Thermorubin
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| Category | Antibiotics |
| Catalog number | BBF-03118 |
| CAS | 37577-75-6 |
| Molecular Weight | 600.52 |
| Molecular Formula | C32H24O12 |
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Description
Thermorubin A is an antibiotic produced by Thermoactinomyces antibioticus TA/124. It has broad-spectrum antibacterial effect, but weaker effect on mycobacteria. Serum has the effect of reducing antibacterial activity. It has a protective effect on mice infected with Staphylococcus aureus by intraperitoneal administration.
Specification
| Synonyms | Thermorubin A |
| IUPAC Name | 2-[12-hydroxy-9-[(Z)-3-hydroxy-3-(2-hydroxyphenyl)prop-2-enoyl]-10,11-dimethoxy-3-methoxycarbonyl-1-oxonaphtho[3,2-g]isochromen-8-yl]acetic acid |
| Canonical SMILES | COC1=C2C(=CC3=CC(=C(C(=C31)OC)C(=O)C=C(C4=CC=CC=C4O)O)CC(=O)O)C=C5C=C(OC(=O)C5=C2O)C(=O)OC |
| InChI | InChI=1S/C32H24O12/c1-41-29-24(21(35)13-20(34)18-6-4-5-7-19(18)33)17(12-23(36)37)10-15-8-14-9-16-11-22(31(39)43-3)44-32(40)26(16)28(38)25(14)30(42-2)27(15)29/h4-11,13,33-34,38H,12H2,1-3H3,(H,36,37)/b20-13- |
| InChI Key | GGEDVBUCHDZLTH-MOSHPQCFSA-N |
Properties
| Appearance | Orange-red Crystal |
| Antibiotic Activity Spectrum | bacteria; mycobacteria |
| Boiling Point | 942.8±65.0°C |
| Density | 1.522±0.06 g/cm3 |
Reference Reading
1. Thermorubin Biosynthesis Initiated by a Salicylate Synthase Suggests an Unusual Conversion of Phenols to Pyrones
Jennifer P McCord, Zachary A Kohanov, Andrew N Lowell ACS Chem Biol. 2022 Nov 18;17(11):3169-3177. doi: 10.1021/acschembio.2c00606. Epub 2022 Oct 18.
Thermorubin is a tetracyclic naphthoisocoumarin natural product that demands investigation due to its novel mechanism of bacterial protein synthesis inhibition and its unusual structural features. In this work, we describe the identification of the biosynthetic cluster responsible for thermorubin from the sequenced Laceyella sacchari producer species and its confirmation via heterologous production in Escherichia coli. Based on an in-depth annotation of the cluster, we propose a biosynthetic pathway that accounts for the formation of the unique, nonterminal pyrone. Additionally, the expression and use of salicylate synthase TheO enabled testing of the stability properties of this extremophile-derived enzyme. TheO displayed rapid kinetics and a remarkably robust secondary structure, converting chorismate to salicylate with a KM of 109 ± 12 μM, kcat of 9.17 ± 0.36 min-1, and catalytic efficiency (kcat/KM) of 84 ± 9 nM-1 min-1, and retained significant activity up to 50 °C. These studies serve as the basis for continued biosynthetic investigations and bioinspired synthetic approaches.
2. Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria
Narayan Prasad Parajuli, Andrew Emmerich, Chandra Sekhar Mandava, Michael Y Pavlov, Suparna Sanyal Nat Commun. 2023 Feb 17;14(1):918. doi: 10.1038/s41467-023-36528-7.
Thermorubin (THB) is a long-known broad-spectrum ribosome-targeting antibiotic, but the molecular mechanism of its action was unclear. Here, our precise fast-kinetics assays in a reconstituted Escherichia coli translation system and 1.96 Å resolution cryo-EM structure of THB-bound 70S ribosome with mRNA and initiator tRNA, independently suggest that THB binding at the intersubunit bridge B2a near decoding center of the ribosome interferes with the binding of A-site substrates aminoacyl-tRNAs and class-I release factors, thereby inhibiting elongation and termination steps of bacterial translation. Furthermore, THB acts as an anti-dissociation agent that tethers the ribosomal subunits and blocks ribosome recycling, subsequently reducing the pool of active ribosomes. Our results show that THB does not inhibit translation initiation as proposed earlier and provide a complete mechanism of how THB perturbs bacterial protein synthesis. This in-depth characterization will hopefully spur efforts toward the design of THB analogs with improved solubility and effectivity against multidrug-resistant bacteria.
3. Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin
Madhura N Paranjpe, Valeria I Marina, Aleksandr A Grachev, Tinashe P Maviza, Olga A Tolicheva, Alena Paleskava, Ilya A Osterman, Petr V Sergiev, Andrey L Konevega, Yury S Polikanov, Matthieu G Gagnon Nucleic Acids Res. 2023 Jan 11;51(1):449-462. doi: 10.1093/nar/gkac1189.
Thermorubin (THR) is an aromatic anthracenopyranone antibiotic active against both Gram-positive and Gram-negative bacteria. It is known to bind to the 70S ribosome at the intersubunit bridge B2a and was thought to inhibit factor-dependent initiation of translation and obstruct the accommodation of tRNAs into the A site. Here, we show that thermorubin causes ribosomes to stall in vivo and in vitro at internal and termination codons, thereby allowing the ribosome to initiate protein synthesis and translate at least a few codons before stalling. Our biochemical data show that THR affects multiple steps of translation elongation with a significant impact on the binding stability of the tRNA in the A site, explaining premature cessation of translation. Our high-resolution crystal and cryo-EM structures of the 70S-THR complex show that THR can co-exist with P- and A-site tRNAs, explaining how ribosomes can elongate in the presence of the drug. Remarkable is the ability of THR to arrest ribosomes at the stop codons. Our data suggest that by causing structural re-arrangements in the decoding center, THR interferes with the accommodation of tRNAs or release factors into the ribosomal A site.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
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g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
