Molecular and functional analysis of Glucose-6-phosphate dehydrogenase variants

Abstract

Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is a hereditary genetic defect which is one of the most prevalent polymorphisms and enzymopathies in humans, affecting approximately 500 million people worldwide. Antimalarial medications, such as primaquine and tafenoquine, have been linked to the hemolysis in the G6PD-deficient individuals. As a result, hemolytic toxicity caused by G6PD deficiency has a significant impact on the malaria treatment, particularly in the malaria-endemic areas. In addition, the risk of hemolytic anemia varies widely among the G6PD-deficient individuals. In order to understand the molecular mechanisms underlying the clinical features of G6PD deficiency, the biochemical properties and structural stability of eleven G6PD variants which included three single, seven double, and one triple variants were investigated in this study. All G6PD variants were constructed, expressed, purified, and biochemically characterized. G6PD A, a neutral variant, shared the similar biochemical properties and structural staiblity to the native enzyme. Among other G6PD variants studied here, the structural instability largely contributed to the enzyme deficiency and, as a consequence, to clinical manifestations.The cumulative effects between two and three mutations, sharing G6PD A and causing the G6PD deficiency, were observed in the G6PD variants with double and triple mutations.