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O-GlcNAcase

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Target not currently curated in GtoImmuPdb

Target id: 3101

Nomenclature: O-GlcNAcase

Family: Hydrolases

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 916 10q24.32 OGA O-GlcNAcase
Mouse - 916 19 38.75 cM Oga O-GlcNAcase
Rat - 916 1q54 Oga O-GlcNAcase
Previous and Unofficial Names Click here for help
MEA5 | MGEA5 | NCOAT | glycoside hydrolase O-GlcNAcase | O-GlcNAc hydrolase
Database Links Click here for help
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BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
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RefSeq Nucleotide
RefSeq Protein
UniProtKB
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Enzyme Reaction Click here for help
EC Number: 3.2.1.169

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MK-8719 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.1 pKi 3
pKi 8.1 (Ki 7.9x10-9 M) [3]
Description: In vitro enzyme inhibition assay.
thiamet-G Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.7 pKi 4
pKi 7.7 (Ki 2.1x10-8 M) [4]
MK-8719 Small molecule or natural product Ligand has a PDB structure Rn Inhibition 7.3 pEC50 3
pEC50 7.3 (EC50 5.27x10-8 M) [3]
Description: Determined in an ELISA-based assay with rat PC12 cells to measure EC50 values for elevation of all protein O-GlcNAc levels in the presence of test compound.
LY3372689 Small molecule or natural product Hs Inhibition 8.6 pIC50 1
pIC50 8.6 (IC50 2.36x10-9 M) [1]
Description: Inhibition of OGA enzyme activity in vitro
View species-specific inhibitor tables
Inhibitor Comments
Asceneuron have developed ASN120290 (previously ASN-561; structure not yet disclosed) as a brain-permeable and orally active small-molecule O-GlcNAcase enzyme inhibitor. It is reported in a 2018 review of in-development tau-based therapeutics that ASN120290 is being progressed to Phase 2 clinical trial, but there are no records for this agent (or ASN-561) on ClinicalTrials.gov, or any citable data in PubMed articles (as far as we can ascertain). Asceneuron's patent WO2017144639A1 claims glycosidase inhibitors for the treatment of tauopathies [2].
General Comments
Post-translational O-linked N-acetylglucosamine (O-GlcNAc) modification of proteins is a widely used mechanism that is crucial for regulating various cellular processes. The modifications are dynamic, with O-linked GlcNAc transferase (OGT) adding the O-GlcNAc modifications to protein serine and threonine residues, and O-GlcNAcase (OGA) removing them. The absence of O-GlcNAc chains leaves the serines and threonines available for phosphorylation. Two variants of the protein are produced from the human OGA gene. Both retain O-GlcNAcase enzymatic function.
Multiple lines of evidence indicate that aberrant phosphorylation of the tau protein drives its aggregation and the accumulation of toxic neurofibrillary tangles. Pharmacological blockade of O-GlcNAcase (i.e. to prevent O-GlcNAc removal and decrease phosphorylation) is being investigated as a novel mechanism to reduce tau hyperphosphorylation. Selective small-molecule O-GlcNAcase inhibitors are therefore being scrutinised for clinical utility in the treatment/prevention of neurodegenerative tauopathies, including Alzheimer's disease. To date, clinical progress has focussed on disease modification in patients with progressive supranuclear palsy, which is a rapidly progressing neurodegenerative disorder for which no current effective therapy exists..

References

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1. Dreyfus NJF, Lindsay-Scott PJ. (2018) N-[4-fluoro-5-[[(2s,4s)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as oga inhibitor. Patent number: WO2018140299A1. Assignee: Eli Lilly And Company. Priority date: 27/01/2017. Publication date: 02/08/2018.

2. Quattropani A, Kulkarni SS, Giri AG. (2017) Glycosidase inhibitors. Patent number: WO2017144639A1. Assignee: Asceneuron SA. Priority date: 25/02/2016. Publication date: 31/08/2017.

3. Selnick HG, Hess JF, Tang C, Liu K, Schachter JB, Ballard JE, Marcus J, Klein DJ, Wang X, Pearson M et al.. (2019) Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies. J Med Chem, 62 (22): 10062-10097. [PMID:31487175]

4. Yuzwa SA, Macauley MS, Heinonen JE, Shan X, Dennis RJ, He Y, Whitworth GE, Stubbs KA, McEachern EJ, Davies GJ et al.. (2008) A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol, 4 (8): 483-90. [PMID:18587388]

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