Article
Protein S-nitrosylation in Plasmodium falciparum
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Published: | January 29, 2014 |
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The human malaria parasite Plasmodium falciparum is exposed to oxidative and nitrosative stresses due to the rapid proliferation and multiplication of the parasites and the host immune response. Nitric oxide (NO) and NO-derived reactive nitrogen species (RNS) constitute major nitrosative stress involved in the control of malaria parasites. NO has both cytostatic and cytotoxic effects on the cell growth of Plasmodium parasites. However, the action mode and the intraparasitic targets of NO in P. falciparum remain largely unexplored. Protein S-nitrosylation (protein-SNO), a nitrosative stress-induced ubiquitous modification of protein cysteine thiols by NO, has emerged as a principal mechanism by which NO excets biological functions. Although studied intensively in higher eukaryotes and bacteria, protein-SNO has not been systematically studied in human malaria parasites. By using a biotin-switch assay-based proteomic approach, we identified 319 potential S-nitrosylation targets in P. falciparum. Functional profile analysis of the identified proteins suggested S-nitrosylation may influence a variety of cellular metabolic processes in P. falciparum, among which glycolysis appears to be a major targeted pathway. Particularly, glycolytic activity of P. falciparum glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH) was found to be inhibited by S-nitrosylation on tis active-site cysteine. Additionally, we found that P. falciparum thioredoxin 1 (PfTrx1), a central protein disulphide oxidoreductase, can be site-specifically S-nitrosylated at its non-active site cysteine (Cys43). More importantly, we reported that PfTrx1 possesses both denitrosylating and transnitrosylating activities mediated by its active site cysteine residues and Cys43, respectively. A redox status-based model of PfTrx1 in the regulation of protein-SNO in the parasites was proposed.