text: Aside from sharing the same absolute stereochemistry as leptomycin B, callystatin A was discovered to have similar biological activity with leptomycin B as well. The anti-tumor activity of leptomycin B and callystatin A arises because many NES-cargo molecules blocked by these antibiotics are those involved in the cellular processes of proliferation, differentiation, and development, learning and memory, and hormone action. These molecules include regulatory proteins such as Rev, MAPK/MEK1, c-Abl, Cyclin B1, MDM2/p53, IkB, MPF, and PKA.
  The most important role of leptomycin B is its inhibitory effect on the NES-dependent nuclear export mechanism, leading to the cell cycle arrest during G1 and G2 phases in eukaryotic cells. In wild-type cells, macromolecules in the nucleus with the leucine-rich nuclear export signal (NES) can be transported to the cytoplasm by binding to a karyopherin protein called chromosome region maintenance 1 (CRM1)/exportin 1. This CRM1/exportin1/NES-cargo interaction is stabilized by Ran-GTP binding which forms a complex that can transport the cargo to the cytoplasm. There, the cargo will be released when the Ran-GTP protein is hydrolyzed by a cytoplasmic Ran-GTPase enzyme to form Ran-GDP. This step completes the transport process and CRM1/exportin1 reenters the nucleus for more cargo binding. Leptomycin B and callystatin A inhibit the action of CRM1/exportin1 by a likely Michael-type addition of the thiol group from a cysteine residue of CRM1/exportin1 to form a covalent bond. This interaction prevents CRM1/exportin1 from recognizing and binding the NES of the cargo molecules because it occurs within the same binding site. Thus, macromolecules intended to be transported out of the nucleus will accumulate there instead.