RESUMEN

Natural products are a valuable source for novel lead structures in drug discovery, but for the majority of isolated bioactive compounds, the cellular targets are unknown. The structurally unique ansa-polyketide kendomycin (KM) was reported to exert its potent cytotoxic effects via impairment of the ubiquitin proteasome system, but the exact mode of action remained unclear. Here, we present a systematic biochemical characterization of KM-proteasome interactions in vitro and in vivo, including complex structures of wild type and mutant yeast 20S proteasome with KM. Our results provide evidence for a polypharmacological mode of action for KM's cytotoxic effect on cancer cells.

Asunto(s)

Productos Biológicos/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/metabolismo , Rifabutina/análogos & derivados , Saccharomyces cerevisiae/metabolismo , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Citoplasma/metabolismo , Femenino , Células HeLa , Humanos , Cinética , Espectrometría de Masas , Modelos Moleculares , Mutación , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/aislamiento & purificación , Unión Proteica , Rifabutina/química , Rifabutina/aislamiento & purificación , Rifabutina/metabolismo , Ubiquitina/metabolismo