UDP-GlcNAc-dependent glycosyltransferases

UDP-GlcNAc-dependent glycosyltransferases are a superfamily of enzymes that utilize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) as a donor substrate to transfer N-acetylglucosamine (GlcNAc) to various acceptor molecules, including proteins, lipids, and glycans (1.1.2, 1.3.3). The most prominent human member is O-GlcNAc transferase (OGT), which modifies nucleocytoplasmic proteins with a single O-GlcNAc moiety, serving as a critical nutrient sensor that regulates signal transduction, gene expression, and proteasomal degradation (1.1.1, 1.2.2). Dysregulation of OGT-mediated O-GlcNAcylation is linked to the pathogenesis of type 2 diabetes, Alzheimer's disease, and several cancers, where it often promotes tumor cell survival and metastasis (1.1.3, 1.2.3). In the bacterial context, enzymes like MurG are essential for peptidoglycan biosynthesis, making them high-priority targets for the development of new antibiotics against multi-drug resistant pathogens (1.3.2, 1.3.3). Drug discovery efforts have produced several classes of inhibitors, including donor-mimetic small molecules (e.g., OSMI series) and bisubstrate analogs, though many remain in the preclinical stage due to challenges with cell permeability and selectivity across the glycosyltransferase family (1.4.1, 1.4.2).

Other names

N-acetylglucosaminyltransferasesGlcNAc transferasesUDP-N-acetylglucosamine-dependent glycosyltransferases

Competitive inhibition of the UDP-GlcNAc donor binding site, bisubstrate inhibition mimicking both donor and acceptor moieties, and irreversible covalent inactivation of the enzyme active site.