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Biochemical Analysis of Two Single Mutants that Give Rise to a Polymorphic G6PD A-Double Mutant

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 th...

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Detalles Bibliográficos
Autores principales: Ramírez-Nava, Edson Jiovany, Ortega-Cuellar, Daniel, Serrano-Posada, Hugo, González-Valdez, Abigail, Vanoye-Carlo, America, Hernández-Ochoa, Beatriz, Sierra-Palacios, Edgar, Hernández-Pineda, Jessica, Rodríguez-Bustamante, Eduardo, Arreguin-Espinosa, Roberto, Oria-Hernández, Jesús, Reyes-Vivas, Horacio, Marcial-Quino, Jaime, Gómez-Manzo, Saúl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713214/
https://www.ncbi.nlm.nih.gov/pubmed/29072585
http://dx.doi.org/10.3390/ijms18112244
Descripción
Sumario: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.