Leptomycin

Leptomycin
IUPAC name

(2E,5S,6R,7S,9R,10E,12E,15R,16Z,18E)-
17-ethyl-6-hydroxy-3,5,7,9,11,15-hexamethyl-
19-[(2S,3S)-3-methyl-6-oxo-2,3-dihydropyran-
2-yl]-8-oxononadeca-2,10,12,16,18-pentaenoic acid
Identifiers
CAS number 87081-35-4
PubChem 6917907
ChemSpider 21106330 Y
Jmol-3D images Image 1
Properties
Molecular formula C33H48O6
Molar mass 540.73 g mol−1
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Leptomycin B is a secondary metabolite produced by Streptomyces spp.

Leptomycin B (LMB) was originally discovered as a potent anti-fungal antibiotic[1]. Leptomycin B was found to cause cell elongation of the fission yeast Schizosaccharomyces pombe. Since then this elongation effect has been used for the bioassay of leptomycin. However, recent data (2003) shows that Leptomycin causes G1 cell cycle arrest in mammalian cells and is a potent anti-tumor agent against murine experimental tumors.

Leptomycin B has been shown to be a potent and specific nuclear export inhibitor in human[2] and the fission yeast Schizosaccharomyces pombe[3]. Leptomycin B alkylates and inhibits CRM1 (chromosomal region maintenance)/exportin 1 (XPO1), a protein required for nuclear export of proteins containing a nuclear export sequence (NES), by glycosylating a cysteine residue (cysteine 529 in S. pombe)[4]. In addition to antifungal and antibacterial activities, Leptomycin B blocks the cell cycle and is a potent anti-tumor agent. At low nM concentrations, Leptomycin B blocks the nuclear export of many proteins including HIV-1 Rev, MAPK/ERK, and NF-κB/IκB, and it inhibits the inactivation of p53[5]. Leptomycin B also inhibits the export and translation of many RNAs, including COX-2 and c-Fos mRNAs, by inhibiting export of ribonucleoproteins.

Leptomycin A (LPA) was discovered together with LMB. LMB is twice as potent as LPA.

References

  1. ^ Hamamoto T, Seto H, Beppu T (1983). "Leptomycins A and B, new antifungal antibiotics. II. Structure elucidation". J. Antibiot. 36 (6): 646–50. PMID 6874586. 
  2. ^ Kudo N, Wolff B, Sekimoto T, et al. (August 1998). "Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1". Exp. Cell Res. 242 (2): 540–7. doi:10.1006/excr.1998.4136. PMID 9683540. 
  3. ^ Nishi K, Yoshida M, Fujiwara D, Nishikawa M, Horinouchi S, Beppu T (March 1994). "Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression". J. Biol. Chem. 269 (9): 6320–4. PMID 8119981. http://www.jbc.org/content/269/9/6320.abstract. 
  4. ^ Kudo N, Matsumori N, Taoka H, et al. (August 1999). "Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region". Proc. Natl. Acad. Sci. U.S.A. 96 (16): 9112–7. doi:10.1073/pnas.96.16.9112. PMC 17741. PMID 10430904. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=17741. 
  5. ^ Hietanen S, Lain S, Krausz E, Blattner C, Lane DP (2000). "Activation of p53 in cervical carcinoma cells by small molecules.". Proc Natl Acad Sci U S A 97 (15): 8501–6. doi:10.1073/pnas.97.15.8501. PMC 26977. PMID 10900010. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10900010. 

External links

Original data copied with permission from Leptomycin B manufacturer product page (Fermentek)