Structural, functional and unfolding characteristics of glutathione S-transferase of Plasmodium vivax.
Glutathione S-transferases (GSTs) of Plasmodium parasites are potential targets for antimalarial drug and vaccine development. We investigated the equilibrium unfolding, functional activity regulation and stability characteristics of the unique GST of Plasmodium vivax (PvGST). Despite high sequence, structural, functional, and evolutionary similarity, the unfolding behavior of PvGST was significantly different from Plasmodium falciparum GST (PfGST). The unfolding pathway of PvGST was non-cooperative with stabilization of an inactive dimeric intermediate. The absence of any compact, folded monomeric intermediate during the unfolding transition suggests that inter-subunit interactions play an important role in stabilizing the protein. Presence of salts effectively inhibited PvGST enzymatic activity by quenching the nucleophilicity of the thiolate anion of GSH. Based on the present findings, together with our previous studies on PfGST, we propose that the regulation of GST enzymatic activity through a dimer-tetramer transition via GSH binding is an exclusive feature of Plasmodium.
Tripathi
Timir
T
Division of Molecular and Structural Biology, Central Drug Research Institute, Lucknow 226 001, India.
Na
Byoung-Kuk
BK
Sohn
Woon-Mok
WM
Becker
Katja
K
Bhakuni
Vinod
V
D000818:Animals; D004795:Enzyme Stability / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism*; D019791:Guanidine / Q000494:pharmacology; D008958:Models, Molecular; D010966:Plasmodium vivax / Q000201:enzymology*; D011489:Protein Denaturation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D012492:Salts / Q000494:pharmacology; D012997:Solvents / Q000494:pharmacology; D013057:Spectrum Analysis; D014508:Urea / Q000494:pharmacology
D012492:Salts; D012997:Solvents; D014508:Urea; D005982:Glutathione Transferase; D005978:Glutathione; D019791:Guanidine