IJMS, Vol. 18, Pages 2244: Biochemical Analysis of Two Single Mutants that Give Rise to a Polymorphic G6PD A-Double Mutant

IJMS, Vol. 18, Pages 2244: Biochemical Analysis of Two Single Mutants that Give Rise to a Polymorphic G6PD A-Double Mutant

International Journal of Molecular Sciences doi: 10.3390/ijms18112244

Authors: Edson Ramírez-Nava Daniel Ortega-Cuellar Hugo Serrano-Posada Abigail González-Valdez America Vanoye-Carlo Beatriz Hernández-Ochoa Edgar Sierra-Palacios Jessica Hernández-Pineda Eduardo Rodríguez-Bustamante Roberto Arreguin-Espinosa Jesús Oria-Hernández Horacio Reyes-Vivas Jaime Marcial-Quino Saúl Gómez-Manzo

Glucose-6-phosphate dehydrogenase (G6PD) is a key regulatory enzyme that plays a crucial role in the regulation of cellular energy and redox balance. Mutations in the gene encoding G6PD cause the most common enzymopathy that drives hereditary nonspherocytic hemolytic anemia. To gain insights into the effects of mutations in G6PD enzyme efficiency, we have investigated the biochemical, kinetic, and structural changes of three clinical G6PD variants, the single mutations G6PD A+ (Asn126AspD) and G6PD Nefza (Leu323Pro), and the double mutant G6PD A− (Asn126Asp + Leu323Pro). The mutants showed lower residual activity (≤50% of WT G6PD) and displayed important kinetic changes. Although all Class III mutants were located in different regions of the three-dimensional structure of the enzyme and were not close to the active site, these mutants had a deleterious effect over catalytic activity and structural stability. The results indicated that the G6PD Nefza mutation was mainly responsible for the functional and structural alterations observed in the double mutant G6PD A−. Moreover, our study suggests that the G6PD Nefza and G6PD A− mutations affect enzyme functions in a similar fashion to those reported for Class I mutations.

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