Inhibition of Eukaryotic Translation Initiation by the Natural Product Pateamine A

Translation initiation in eukaryotes is accomplished through the coordinated and orderly action of a large number of proteins known as initiation factors and the ribosomal subunits. Herein we report that pateamine A (PatA), a potent antiproliferative and proapoptotic marine natural product, inhibits cap‐dependent eukaryotic translation initiation. Crucial to the eukaryotic cap‐dependent translation initiation mechanism is the multisubunit initiation factor eIF4F, which is composed of the eIF4G, eIF4E, and eIF4A factors. PatA bound to and enhanced the intrinsic enzymatic activities of eIF4A, yet it inhibited eIF4A‐eIF4G association. Furthermore, PatA caused an increase of association between eIF4A and eIF4B, another initiation factor known to increase eIF4A activity. These changes in eIF4A affinity for its partner proteins upon binding to PatA caused the stalling of initiation complexes on mRNA in vitro and caused inhibition of translation in vivo. These results suggest that PatA will be a valuable molecular probe for future studies of eukaryotic translation initiation and may serve as a lead compound for the development of anticancer agents.