Biochemical characterization of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphorybosyltransferase: role of histidine residue in substrate selectivity

Molecular and Biochemical Parasitology
Dhiman SarkarSantanu Datta

Abstract

The enzyme hypoxanthine-guanine phosphorybosyltransferase (HGPRT) in the malarial parasite Plasmodium falciparum (Pf) is central to the salvage pathway for purine nucleotide biosynthesis and is a potential antimalarial chemotherapeutic target. The pH profile of the enzyme activity using xanthine as a substrate shows the possible involvement of a histidine residue in the activity of the enzyme. Chemical modification studies using diethylpyrocarbonate (DEPC) also corroborate this hypothesis. A comparative sequence alignment of Pf HGPRT with the human, Tricomonus foetus and Toxoplasma gondii HGPRT, coupled with the 3D structural alignment between these enzymes indicated that a histidine residue at position 196 of the Pf HGPRT sequence was located in the close proximity to the active site. Site directed mutagenesis of this histidine residue to lysine (the corresponding residue in the human enzyme) specifically abrogated xanthine and guanine utilization of the enzyme without affecting the conversion of hypoxanthine to its corresponding nucleotide. The mechanism of action for this enzyme was evaluated by steady state kinetics for the substrates xanthine, guanine and PRPP and product inhibition studies. The results indicate the possib...Continue Reading

References

Apr 1, 1989·Computer Applications in the Biosciences : CABIOS·D G Higgins, P M Sharp
Aug 15, 1997·Nucleic Acids Research·S H Ke, E L Madison

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Citations

Feb 24, 2016·Molecular and Biochemical Parasitology·Sourav RoyHemalatha Balaram
Feb 10, 2016·Proceedings of the National Academy of Sciences of the United States of America·Hanafy M IsmailStephen A Ward
Apr 10, 2019·Journal of Medicinal Chemistry·Thomas ChevietSuzanne Peyrottes

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