title: Characterization and redox regulation of Plasmodium falciparum methionine adenosyltransferase.
abstract: As a methyl group donor for biochemical reactions, S-adenosylmethionine plays a central metabolic role in most organisms. Depletion of S-adenosylmethionine has downstream effects on polyamine metabolism and methylation reactions, and is an effective way to combat pathogenic microorganisms such as malaria parasites. Inhibition of both the methylation cycle and polyamine synthesis strongly affects Plasmodium falciparum growth. Despite its central position in the methylation cycle, not much is currently known about P. falciparum methionine adenosyltransferase (PfalMAT). Notably, however, PfalMAT has been discussed as a target of different redox regulatory modifications. Modulating the redox state of critical cysteine residues is a way to regulate enzyme activity in different pathways in response to changes in the cellular redox state. In the present study, we optimized an assay for detailed characterization of enzymatic activity and redox regulation of PfalMAT. While the presence of reduced thioredoxin increases the activity of the enzyme, it was found to be inhibited upon S-glutathionylation and S-nitrosylation. A homology model and site-directed mutagenesis studies revealed a contribution of the residues Cys52, Cys113 and Cys187 to redox regulation of PfalMAT by influencing its structure and activity. This phenomenon connects cellular S-adenosylmethionine synthesis to the redox state of PfalMAT and therefore to the cellular redox homeostasis.
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
authors.forename: Jette
authors.initials: J
authors.lastname: Pretzel
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Gehr
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Eisenkolb
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Fritz-Wolf
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rahlfs
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.affiliation: Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany esther.jortzik@ernaehrung.uni-giessen.de.
authors.forename: Esther
authors.initials: E
authors.lastname: Jortzik
mesh_terms: D019943:Amino Acid Substitution; D008716:Methionine Adenosyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D015800:Protozoan Proteins; D008716:Methionine Adenosyltransferase
keywords: 
  S-glutathionylation; 
  S-nitrosylation; S-adenosylmethionine; malaria parasites; redox regulation