UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase (OGT) (OGT)

O-GlcNAc transferase (OGT) is a unique and essential glycosyltransferase that catalyzes the addition of a single N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of thousands of nuclear, cytoplasmic, and mitochondrial proteins [1, 3, 15]. Unlike most glycosyltransferases that operate in the secretory pathway, OGT functions within the cell to regulate a wide array of biological processes, including signal transduction, gene expression, and nutrient sensing [2, 8, 16]. It acts as a metabolic sensor, as its activity is directly linked to the concentration of UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway [16, 24]. Dysregulation of OGT and protein O-GlcNAcylation is strongly implicated in the pathogenesis of various diseases, most notably cancer, where it promotes tumor cell proliferation and survival, and diabetes, where it contributes to insulin resistance [1, 12, 20, 25]. In neurodegenerative conditions like Alzheimer's disease, OGT-mediated modification of proteins such as Tau plays a critical role in disease progression [1, 4, 9]. Consequently, OGT has emerged as a promising therapeutic target, with several small-molecule inhibitors like the OSMI series and BZX2 being developed to modulate its activity [17, 18, 20]. However, the essential nature of OGT for cell viability and its broad substrate range present significant challenges for the development of safe and selective clinical therapies [8, 12, 19].

Other names

O-GlcNAc transferaseO-linked N-acetylglucosamine transferaseUDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunitHRNT1OGT1

Inhibition of O-GlcNAc transferase enzyme activity to reduce the O-GlcNAcylation of intracellular proteins.