title: Plasmodium falciparum antioxidant protein reveals a novel mechanism for balancing turnover and inactivation of peroxiredoxins.
abstract: Life under aerobic conditions has shaped peroxiredoxins (Prx) as ubiquitous thiol-dependent hydroperoxidases and redox sensors. Structural features that balance the catalytically active or inactive redox states of Prx, and, therefore, their hydroperoxidase or sensor function, have so far been analyzed predominantly for Prx1-type enzymes. Here we identify and characterize two modulatory residues of the Prx5-type model enzyme PfAOP from the malaria parasite Plasmodium falciparum. Gain- and loss-of-function mutants reveal a correlation between the enzyme parameters and the inactivation susceptibility of PfAOP with the size of residue 109 and the presence or absence of a catalytically relevant but nonessential cysteine residue. Based on our kinetic data and the crystal structure of PfAOP(L109M), we suggest a novel mechanism for balancing the hydroperoxidase activity and inactivation susceptibility of Prx5-type enzymes. Our study provides unexpected insights into Prx structure-function relationships and contributes to our understanding of what makes Prx good enzymes or redox sensors.
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Staudacher
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Carine F
authors.initials: CF
authors.lastname: Djuika
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Joshua
authors.initials: J
authors.lastname: Koduka
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schlossarek
authors.affiliation: Biochemistry Center (BZH), Ruprecht-Karls University, D-69120 Heidelberg, Germany; Cellnetworks Excellence Cluster, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kopp
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Marleen
authors.initials: M
authors.lastname: Büchler
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lanzer
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany. Electronic address: marcel.deponte@gmx.de.
authors.forename: Marcel
authors.initials: M
authors.lastname: Deponte
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008969:Molecular Sequence Data; D054464:Peroxiredoxins / Q000737:chemistry / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D054464:Peroxiredoxins
keywords: Catalytic mechanism; Inactivation; Molecular evolution; Peroxiredoxin; Redox regulation