15-deoxyspergualin primarily targets the trafficking of apicoplast proteins in Plasmodium falciparum.
15-Deoxyspergualin, an immunosuppressant with tumoricidal and antimalarial properties, has been implicated in the inhibition of a diverse array of cellular processes including polyamine synthesis and protein synthesis. Endeavoring to identify the mechanism of antimalarial action of this molecule, we examined its effect on Plasmodium falciparum protein synthesis, polyamine biosynthesis, and transport. 15-Deoxyspergualin stalled protein synthesis in P. falciparum through Hsp70 sequestration and subsequent phosphorylation of the eukaryotic initiation factor eIF2alpha. However, protein synthesis inhibition as well as polyamine depletion were invoked only by high micromolar concentrations of 15-deoxyspergualin, in contrast to the submicromolar concentrations sufficient to inhibit parasite growth. Further investigations demonstrated that 15-deoxyspergualin in the malaria parasite primarily targets the hitherto underexplored process of trafficking of nucleus-encoded proteins to the apicoplast. Our finding that 15-deoxyspergualin kills the malaria parasite by interfering with targeting of nucleus-encoded proteins to the apicoplast not only exposes a chink in the armor of the malaria parasite, but also reveals new realms in our endeavors to study this intriguing biological process.
Ramya
T N C
TN
Indian Institute of Science, Bangalore 560012, India.
Karmodiya
Krishanpal
K
Surolia
Avadhesha
A
Surolia
Namita
N
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects*; D011073:Polyamines; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015800:Protozoan Proteins / Q000187:drug effects* / Q000378:metabolism
D000962:Antimalarials; D015852:Eukaryotic Initiation Factor-2; D006146:Guanidines; D018840:HSP70 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D011073:Polyamines; D015800:Protozoan Proteins; C037258:gusperimus