title: Functional characterization of a SUMO deconjugating protease of Plasmodium falciparum using newly identified small molecule inhibitors.
abstract: 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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Ponder
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Albrow
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Leader
authors.forename: Miklós
authors.initials: M
authors.lastname: Békés
authors.forename: Jowita
authors.initials: J
authors.lastname: Mikolajczyk
authors.forename: Urša Pečar
authors.initials: UP
authors.lastname: Fonović
authors.forename: Aimee
authors.initials: A
authors.lastname: Shen
authors.forename: Marcin
authors.initials: M
authors.lastname: Drag
authors.forename: Junpeng
authors.initials: J
authors.lastname: Xiao
authors.forename: Edgar
authors.initials: E
authors.lastname: Deu
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Campbell
authors.forename: James C
authors.initials: JC
authors.lastname: Powers
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010795:Phthalic Acids / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D006834:Hydrazines; C562061:JCP 666; D010795:Phthalic Acids; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C562062:VEA 260; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases