Anisomycin
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| IUPAC name
(2R,3S,4S)-4-hydroxy-2-(4-methoxybenzyl)-pyrrolidin-3-yl acetate
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| Other names
Flagecidin
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| Identifiers | |
3D model (JSmol)
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| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.041.139 |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties | |
| C14H19NO4 | |
| Molar mass | 265.31 g/mol |
| Melting point | 139-143 °C |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Anisomycin, also known as flagecidin is an antibiotic produced by Streptomyces griseolus which inhibits protein synthesis. Partial inhibition of DNA synthesis occurs at anisomycin concentrations that effect 95% inhibition of protein synthesis.[2] Anisomycin can activate stress-activated protein kinases, MAP kinase and other signal transduction pathways.
Anisomycin is inactive against bacteria.
Pharmacology
Anisomycin interferes with protein and DNA synthesis by inhibiting peptidyl transferase or the 80S ribosome system.
Anisomycin is also mentioned as a potential psychiatric drug, as it may inhibit the consolidation of new context-specific long-term memories.".[3]
Injection of anisomycin into the hippocampus has been proposed for selective removal of memories.[4]
Biosynthesis
Despite anisomycin's wide usage as a protein biosynthesis inhibitor, there have been few studies centered around the biosynthesis of anisomycin. One study by Butler in 1965 proposed possible precursors to this natural product. Fermentation of Streptomyces with labeled amino acids was followed by a degradation of the radioactive anisomycin and deacetylanisomycin products to determine the locations of the labeled carbons. Although its pyrrolidine-based structure suggests that it is derived from proline, the results from the experiments indicated that tyrosine, glycine, methionine, and acetate are the primary precursors for the biosynthesis of anisomycin. Tyrosine and, to a limited degree, phenylalanine, contribute to C-2 of the pyrrolidine ring. Methionine is likely responsible for the methylation of the hydroxyl group on the aromatic ring as S-adenosylmethionine (SAM). Glycine or acetate account for C-4 and C-5 on the pyrrolidine ring. It was noted that deacetylanisomycin was a prominent product in the first few days of fermentation, suggesting that acetylation of the C-3 hydroxyl group by acetyl Co-A is the final step in the biosynthesis of anisomycin. The source of the nitrogen within the ring and C-3 were undetermined. However, C-3 is not likely to be provided by the carboxylic acid group of tyrosine because tracking of radioactivity indicated that tyrosine undergoes decarboxylation during fermentation.[5]
Other uses
Anisomycin is used as a component of Martin Lewis Agar, an in- vitro diagnostic product which is used extensively in the United States for the selective isolation of Neisseria gonorrhoeae and Neisseria meningitidis.[1]
Using a novel high-throughput screening assay, Mawji et al. showed that anisomycin can sensitize metastatic epithelial cells to anoikis and reduce circulating tumor cell implantation in vivo.[6] Anisomycin achieved this anti-metastatic activity in part by decreasing the abundance of the death receptor inhibiting protein FLIP. In related work, Mawji's team showed that FLIP levels are higher in metastatic cells than non-metastatic cells, and that reducing FLIP levels using RNAi (RNA Interference) or other small molecule inhibitors of FLIP can sensitize metastatic cells to anoikis.[7] Given that FLIP is an inhibitor of anoikis, and that reducing FLIP can sensitize metastatic cells to anoikis, Mawji et al. hypothesize that FLIP reduction may be a viable therapeutic strategy against cancer metastasis.
See also
References
- ^ a b Anisomycin from Sigma Aldrich
- ^ Grollman, Arthur P. (1967). "Inhibitors of protein biosynthesis. II. Mode of action of anisomycin". The Journal of Biological Chemistry. 242 (13): 3226–33. PMID 6027796.
- ^ Barrientos, Ruth M; O'Reilly, Randall C; Rudy, Jerry W (2002). "Memory for context is impaired by injecting anisomycin into dorsal hippocampus following context exploration". Behavioural Brain Research. 134 (1–2): 299–306. doi:10.1016/S0166-4328(02)00045-1. PMID 12191817.
- ^ Wang, S.-H.; Ostlund, SB; Nader, K; Balleine, BW (2005). "Consolidation and Reconsolidation of Incentive Learning in the Amygdala". Journal of Neuroscience. 25 (4): 830–5. doi:10.1523/JNEUROSCI.4716-04.2005. PMID 15673662.
- ^ Butler, K. (1966). "Anisomycin. II.1 Biosynthesis of Anisomycin". The Journal of Organic Chemistry. 31 (1): 317–20. doi:10.1021/jo01339a503. PMID 5900818.
- ^ Mawji, Imtiaz A.; Simpson, Craig D.; Gronda, Marcela; Williams, Moyo A.; Hurren, Rose; Henderson, Clare J.; Datti, Alessandro; Wrana, Jeffrey L.; Schimmer, Aaron D. (2007). "A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis". Cancer Research. 67 (17): 8307–15. doi:10.1158/0008-5472.CAN-07-1687. PMID 17804746.
- ^ Mawji, Imtiaz A.; Simpson, Craig D.; Hurren, Rose; Gronda, Marcela; Williams, Moyo A.; Filmus, Jorge; Jonkman, James; Da Costa, Ralph S.; Wilson, ian C. (2007). "Critical Role for Fas-Associated Death Domain-Like Interleukin-1-Converting Enzyme-Like Inhibitory Protein in Anoikis Resistance and Distant Tumor Formation". Journal of the National Cancer Institute. 99 (10): 811–22. doi:10.1093/jnci/djk182. PMID 17505076.