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Py-1-Cys-PRX: Plasmodium yoelii 1-Cys Peroxiredoxin

PDB entry: 1XCC

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All aerobic mechanisms have well developed detoxification mechanisms to deal with oxidative stress. Specifically, failure to maintain tolerable reactive oxygen species (ROS) such as superoxide anions (O2•-), hydrogen peroxide and hydroxyl radicals would lead to cellular damage. Malaria parasites are particularly dependent on redox control because digestion of host hemoglogin produces free haem which in turn generates O2•-. Three systems are involved in elimination of ROS at different stages: the superoxide dismutase system, the glutathione system and the thioredoxin system.1, 2 Catalases are also involved in many organisms but not protozoans.

The thioredoxin system includes the peroxiredoxins, also known as thioredoxin peroxidases or thiol-dependent peroxidases. Unlike other peroxidases, peroxiredoxins act without the benefit of redox co-factors. So far, both 1-cys-peroxiredoxin (1-cys-Prx) and 2-cys-preoxiredoxin (2-cys-Prx) have been identified and characterized in both P. falciparum3 and P. yoelii.4 As their names imply, these two classes of peroxiredoxins are distinguished by the number of redox-active cysteines.


All peroxiredoxins have in common a N-terminal peroxidatic cysteine which is oxidized to cysteine sulfenic acid upon attacking peroxide substrates. This is often the 47th residue in 1-cys-Prx and the 50th residue in 2-cys-Prx. 2-cys-Prx has a second catalytic cysteine, dubbed the resolving cysteine and typically from the other subunit of a homodimer in a domain swapping arrangement, to reduce the peroxidatic cysteine via formation of a disulfide bond. In contrast, 1-cys-Prx depends on a thiol-containing redox partner.

Our structure of Py-1-cys-Prx (PY04285, ortholog of P. falciparum protein PF08_0131) is a homodimer, the common conformation of all active peroxiredoxins. Similar to the human 1-cys-Prx structure (1PRX), each monomer features a thioredoxin domain and a C-terminal domain connected by a helix and a loop. The homodimer is held in place by interaction between the thioredoxin domain of one subunit and the C-terminal domain of the other.

See SGC's Py-2-cys-Prx structure.

References

1. Z. A. Wood, E. Schröder, J. R. Harris, and L. B. Poole. Structure, mechanism, and regulation of peroxiredoxins. Trends Biochem. Sci. 28 (2003) 32-40.

2. Sylke Müller. Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Molecular Microbiology (2004) 53 (5), 1291–1305

3. Z. Krnajski, R. D. Walter, S. Muller. Isolation and functional analysis of two thioredoxin peroxidases (peroxiredoxins) from Plasmodium falciparum. Molecular & Biochemical Parasitology 113 (2001) 303–308.

4. Kawazu S, Nozaki T, Tsuboi T, Nakano Y, Komaki-Yasuda K, Ikenoue N, Torii M, Kano S. Expression profiles of peroxiredoxin proteins of the rodent malaria parasite Plasmodium yoelii. Int J Parasitol. (2003) Nov; 33(13):1455-61.

5. Choi HJ, Kang SW, Yang CH, Rhee SG, Ryu SE. Crystal structure of a novel human peroxidase enzyme at 2.0 A resolution. Nat Struct Biol. 1998 May;5(5):400-6.

Materials and Methods