 | |
| Names | |
|---|---|
| IUPAC name (E)-N-[(2S,3R,4R,5R,6R)-2-[(2R,3R,4R,5S,6R)- 3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[2-[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl]-4,5-dihydroxyoxan- 3-yl]-5-methylhex-2-enamide | |
| Other names NSC 177382 | |
| Identifiers | |
3D model (JSmol) | |
| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.115.295 |
| EC Number |
|
| MeSH | Tunicamycin |
| UNII | |
| |
| |
| Properties | |
| C39H64N4O16 | |
| Molar mass | N/A |
| Hazards | |
| GHS labelling:[1] | |
 | |
| Danger | |
| H300 | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
 | This articlemay be too technical for most readers to understand. Pleasehelp improve it tomake it understandable to non-experts, without removing the technical details.(October 2020) (Learn how and when to remove this message) |
Tunicamycin is a mixture ofhomologousnucleosideantibiotics that inhibits the UDP-HexNAc: polyprenol-P HexNAc-1-P family of enzymes. Ineukaryotes, this includes the enzymeGlcNAc phosphotransferase (GPT), which catalyzes the transfer ofN-acetylglucosamine-1-phosphate fromUDP-N-acetylglucosamine todolichol phosphate in the first step ofglycoprotein synthesis. Tunicamycin blocksN-linked glycosylation (N-glycans) and treatment of cultured human cells with tunicamycin causescell cycle arrest inG1 phase. It is used as an experimental tool inbiology, e.g. to induceunfolded protein response.[2] Tunicamycin is produced by severalbacteria, includingStreptomyces clavuligerus andStreptomyces lysosuperificus.
Tunicamycin homologues have varying molecular weights owing to the variability infatty acid side chain conjugates.[3]
The biosynthesis of tunicamycins was studied inStreptomyces chartreusis and a proposed biosynthetic pathway was characterized. The bacteria utilize the enzymes in thetun gene cluster (TunA-N) to make tunicamycins.[4]
TunA uses the starter unit uridine diphosphate-N-acetyl-glucosamine (UDP-GlcNAc) and catalyzes the dehydration of the 6’ hydroxyl group. First, a Tyr residue in TunA abstracts a proton from the 4’ hydroxyl group, forming a ketone at that position. A hydride is subsequently abstracted from the 4’ carbon by NAD+, forming NADH. The ketone is stabilized by hydrogen bonding from the Tyr residue, and a nearby Thr residue. A glutamate residue then abstracts a proton from the 5’ carbon, pushing the electrons up to form a double bond between the 5’ and 6’ carbon. A nearby cysteine donates a proton to the hydroxyl group as it leaves as water. NADH donates a hydride to the 4’ carbon, reforming a hydroxide in that position and forming UDP-6’-deoxy-5-6-ene-GlcNAc. TunF then catalyzes the epimerization of the intermediate to UDP-6’-deoxy-5-6-ene-GalNAc, changing the 4’ hydroxyl from the equatorial to axial position.[5]
The other starter unit for tunicamycin is uridine, which is produced from uridine triphosphate (UTP). TunN is a nucleotide diphosphatase, and catalyzes the removal of pyrophosphate from UTP to form uridine monophosphate. The last phosphate is removed by the putative monophosphatase, TunG.
Once uridine and UDP-6’-deoxy-5-6-ene-GalNAc are produced, TunB catalyzes their linkage at the 6’ carbon of UDP-6’-deoxy-5-6-ene-GalNAc. TunB usesS-adenyslmethionine (SAM) to form a radical on the 5’ carbon of the ribose on uracil. TunM is thought to catalyze the formation of a new bond between the 5’ carbon of uridine and the 6’ carbon of UDP-6’-deoxy-5-6-ene-GalNAc using the electron from the uridine radical and one of the electrons from the double bond of UDP-6’-deoxy-5-6-ene-GalNAc. The radical on UDP-6’-deoxy-5-6-ene-GalNAc is then quenched by abstracting a hydrogen from SAM.[6] The resulting molecule is UDP-N-acetyl-tunicamine. TunH then catalyzes the hydrolysis of UDP from UDP-N-acetyl-tunicamine. Another molecule of UDP-GlcNAc is introduced, and a β-1,1 glycosidic bond is subsequently formed, catalyzed by TunD. The resulting molecule is deacetylated by TunE. TunL and a fatty acyl-ACP ligase are used to load metabolic fatty acids onto the acyl carrier protein, TunK. TunC then attaches the fatty acid to the free amine, producing tunicamycin.
