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Publications

Journal Article Epublish

PubMed: 39684266 DOI: 10.3390/ijms252312556

Evaluation of Three Mutations in Codon 385 of Glucose-6-Phosphate Dehydrogenase via Biochemical and In Silico Analysis.

Int J Mol Sci 25(23)

Authors: Adriana Gálvez-Ramírez, Abigail González-Valdez, Beatriz Hernández-Ochoa, Luis Miguel Canseco-Ávila, Alexander López-Roblero, Roberto Arreguin-Espinosa, Verónica Pérez de la Cruz, Elizabeth Hernández-Urzua, Noemi Cárdenas-Rodríguez, Sergio Enríquez-Flores, Ignacio De la Mora-De la Mora, Abraham Vidal-Limon, Saúl Gómez-Manzo

Affiliations

  • Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico.
  • Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Laboratorio de Inmunoquímica, Hospital Infantil de México Federico Gómez, Secretaría de Salud, Mexico City 06720, Mexico.
  • Facultad de Ciencias Químicas, Campus IV, Universidad Autónoma de Chiapas, Tapachula City 30580, Mexico.
  • Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
  • Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico.
  • Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico.
  • Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico.
  • Laboratorio de Biomoléculas y Salud Infantil, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico.
  • Red de Estudios Moleculares Avanzados, Clúster Científico y Tecnológico BioMimic, Instituto de Ecología A.C. (INECOL), Carretera Antigua a Coatepec 351, El Haya, Xalapa 91073, Mexico.

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an enzymopathy that affects approximately 500 million people worldwide. A great number of mutations in the gene have been described. However, three class A G6PD variants known as G6PD Tomah (C385R), G6PD Kangnam (C385G), and G6PD Madrid (C385W) have been reported to be clinically important due to their associations with severe clinical manifestations such as hemolytic anemia. Therefore, this work aimed to perform, for the first time, biochemical and functional characterizations of these variants. The G6PD variants were cloned and purified for this purpose, followed by analyses of their kinetic parameters and thermal stability, as well as in silico studies. The results showed that the mutations induced changes in the proteins. Regarding the kinetic parameters, it was observed that the three variants showed lower affinities for G6P and NADP, as well as lower thermal stability compared to WT-G6PD. Molecular dynamics simulations showed that C385 mutations induced changes around neighboring amino acids. Metadynamics simulations showed that most remarkable changes account for the binding pocket volumes, particularly in the structural NADP binding site, with a concomitant loss of affinity for catalytic processes.

MeSH

Oxidoreductases, Codon, Molecular Dynamics Simulation, Glucose-6-Phosphate, Mutation, Glucosephosphate Dehydrogenase