Functional characterization of a SUMO deconjugating protease of Plasmodium falciparum using newly identified small molecule inhibitors
Authors listElizabeth L Ponder Victoria E Albrow Brittany A Leader Miklós Békés Jowita Mikolajczyk Urša Pečar Fonović Aimee Shen Marcin Drag Junpeng Xiao Edgar Deu Sandoval Amy J Campbell James C Powers Guy S Salvesen Matthew Bogyo
Small ubiquitin-related modifier (SUMO) is implicated in the regulation of numerous biological processes including transcription, protein localization, and cell cycle control. Protein modification by SUMO is found in Plasmodium falciparum; however, its role in the regulation of the parasite life cycle is poorly understood. Here we describe functional studies of a SUMO-specific protease (SENP) of P. falciparum, PfSENP1 (PFL1635w). Expression of the catalytic domain of PfSENP1 and biochemical profiling using a positional scanning substrate library demonstrated that this protease has unique cleavage sequence preference relative to the human SENPs. In addition, we describe a class of small molecule inhibitors of this protease. The most potent lead compound inhibited both recombinant PfSENP1 activity and P. falciparum replication in infected human blood. These studies provide valuable new tools for the study of SUMOylation in P. falciparum.