O‐GlcNAc Transferase: Structural Characteristics, Catalytic Mechanism and Small‐Molecule Inhibitors

Abstract

Modifications of nuclear and cytoplasmic proteins with a single sugar, N-acetylglucosamine (GlcNAc), play roles in a wide variety of fundamental cellular processes, and aberrant O-GlcNAc profiles are associated with pathological progression of several chronic diseases. O-GlcNAc transferase (OGT) is the only enzyme to catalyze the attachment of GlcNAc to intracellular protein substrates. Considering its biological significance, selective and potent OGT inhibitors are invaluable tools for enhancing our understanding of the precise biological functions of the enzyme, for revealing its unknown functions, and for validating OGT as a therapeutic target. In this minireview, human OGT (hOGT) inhibitors and their catalytic mechanisms will be explored. In addition, a brief overview of recent findings on the 3D structural characteristics of hOGT that have contributed greatly to the development of novel inhibitors of hOGT is provided.

Hyperglycemic O-GlcNAc transferase activity drives cancer stem cell induction in TNBC

“…A small molecule probe, OSMI-4, was recently reported to inhibit OGT with a K i of 8 nM and high selectivity over other human glycosyltransferases. 34,41 We treated TNBC cell lines with the OGT inhibitor OSMI-4 and observed globally inhibited overall O-GlcNAcylation, as measured with a pan-O-GlcNAc antibody to detect global cell O-GlcNAc modifications on proteins ( Fig 2A ). Active TET1 leads to TARDBP expression, so we used TARDBP mRNA levels as a readout for TET1 activity.…”

How Nanotechniques Could Vitalize the O-GlcNAcylation-Targeting Approach for Cancer Therapy

“…Alloxan, a uracil mimic, has been shown to bind to various enzymes that uses UDP-sugars as substrate, and to inhibit a broad-spectrum of enzymes including OGT and other glycosylation enzymes. 15 This low-specificity not only affected its OGT-inhibitory efficiency, but may also cause side effects. The later developed bisubstrate-linked inhibitor goblin1/2 contains an UDP group covalently connected to the serine of a synthetic peptide (VTPVSTA).…”

“…The currently available UDP-analogous and OGT-catalytic inhibitors including Ac-5S-GlcNAc, L01, and OSMI-1 have a common shortage of low solubility. 15 It is noted that these compounds carry the hydroxyl and other ionizable groups that potentiate the chemical coupling to the phospholipid bilayers of a liposomal nanocarrier. However, the multiple labile groups tend to form diversified by-products during modification, which may complicate the downstream purification process.…”

“…Zhu and Harrt summarized the abnormal O-GlcNAcylation in cancers, diabetes and neurodegenerative diseases, and discussed the novel approaches for therapeutic application of O-GlcNAcylation. 14 Although several types of compounds capable of inhibiting O-GlcNAcylation have been developed, 15 technical barriers such as the low solubility, the poor permeability and delivery efficiency need to be cleared for in vivo and pre-clinical studies. Nanocarriers have the advantages of controllable drug release and active cancer-targeting capability.…”

Synthesis of Thiodisaccharides Bearing N‐Acetylhexosamine Residues: Challenges, Achievements and Perspectives

“…Remarkably, the incorporation of GlcNAc into several proteins, has tremendous consequences on key cellular processes, and aberrant glycosylation has been associated with the progression of many chronic conditions, such as cardiovascular diseases [35,36] . In this respect, some small‐molecule inhibitors of O ‐GlcNAc transferase [37] have been developed with the aim to understand the biochemical mechanisms involved [38] . On the other hand, it has been demonstrated that the introduction of S ‐ d ‐GlcNAc moieties results in enzymatically stable glycoconjugates as glycopeptides and glycoproteins [19] .…”