Leptomycins are
secondary metabolites produced by ''
Streptomyces
''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...
'' spp.
Leptomycin B (LMB) was originally discovered as a potent
antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...
compound. 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 shows that leptomycin causes G1 cell cycle arrest in mammalian cells and is a potent anti-tumor agent against murine experimental tumors in combination therapy.
Leptomycin B has been shown to be a potent and specific nuclear export inhibitor in human and the fission yeast ''S. pombe''. Leptomycin B alkylates and inhibits ''CRM1'' (chromosomal region maintenance)/
exportin 1 (), a protein required for nuclear export of proteins containing a
nuclear export sequence
A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite ...
(NES), by glycosylating a
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residue (cysteine 529 in ''S. pombe'').
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
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling ...
, and
NF-κB/IκB, and it inhibits the inactivation of
p53.
Leptomycin B also inhibits the export and translation of many
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
s, including
COX-2 and
c-Fos
Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkin ...
mRNAs, by inhibiting export of
ribonucleoproteins.
Leptomycin A (LPA) was discovered together with LMB. LMB is twice as potent as LPA.
See also
*
Selective inhibitor of nuclear export
References
External links
* {{MeshName, leptomycin+B
Original data copied with permission fro
Leptomycin B manufacturer product page(
Fermentek)
Antibiotics