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O-GlcNAcase: Emerging Mechanism, Substrate Recognition and Small-Molecule Inhibitors
Ahmed A Elbatrawy1,2, Eun Ju Kim3, Ghilsoo Nam1,2
1Center for Neuro-Medicine Brain Science Institute, Korea Institutes of Science and Technology, Seoul, 02792 (Republic of, Korea.
Chemmedchem
|June 5, 2020
Summary
O-GlcNAcylation regulates cell cycles but is linked to diseases. This review details human O-GlcNAcase structure and function, and explores small-molecule inhibitors for therapeutic potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Glycobiology
Background:
- O-GlcNAcylation is a dynamic post-translational modification regulating nucleocytoplasmic proteins.
- This process is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA).
- Dysregulated O-GlcNAcylation is implicated in diseases like cancer, diabetes, and neurodegeneration.
Purpose of the Study:
- To review recent structural insights into human O-GlcNAcase and its isoforms.
- To elucidate the catalytic mechanism and substrate recognition of OGA.
- To provide an updated overview of small-molecule OGA inhibitors, focusing on their structure, selectivity, and cellular applications.
Main Methods:
- Structural analysis of human O-GlcNAcase.
- Biochemical assays to study catalytic mechanism and substrate binding.
- Review of literature on small-molecule OGA inhibitors.
Main Results:
- Recent advancements in understanding human O-GlcNAcase structure and isoforms.
- Detailed insights into OGA's catalytic mechanism and substrate recognition.
- Comprehensive summary of carbohydrate and noncarbohydrate OGA inhibitors, including their binding modes and selectivity.
Conclusions:
- Understanding OGA structure is crucial for designing selective inhibitors.
- Small-molecule inhibitors offer potential for probing O-GlcNAcylation in cellular contexts.
- Targeting OGA may hold therapeutic promise for diseases linked to O-GlcNAcylation dysregulation.
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