Bioinformatic Analysis of Plasmodium berghei Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGPRT): a Potential Therapeutic Target

Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGPRT) is essential for purine nucleotide and nucleic acid synthesis in the malaria parasite, Plasmodium spp. The gene is annotated as encoding PRTase activity and proposed as essential for P. berghei survival. The aims of this work were to investigate the HGPRT structure from P. berghei and to compare the key features of the enzyme to other PRTases employing computational modeling, and bioinformatic tools. Bioinformatics was employed to analyze the sequence of P. berghei HGPRT, and a structural model of the HGPRT was built using comparative modelling techniques. It was demonstrated that the HGPRT gene of P. berghei encodes a functional fold of the phosphoribosyltransferase family. Sequence Analysis showed that the HGPRT is significantly divergent from equivalent mammalian enzymes. Modelling identified specific features of PbHGPRT and key residues involved in binding ligands and catalysis. A model of an open, unliganded form of PbHPRT was constructed based on sequence homology to P. falciparum, human, Toxoplasma gondii and Bacillus anthracis HGPRT using the program PHYRE2. The active site of the open structure is much larger and will be useful for docking of inhibitors. The P. berghei HGPRT is structurally similar to P. falciparum HGPRT and other RPTases, but there were significant differences in the RPTase domain of PbHGPRT and other RPTases.