Tunicamycin Inhibits N-linked Glycosylation, GlcNAc Phosphotransferase and Induces ER Stress

By Edward Jenner 2021-08-28 #Antibiotic, #ER Stress, #GlcNAc, #GPT

N-linked glycosylation (NLG) is the attachment of an oligosaccharide and a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein) in a process called N-glycosylation. NLG plays a central role in sustaining protein stability, trafficking, and function. The N-linked glycosylation process occurs in eukaryotes and widely in archaea, but very rarely in bacteria. In addition, N-linked protein glycosylation in the endoplasmic reticulum (ER) covalently modifies a large number of proteins. N-linked protein glycosylation in the ER is a conserved two phase process in eukaryotic cells. The N-glycosylation pathway in the ER modifies a multitude of proteins at one or more asparagine residues. Changes in N-linked glycosylation has been associated with different diseases including rheumatoid arthritis, type 1 diabetes, Crohn’s disease, and cancers.

Tunicamycin is a mixture of homologous nucleoside antibiotic that inhibits N-linked glycosylation (NLG) and blocks GlcNAc phosphotransferase (GPT). Tunicamycin potently inhibits NLG by competitively inhibiting UDP-GlcNAc-dolichol-phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) activity. In addition, Tunicamycin causes accumulation of unfolded proteins in cell endoplasmic reticulum (ER) and induces ER stress, and causes blocking of DNA synthesis. Similarly, Tunicamycin activates the unfolded protein response (UPR) response, and leads to accumulation of p27 and G1 cell cycle arrest in melanoma cells. Moreover, it also can target several types of tumors by reducing angiogenesis, inhibiting colony formation, and enhancing TRAIL-induced apoptosis. Besides, Tunicamycin shows anti-hepatocellular carcinoma activities by targeting the DPAGT1/Akt/ABCG2 pathway. Finally, Tunicamycin also inhibits Gram-positive bacteria, yeasts, fungi, and viruses.