The O-GlcNAc modification: three-dimensional structure, enzymology and the development of selective inhibitors to probe disease

Davies, G.J.; Martinez-Fleites, C.

doi:10.1042/bst0381179

Cited by 7 publications

(3 citation statements)

References 77 publications

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“…The lethal outcome of OGT-based genetic models prevents analysis of roles of OGT in adult and ageing brain, which is our main interest. Pharmacological inhibition of OGT is hampered, if not prohibited, by its structural complexity [2,3] while effective inhibitors are available for OGA, the enzyme that removes O-GlcNAc moieties from proteins [2,3]. A promising inhibitor denoted Thiamet-G [10,11] remains to be independently tested and validated in dedicated disease models in vivo.…”

Section: Introductionmentioning

confidence: 99%

Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

et al. 2013

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The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.

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Section: Introductionmentioning

confidence: 99%

Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

et al. 2013

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“…After ruling out O-GlcNAc elevation alone in interfering with the protective action of insulin, we were curious to understand the inhibitory effect of PUGNAc on insulin action. In mammals, there are two additional enzymes, namely lysosomal hexosaminidases A and B (HexA and HexB or HexA/B), that hydrolyze terminal GlcNAc structure via the same substrate-assisted catalytic mechanism utilized by OGA (Davies and Martinez-Fleites 2010;Slamova et al 2010). Although OGA and HexA/B belong to different CAZy families and reside in distinct cellular compartments, PUGNAc was found to inhibit HexA/B leading to an accumulation of glycosphingolipids (GSLs) in various neuronal cell lines (Stubbs et al 2009;Ho et al 2010).…”

Section: Lysosomal Hexosaminidase B Inhibition Is Not Responsible For...mentioning

confidence: 99%

Dissecting PUGNAc-mediated inhibition of the pro-survival action of insulin

Teo¹,

El-Karim

Wells³

2016

Glycobiology

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Previous studies utilizing PUGNAc, the most widely used β-N-acetylglucosaminidase (OGA) inhibitor to increase global O-N-acetylglucosamine (GlcNAc) levels, have reported a variety of effects including insulin resistance as a direct result of elevated O-GlcNAc levels. The notion of OGA inhibition causing insulin resistance was not replicated in studies in which elevated global O-GlcNAc levels were achieved using two other OGA inhibitors. Related to insulin action, work by others has suggested that O-GlcNAc elevation may inhibit the anti-apoptotic action of insulin. Thus, we examined the pro-survival action of insulin upon serum deprivation in the presence of PUGNAc as well as two selective OGA inhibitors (GlcNAcstatin-g and Thiamet-G), and a selective lysosomal hexosaminidase inhibitor (INJ2). We established that PUGNAc inhibits the pro-survival action of insulin but this effect is not recapitulated by the selective OGA inhibitors suggesting that elevation in O-GlcNAc levels alone is not responsible for PUGNAc's effect on the anti-apoptotic action of insulin. Further, we demonstrate that a selective hexosaminidase A/B (HexA/B) inhibitor does not impact insulin action suggesting that PUGNAc's effect is not due to inhibition of lysosomal hexosaminidase. Finally, we tested a combination of selective OGA and lysosomal hexosaminidase inhibitors but were not able to recapitulate the inhibition of insulin action generated by PUGNAc alone. These results strongly suggest that the defect in insulin action upon PUGNAc treatment does not derive from its inhibition of OGA or HexA/B, and that there is an unknown target of PUGNAc that is the likely culprit in inhibiting the protective effect of insulin from apoptosis.

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“…In addition, neutrophil dysfunction is found as a result of the glucose-6-phosphatase catabolic 3 mutation, resulting in an impaired respiratory burst, defective bacterial killing and susceptibility to infection. Gideon Davies, the recipient of the Biochemical Society's 2010 GlaxoSmithKline Award, contributes a lively account of the deceptively simple O-GlcNAc (O-linked β-Nacetylglucosamine) modification [17]. Quite unlike other glycoprotein glycans, the single monosaccharide O-GlcNAc may be attached and removed from recognized sites on acceptor proteins.…”

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confidence: 99%

Structural Glycobiology and Human Health

Corfield

2010

Biochemical Society Transactions

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The glycans (carbohydrates) form a diverse group of biomolecules which play active parts in most physiological processes. The field of structural glycobiology concerns the structures of the glycans themselves, the proteins which interact with them and the nature of the interactions between the two. The resulting information is important for our understanding of human health and disease, and for development of new therapeutic strategies. A series of articles is introduced based on the topics covered at the Structural Glycobiology and Human Health Biochemical Society Focused Meeting. Their subjects range from in-depth determinations of three-dimensional protein structure to broad screening techniques for glycan-protein interactions relevant to disease processes, including bacterial, parasitic and viral infections, inflammatory processes, cancer and diabetes.

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The O-GlcNAc modification: three-dimensional structure, enzymology and the development of selective inhibitors to probe disease

Cited by 7 publications

References 77 publications

Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

Dissecting PUGNAc-mediated inhibition of the pro-survival action of insulin

Structural Glycobiology and Human Health

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