Figure 1. Overview of the Hexosamine Biosynthetic Pathway (HBP) and O-GlcNAcylation. The HBP integrates four metabolism pathways, including carbohydrate (glucose), amino acid (glutamine), lipid (Acetyl-CoA) and nucleotide (UTP). |
Figure 2: Dynamic Competition between glycosylation and phosphorylation of proteins. A: Competition between OGT and kinase for the serine or threonine functional group of a protein. B: Adjacent-site occupancy where O-GlcNAc and O-phosphatase occur next to each other and can influence the turnover or function of proteins reciprocally. The G circle represents an N-acetylglucosamine group, and the P circle represents a phosphate group. Figure adapted from Hart.[3] |
OGT vs OGA
As a highly dynamic process, O-GlcNAc rapidly cycles onto serine/threonine residues of target proteins in a fashion analogous to phosphorylation (see Figure 2).
While there are roughly 500 kinases and 150 phosphatases that regulate protein phosphorylation in humans, there are only 2 enzymes that regulate the cycling of O-GlcNAc:
- O-GlcNAc transferase (OGT)
- Catalyzes the addition of O-GlcNAc to serine/threonine residues
- OGT utilizes UDP-GlcNAc as the donor sugar for sugar transfer.
- O-GlcNAcase (OGA)
- Catalyzes the removal of O-GlcNAc
The chemical reaction of OGT can be written as:
- UDP-N-acetyl-D-glucosamine + [protein]-L-serine → UDP + [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-serine
- UDP-N-acetyl-D-glucosamine + [protein]-L-threonine → UDP + [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-threonine
Using the below pharmacological compounds, you can control the level of protein O-GlcNAcylation:
In one study,[5] scientists found that NButGT—a specific inhibitor of OGA, reduces Aβ production by lowering γ-secretase activity. Moreover, NButGT
- To decrease it, by administering DON and Azaserine
- To increase it by using OGA blocker
- Such as Glucosamine, PUGNAc, NButGT
- NButGT
- 1,2-dideoxy-2′-propyl-α-d-glucopyranoso-[2,1-D]-Δ2′-thiazoline
- Elevated O-GlcNAc has been associated with diabetes.
NButGT (more-specific) vs PUGNAc (less-specific)
The regulation of OGT is directly involved in diabetes. OGT and O-GlcNAc-modified protein levels are increased in the pancreatic islets of diabetic rats.[6] Overexpression of OGT in liver, muscle and fat tissues causes insulin resistance.[7,8]
This discrepancy might be resulted from the off-target effects (e.g., on lysosomal hexosaminidases) of the less-specific PUGNAc, suggesting the necessity of choosing more specific and selective inhibitors to explore the roles of OGA.
Caution should also be made in terms of inhibitor usage, since effects of the inhibitors are, generally, in a dose- and time-dependent manner, which may cause significant differences in protein O-GlcNAcylation levels in a tissue-specific manner and thus the related diabetic phenotypes.
O-GlcNAcylation–Based Treatments as Potential Interventions for AD
O-GlcNAcylation is notably decreased in Alzheimer’s disease (AD) brain. Necroptosis is activated in AD brain and is positively correlated with neuroinflammation and tau pathology.
In one study,[5] scientists found that NButGT—a specific inhibitor of OGA, reduces Aβ production by lowering γ-secretase activity. Moreover, NButGT
- Reduces Aβ production
- By lowering γ-secretase activity
- Attenuates
- Accumulation of Aβ
- Neuroinflammation
- Memory impairment
in the 5XFAD mice.
This is the first study to show the relationship between Aβ generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD.
O-GlcNAcylation Can Regulate Many Hallmarks of Cancer
Up to this point, nearly all evidence suggests that the HBP helps fuel cancer cell metabolism, growth, survival, and spread. Further research should elucidate whether the HBP plays a role in cancer initiation and maintenance, heterogeneity, and regulation of the tumor microenvironment, including immune surveillance.[13]
References
- Hart, Gerald W.; Slawson, Chad; Ramirez-Correa, Genaro; Lagerlof, Olof (2011-06-07). "Cross Talk Between O-GlcNAcylation and Phosphorylation: Roles in Signaling, Transcription, and Chronic Disease". Annual Review of Biochemistry. 80: 825–858.
- Haltiwanger, RS; Holt, GD; Hart, GW (1990-02-15). "Enzymatic Addition of O-GlcNAc to Nuclear and Cytoplasmic Proteins. Identification of a Uridine diphospho-N-acetylglucosamine:peptide beta-N-acetylglucosaminyltransferase". Journal of Biological Chemistry. 265 (5): 2563–8.
- Hart GW, Housley MP, Slawson C (April 2007). "Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins". Nature. 446 (7139): 1017–22.
- Macauley, MS; Bubb, AK; Martinez-Fleites, C; Davies, GJ; Vocadlo, DJ (2008-12-12). "Elevation of Global O-GlcNAc Levels in 3T3-L1 Adipocytes by Selective Inhibition of O-GlcNAcase Does Not Induce Insulin Resistance". The Journal of Biological Chemistry. 283 (50): 34687–95.
- O-GLCNACYLATION AMELIORATES THE PATHOLOGICAL MANIFESTATIONS OF ALZHEIMER’S DISEASE BY INHIBITING NECROPTOSIS
- Akimoto Y, Hart GW, Wells L, et al. Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto-Kakizaki rats. Glycobiology. 2007;17:127–140.
- McClain DA, Lubas WA, Cooksey RC, et al. Altered glycan-dependent signaling induces insulin resistance and hyper-leptinemia. Proc Natl Acad Sci USA. 2002;99:10695–10699.
- Yang X, Ongusaha P, Miles P, et al. Phosphoinositide signaling links O-GlcNAc transferase to insulin resistance. Nature. 2008;451:964–970.
- Macauley MS, Bubb AK, Martinez-Fleites C, et al. Elevation of global O-GlcNAc levels in 3T3-L1 adipocytes by selective inhibition of O-GlcNAcase does not induce insulin resistance. J Biol Chem. 2008;283:34687–34695.
- Macauley MS, He Y, Gloster TM, et al. Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes. Chem Biol. 2010;17:937–948.
- Macauley MS, Shan X, Yuzwa SA, et al. Elevation of global O-GlcNAc in rodents using a selective O-GlcNAcase inhibitor does not cause insulin resistance or perturb glucohomeostasis. Chem Biol. 2010;17:949–958.
- Ferrer CM, Sodi VL, Reginato MJ. O-GlcNAcylation in cancer biology: linking metabolism and signaling. J Mol Biol. 2016;428:3282–94.
- Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer
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