O-GlcNAcase

Function

O-GlcNAcase or hyaluronoglucosaminidase (OGA) is one of two enzymes which modulate the level of O-linked N-acetylglucosamine (O-GlcNAc) attachment to cytoplasmic, nuclear and mitochondrial proteins^[1]. The attachment of O-GlcNAc to proteins is a post-translational modification.

Relevance

Inhibition of OGA is a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy^[2]. The inhibition of OGA hinders formation of tau aggregates and decreases neuronal cell loss^[3].

Structural highlights

The 3D structure of the complex between human OGA and a transition state analog Thiamet-G shows the active site pocket at the base of a V-shaped cleft between the 2 OGA monomers. There are formed between OGA and Thiamet-G as well as some . are defined as catalytic residues^[4].

3D structures of O-GlcNAcase3D structures of O-GlcNAcase

Updated on 17-August-2023

ReferencesReferences

↑ Shen DL, Gloster TM, Yuzwa SA, Vocadlo DJ. Insights into O-linked N-acetylglucosamine ([0-9]O-GlcNAc) processing and dynamics through kinetic analysis of O-GlcNAc transferase and O-GlcNAcase activity on protein substrates. J Biol Chem. 2012 May 4;287(19):15395-408. doi: 10.1074/jbc.M111.310664. Epub, 2012 Feb 6. PMID:22311971 doi:http://dx.doi.org/10.1074/jbc.M111.310664
↑ Selnick HG, Hess JF, Tang C, Liu K, Schachter JB, Ballard JE, Marcus J, Klein DJ, Wang X, Pearson M, Savage MJ, Kaul R, Li TS, Vocadlo DJ, Zhou Y, Zhu Y, Mu C, Wang Y, Wei Z, Bai C, Duffy JL, McEachern EJ. Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies. J Med Chem. 2019 Nov 27;62(22):10062-10097. doi: 10.1021/acs.jmedchem.9b01090., Epub 2019 Sep 29. PMID:31487175 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01090
↑ Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012 Feb 26;8(4):393-9. doi: 10.1038/nchembio.797. PMID:22366723 doi:http://dx.doi.org/10.1038/nchembio.797
↑ Roth C, Chan S, Offen WA, Hemsworth GR, Willems LI, King DT, Varghese V, Britton R, Vocadlo DJ, Davies GJ. Structural and functional insight into human O-GlcNAcase. Nat Chem Biol. 2017 Mar 27. doi: 10.1038/nchembio.2358. PMID:28346405 doi:http://dx.doi.org/10.1038/nchembio.2358

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky

[1] Shen DL, Gloster TM, Yuzwa SA, Vocadlo DJ. Insights into O-linked N-acetylglucosamine ([0-9]O-GlcNAc) processing and dynamics through kinetic analysis of O-GlcNAc transferase and O-GlcNAcase activity on protein substrates. J Biol Chem. 2012 May 4;287(19):15395-408. doi: 10.1074/jbc.M111.310664. Epub, 2012 Feb 6. PMID:22311971 doi:http://dx.doi.org/10.1074/jbc.M111.310664

[2] Selnick HG, Hess JF, Tang C, Liu K, Schachter JB, Ballard JE, Marcus J, Klein DJ, Wang X, Pearson M, Savage MJ, Kaul R, Li TS, Vocadlo DJ, Zhou Y, Zhu Y, Mu C, Wang Y, Wei Z, Bai C, Duffy JL, McEachern EJ. Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies. J Med Chem. 2019 Nov 27;62(22):10062-10097. doi: 10.1021/acs.jmedchem.9b01090., Epub 2019 Sep 29. PMID:31487175 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01090

[3] Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012 Feb 26;8(4):393-9. doi: 10.1038/nchembio.797. PMID:22366723 doi:http://dx.doi.org/10.1038/nchembio.797

[4] Roth C, Chan S, Offen WA, Hemsworth GR, Willems LI, King DT, Varghese V, Britton R, Vocadlo DJ, Davies GJ. Structural and functional insight into human O-GlcNAcase. Nat Chem Biol. 2017 Mar 27. doi: 10.1038/nchembio.2358. PMID:28346405 doi:http://dx.doi.org/10.1038/nchembio.2358

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