Tunicamycin mixture is a mixture of tunicamycins with variable trans-2,3-unsaturated branched chain fatty acid (BFCA) chain lengths. Tunicamycins are anti-microbial agents that are active against Gram-positive bacteria, fungi, and viruses. They inhibit the N-acetylhexosamine (HexNAc) phosphotransferase family of enzymes in bacteria and prevent peptidoglycan biosynthesis. In eukaryotes, they inhibit N-acetylglucosamine (GlcNAc) phosphotransferase (GPT), preventing the first step in N-linked glycosylation and inducing the unfolded protein response and cell death. The cellular toxicity of tunicamycins is linked to the trans-2,3-unsaturated BCFA, and saturated BCFA-containing tunicamycin derivatives, such as TunR1 and TunR2 , have reduced toxicity. Tunicamycins impair glycosylation of the receptor tyrosine kinases EGFR, HER2, HER3, and IGF-1R, which prevents their translocation out of the endoplasmic reticulum and Golgi apparatus and reduces their protein levels and activity. Tunicamycin sensitizes EGFR inhibitor-resistant U251 glioma and Bx/PC-3 pancreatic adenocarcinoma cells to irradiation.
Tunicamycin has been widely used in the study of glycoprotein synthesis in various biological systems. During protein glycosylation, tunicamycin is noted to be an inhibitor of the transfer of saccharide moieties to dolichol during dolichol-linked glycoprotein synthesis. Dose-dependent inhibition of DNA synthesis may be related to the alteration of glycoproteins, which thereby affects the transport of thymidine into cells. Additionally, tunicamycin has been reported to prevent cell cycle progression in primary cultures of rat glial cells, as well as inhibit lipid-mediated protein glycosylation in chick or mouse fibroblasts in a dose-dependent manner.
As a tool in studying glycoproteins in a wide variety of biological systems.
The tunicamycins are a family of lipophilic nucleosides with fatty acids conjugated to an aminoglycoside group. The complex comprises analogues, tunicamycins I to X. This composition is typical of other products less precisely described as tunicamycins A to D. The tunicamycins act by blocking the formation of N-glycoside linkages to proteins via inhibition of formation of dolichol monophosphate from N-acetylglucosamine-1-phosphate. Tunicamycin blocks the synthesis of all N-linked glycoproteins (N-glycans) and causes cell cycle arrest in G1 phase. Tunicamycins are broadly active against prokaryotes, eukaryotes and viruses.
ChEBI: A mixture of antiviral nucleoside antibiotics produced by Streptomyces lysosuperificus. It contains at least 10 homologues comprising uracil, N-acetylglucosamine, an 11-carbon aminodialdose called tunicamine, and a fatty aci
linked to the amino group of the tunicamine. The homologues vary in the composition of the fatty acid moiety.
Tunicamycin was first isolated from Streptomyces lysosuperificus based on its antiviral activity. It contains N-acetylglucosamine and inhibits glycoprotein biosynthesis, including virus membrane glycoproteins.
The components of this nucleotide antibiotic from Streptomyces sp. are purified by recrystallising 3 times from hot glass-distilled MeOH, and the white crystals are dissolved in 25% aqueous MeOH and separated on a Partisil ODS-10_ column (9.4 x 25 cm) [Magnum-9 Whatman] using a 260nm detector. The column is eluted with MeOH/H2O mixture adjusted to 1:4 (v/v) then to 2:4 (v/v). The individual components are recovered and lyophilised. Ten components have been isolated, and all were active (to varying extents) depending on the lengths of the aliphatic side-chains. The mixture has UV max at 205 and 260nm (A 1cm 230 and 110). It is stable in H2O at neutral pH but unstable in acidic solution. It inhibits protein glycosylation. [Mahoney & Duskin J Biol Chem 254 6572 1979, Elnein Trends Biochem Sci 6 219 1981, Takatsuki J Antibiot 24 215 1971.] Uracil, uridine and uridine nucleotides. These are resolved by ion-exchange chromatography with AG1 (Cl form). [Lindsay et al. Anal Biochem 24 506 1968.]
Isolated from Streptomyces lysosuperificus, tunicamycin is a nucleoside antibiotic that inhibits N-linked glycosylation in glycoprotein synthesis. Composed of tunicamycins A, B, C and D, the compound competitively blocks the transfer of N-acetylglucosamine-1-phosphate from UDP-GlcNAc to dolichol-P. By preventing glycoprotein synthesis, tunicamycin inhibits the formation of the “viral coat” known as the tunica or capsid in both RNA and DNA viruses, and thus exhibits antiviral properties. Research studies have shown that tunicamycin will arrest cells in G1 phase, preventing them from entering S-phase and increasing the expression of PERK. Following N-linked glycosylation inhibition, tunicamycin induces autophagy in response to ER stress, ultimately upregulating CHOP and BIP.
[1] THOMAS J. LANGAN Mary C S. Isoprenoids and astroglial cell cycling: Diminished mevalonate availability and inhibition of dolichol-linked glycoprotein synthesis arrest cycling through distinct mechanisms[J]. Journal of Cellular Physiology, 1991, 149 2: 284-292. DOI:
10.1002/jcp.1041490215[2] WEN-XING DING. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival.[J]. The Journal of Biological Chemistry, 2007, 282 7: 4702-4710. DOI:
10.1074/jbc.m609267200[3] CHEN CHEN JIANG. Tunicamycin sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by up-regulation of TRAIL-R2 via the unfolded protein response.[J]. Cancer research, 2007, 67 12: 5880-5888. DOI:
10.1158/0008-5472.can-07-0213[4] SATOSHI ISHII Joseph J V. Dolichol-Linked Glycoprotein Synthesis in G1 Is Necessary for DNA Synthesis in Synchronized Primary Cultures of Cerebral Glia[J]. Journal of Neurochemistry, 1987, 49 5: 1606-1612. DOI:
10.1111/j.1471-4159.1987.tb01034.x
