Plasmodium Glutamine Synthetase as Antimalarial Target

Example 1

Plasmodium glutamine synthetase has not been examined as a target for antimalarial development. PlasmoDB (plasmodb.org/plasmo/app/), a functional genomic database for malaria parasites reveals that P. falciparum possesses only a single GS gene in the genome (Gene ID: PF3D7_0922600). There are three distinct groups of glutamine synthetases. Type I (GS-I, encoded by glnA) and type II (GS-II, glnII) are the predominant forms in prokaryotes and eukaryotes, respectively. Type III (GS-III, glnN) was recently recognized in a few prokaryotes and eukaryotes. A phylogenetic analysis of representative parasite GS from seven phyla and one division was conducted (FIG. 1). GS-II, the predominant form in eukaryotes, is found in three phyla and one division, and GS-III is found in four phyla. In contrast, GS-I, the predominant form in prokaryotes, is also present in the eukaryotic phylum Apicomplexa, including Plasmodium species. The single exception is Perkinsus marinus in the phylum Perkinsozoa. The results demonstrate that Plasmodium GS belongs to the GS-I family. This is consistent with the recent cryoEM structure of PfGS, which shows that it is structurally similar to Salmonella enterica GS-I, forming a homo-dodecameric complex that adopts a two-tiered ring shape with hexametric symmetry.