Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery

Abstract

The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs) of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial.

Keywords: Plasmodium falciparum; animal models; malaria; thioredoxin reductase.

Figure 1

The dimeric structure of P. falciparum thioredoxin reductase (TrxR). The two subunits of TrxR are shown with their bound FAD cofactors in magenta. The redox active disulfide (C88–C93) of the N-terminal redox center is shown for the TrxR monomer on the lower left. H509 and E514 that modulate the reactivity of this N-terminal redox center are supplied by the TrxR monomer on the upper right. Each monomer is bound to substrate Trx via intermolecular disulfide (TrxR C540 to Trx C30). The positions of C535 (TrxR) and C33 (Trx) are indicated by serine residues. These substitutions were made in order to trap the intermolecular disulfide between TrxR and Trx [23]. The 535 and 540 residues shown are supplied by the TrxR monomer on the upper right. The Plasmodium-unique insertions H438–S452 and G536–K539 are highlighted by a and b, respectively. Coordinates are drawn from PDB accession 4J56 [23]. The figure was generated using PyMOL 1.6.0.0.

Figure 2

Active site comparison between human and Plasmodium species for (A) the N-Terminal and (B) the C-Terminal. Black shaded amino acids represent identity with the corresponding black shaded amino acids of other species’ TrxR while grey represents amino acids with similar properties and no shading represent no identity. The figure was generated with ClustalW2 MSA (Multiple Sequence Alignment) program.