Advances in chemical probing of protein O-GlcNAc glycosylation: structural role and molecular mechanisms. (2nd August 2021)

• Record Type: Journal Article
• Authors: Saha, Abhijit; Bello, Davide; Fernández-Tejada, Alberto
• Is Part Of: Chemical Society reviews. Volume 50:Number 18(2021)
• Page Start: 10451
• Page End: 10485
• Publication Date: 2021-08-02
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1039/d0cs01275k
• Languages: English
• ISSNs: 0306-0012

Abstract

Abstract : This review describes the recent developments in chemical probing of O -GlcNAcylation with a special focus on its molecular, structural and mechanistic implications. Abstract : The addition of O -linked-β-d - N -acetylglucosamine ( O -GlcNAc) onto serine and threonine residues of nuclear and cytoplasmic proteins is an abundant, unique post-translational modification governing important biological processes. O -GlcNAc dysregulation underlies several metabolic disorders leading to human diseases, including cancer, neurodegeneration and diabetes. This review provides an extensive summary of the recent progress in probing O -GlcNAcylation using mainly chemical methods, with a special focus on discussing mechanistic insights and the structural role of O -GlcNAc at the molecular level. We highlight key aspects of the O -GlcNAc enzymes, including development of OGT and OGA small-molecule inhibitors, and describe a variety of chemoenzymatic and chemical biology approaches for the study of O -GlcNAcylation. Special emphasis is placed on the power of chemistry in the form of synthetic glycopeptide and glycoprotein tools for investigating the site-specific functional consequences of the modification. Finally, we discuss in detail the conformational effects of O -GlcNAc glycosylation on protein structure and stability, relevant O -GlcNAc-mediated protein interactions and its molecular recognition features by biological receptors. Future research in this field will provide novel, more effective chemical strategies and probes for the molecular interrogation of O -GlcNAcylation, elucidating new mechanisms and functional roles of O -GlcNAc with potential therapeutic applications in human health.