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Background  In contrast to many other organisms, the malarial parasite  Plasmodium falciparum  possesses only one typical glutathione  S -transferase. This enzyme,  Pf GST, cannot be assigned to any of the known GST classes and represents a most interesting target for antimalarial drug development. The  Pf GST under native conditions forms non-covalently linked higher aggregates with major population (~98%) being tetramer. However, in the presence of 2 mM GSH, a dimer of  Pf GST is observed. Recently reported study on binding and catalytic properties of  Pf GST indicated a GSH dependent low-high affinity transition with simultaneous binding of two GSH molecules to  Pf GST dimer suggesting that GSH binds to low affinity inactive enzyme dimer converting it to high affinity functionally active dimer. In order to understand the role of GSH in tetramer-dimer transition of  Pf GST as well as in modulation of functional activity of the enzyme, detailed structural, functional and stability studies on recombinant  Pf GST in the presence and absence of GSH were carried out.    Results  Our data indicate that the dimer – and not the tetramer – is the active form of  Pf GST, and that substrate saturation is directly paralleled by dissociation of the tetramer. Furthermore, this dissociation is a reversible process indicating that the tetramer-dimer equilibrium of  Pf GST is defined by the surrounding GSH concentration. Equilibrium denaturation studies show that the  Pf GST tetramer has significantly higher stability compared to the dimer. The enhanced stability of the tetramer is likely to be due to stronger ionic interactions existing in it.    Conclusion  This is the first report for any GST where an alteration in oligomeric structure and not just small conformational change is observed upon GSH binding to the enzyme. Furthermore we also demonstrate a reversible mechanism of regulation of functional activity of  Plasmodium falciparum  glutathione  S -transferase via GSH induced dissociation of functionally inactive tetramer into active dimers.

Glutathione mediated regulation of oligomeric structure and functional activity of Plasmodium falciparum glutathione S-transferase