Single-Nucleotide Polymorphisms in Glucose-6-Phosphate Dehydrogenase and their Relevance for the Deployment of Primaquine as a Radical Cure for Malaria

Abstract

Malaria remains an important public health problem despite efforts to control it. Besides active transmission, relapsing malaria caused by dormant liver stages of Plasmodium vivax and Plasmodium ovale hypnozoites is a major hurdle in malaria control and elimination programs. Primaquine (PQ) is the most widely used drug for radical cure of malaria. Due to its anti-hypnozoite and gametocidal activity, PQ plays a key role in malaria relapse and transmission. The human enzyme glucose-6-phosphate dehydrogenase (G6PD) is crucial in determining the safety of PQ because G6PD-deficient individuals are prone to hemolysis if treated with PQ. Therefore, there is a need to study the prevalence of G6PD-deficient genetic variants in endemic populations to assess the risk of PQ treatment and the necessity to develop alternative treatments. In this work, we discuss the common G6PD variants, their varying enzymatic activity, and their distribution on the three-dimensional structure of G6PD. Our work highlights the important G6PD variants and the need for large-scale G6PD gene polymorphism studies to predict populations at risk of PQ-induced toxicity.

Figure 1.

Primaquine (PQ) treatment outcome in glucose-6-phosphate dehydrogenase (G6PD)-normal and G6PD-deficient individuals.

Figure 2.

Structural mapping of worldwide variants on the three-dimensional structure of wild-type human glucose-6-phosphate dehydrogenase (G6PD) (PDB IDs: 2BHL and 2BH9; Protein Data Bank; www.rcsb.org). G6PD dimer is shown as surface, and monomers are colored white and grey. Structural NADP⁺ is colored orange; catalytic NADP⁺ is colored green and shown as surface. Substrate G6P is colored yellow. Class I, II, and III mutations are colored blue, cyan, and teal, respectively. Two prominent clusters of class I mutations are marked with magenta spheres. Class I mutations cluster proximal to the structural NADP⁺ binding site, and the dimer interface and Veracruz R365H, in particular, is present at the active site Supplemental Table 1). Class II and III mutations lie scattered on the enzyme surface. Two class II mutations are present in the dimer interface Supplemental Table 1). The ligands and mutations are highlighted for only one monomer for simplicity. All depictions are made using Pymol (www.pymol.org).

Figure 3.

Prevalent glucose-6-phosphate dehydrogenase (G6PD) variants in Asia including Plasmodium vivax–endemic countries. The G6PD dimer is shown as a ribbon, and monomers are colored white and grey. Structural NADP⁺ is colored orange, and catalytic NADP⁺ is colored green and shown as surface. Substrate G6P is colored yellow. Class II and III mutations are colored cyan and teal, respectively. Buried residues are marked with a red star. The ligands and mutations are highlighted for only one monomer for simplicity.