonine residues of nuclear or cytoplasmic proteins by O-GlcNAc transferase (OGT) and which can be reversibly removed by O-GlcNAcase (OGA). O-GlcNAcylation couples the processes of nutrient sensing, metabolism, signal transduction and transcription, and plays important roles in development, normal physiology and physiopathology. Cumulative studies have indicated that O-GlcNAcylation affects the functions of protein substrates in a number of ways, including protein cellular localization, protein stability and protein/protein interaction. Particularly, O-GlcNAcylation has been shown to have intricate crosstalk with phosphorylation as they both modify serine or threonine residues. Aberrant O-GlcNAcylation on various protein substrates has been implicated in many diseases, including neurodegenerative diseases, diabetes and cancers. However, the role of protein O-GlcNAcylation in immune cell lineages has been less explored. This review summarizes the current understanding of the fundamental biochemistry of O-GlcNAcylation, and discusses the molecular mechanisms by which O-GlcNAcylation regulates the development, maturation and functions of immune cells. In brief, O-GlcNAcylation promotes the development, proliferation, and activation of T and B cells. O-GlcNAcylation regulates inflammatory and antiviral responses of macrophages. O-GlcNAcylation promotes the function of activated neutrophils, but inhibits the activity of nature killer cells.

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Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation and its role in the immune system

2020

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“…The modification of proteins with O‐GlcNAc is thus limited by UDP‐GlcNAc availability and occurs in a specific manner on serine or threonine residues of nearly 4000 proteins, thus modulating protein‐protein interactions, phosphorylation and enzymatic stability . In this manner, protein modification by O‐GlcNAc controls a wide range of processes including signaling networks, transcription, cell metabolism, amino acid and nucleotide metabolism, nutrient sensing and the cell stress response . Within this broad control of cell physiology, it is emerging that O‐GlcNAc modification also controls specific aspects of endocytic membrane traffic, including that of proteins that regulate membrane transport of metabolites, ions and proteins, although much remains to be understood about this phenomenon.…”

Section: Direct Control Of Endocytic Membrane Traffic By Metabolitesmentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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“…[44] 5SGlcNHex inhibits OGT and decreases O-GlcNAc levels in cells and in vivo. [44] 5SGlcNHex is a substrate for GlcNAc kinase (GNK) and for Nacetyl-glucosamine-6-phosphate de-N-acetylase (NAGA). It, however, is not a substrate for phosphoglucosamine mutase (AGM) which catalyzes a transfer of phosphate group from C6 position to the anomeric carbon (C1).…”

Section: Udp-5sglcnacmentioning

confidence: 97%

“…[43] 5SGlcNHex metabolic precursor: 2-Deoxy-2-N-hexanamide-5-thio-d-glucopyranose (5SGlcNHex) has been developed as an in vivo OGT inhibitor by addressing the inherent low aqueoussolubility problem of Ac 4 -5SGlcNAc. [44] This inhibitor properly balances between its lipophilicity and hydrophilicity rendering it to diffuse into cells yet to be water-soluble. Its hydrophilic property is conferred from several unprotected hydroxyl groups whereas its lipophilic property is arisen from the attached hydrophobic N-hexanoyl substituent at C2.…”

Section: Udp-5sglcnacmentioning

confidence: 99%

O‐GlcNAc Transferase: Structural Characteristics, Catalytic Mechanism and Small‐Molecule Inhibitors

Kim

2020

ChemBioChem

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Modifications of nuclear and cytoplasmic proteins with a single sugar, N-acetylglucosamine (GlcNAc), play roles in a wide variety of fundamental cellular processes, and aberrant O-GlcNAc profiles are associated with pathological progression of several chronic diseases. O-GlcNAc transferase (OGT) is the only enzyme to catalyze the attachment of GlcNAc to intracellular protein substrates. Considering its biological significance, selective and potent OGT inhibitors are invaluable tools for enhancing our understanding of the precise biological functions of the enzyme, for revealing its unknown functions, and for validating OGT as a therapeutic target. In this minireview, human OGT (hOGT) inhibitors and their catalytic mechanisms will be explored. In addition, a brief overview of recent findings on the 3D structural characteristics of hOGT that have contributed greatly to the development of novel inhibitors of hOGT is provided.

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

Cited by 56 publications

References 37 publications

O-GlcNAcylation and its role in the immune system

O-GlcNAcylation and its role in the immune system

Energetic adaptations: Metabolic control of endocytic membrane traffic

O‐GlcNAc Transferase: Structural Characteristics, Catalytic Mechanism and Small‐Molecule Inhibitors

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