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International journal of molecular sciences
Nov 22, 2024;25 (23):

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

Adriana G��lvez-Ram��rez, Abigail Gonz��lez-Valdez, Beatriz Hern��ndez-Ochoa, Luis Miguel Canseco-��vila, Alexander L��pez-Roblero, Roberto Arreguin-Espinosa, Ver��nica P��rez de la Cruz, Elizabeth Hern��ndez-Urzua, Noemi C��rdenas-Rodr��guez, Sergio Enr��quez-Flores, Ignacio De la Mora-De la Mora, Abraham Vidal-Limon, Sa��l G��mez-Manzo
Author Information
  1. Adriana G��lvez-Ram��rez: Laboratorio de Bioqu��mica Gen��tica, Instituto Nacional de Pediatr��a, Secretar��a de Salud, Mexico City 04530, Mexico.
  2. Abigail Gonz��lez-Valdez: Departamento de Biolog��a Molecular y Biotecnolog��a, Instituto de Investigaciones Biom��dicas, Universidad Nacional Aut��noma de M��xico, Mexico City 04510, Mexico.
  3. Beatriz Hern��ndez-Ochoa: Laboratorio de Inmunoqu��mica, Hospital Infantil de M��xico Federico G��mez, Secretar��a de Salud, Mexico City 06720, Mexico.
  4. Luis Miguel Canseco-��vila: Facultad de Ciencias Qu��micas, Campus IV, Universidad Aut��noma de Chiapas, Tapachula City 30580, Mexico. ORCID
  5. Alexander L��pez-Roblero: Facultad de Ciencias Qu��micas, Campus IV, Universidad Aut��noma de Chiapas, Tapachula City 30580, Mexico. ORCID
  6. Roberto Arreguin-Espinosa: Departamento de Qu��mica de Biomacromol��culas, Instituto de Qu��mica, Universidad Nacional Aut��noma de M��xico, Mexico City 04510, Mexico. ORCID
  7. Ver��nica P��rez de la Cruz: Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery "Manuel Velasco Su��rez", Mexico City 14269, Mexico. ORCID
  8. Elizabeth Hern��ndez-Urzua: Laboratorio de Toxicolog��a Gen��tica, Instituto Nacional de Pediatr��a, Secretar��a de Salud, Mexico City 04530, Mexico.
  9. Noemi C��rdenas-Rodr��guez: Laboratorio de Neurociencias, Instituto Nacional de Pediatr��a, Secretar��a de Salud, Mexico City 04530, Mexico. ORCID
  10. Sergio Enr��quez-Flores: Laboratorio de Biomol��culas y Salud Infantil, Instituto Nacional de Pediatr��a, Secretar��a de Salud, Mexico City 04530, Mexico. ORCID
  11. Ignacio De la Mora-De la Mora: Laboratorio de Biomol��culas y Salud Infantil, Instituto Nacional de Pediatr��a, Secretar��a de Salud, Mexico City 04530, Mexico. ORCID
  12. Abraham Vidal-Limon: Red de Estudios Moleculares Avanzados, Cl��ster Cient��fico y Tecnol��gico BioMimic, Instituto de Ecolog��a A.C. (INECOL), Carretera Antigua a Coatepec 351, El Haya, Xalapa 91073, Mexico. ORCID
  13. Sa��l G��mez-Manzo: Laboratorio de Bioqu��mica Gen��tica, Instituto Nacional de Pediatr��a, Secretar��a de Salud, Mexico City 04530, Mexico. ORCID
PMID: 39684266 DOI: 10.3390/ijms252312556

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.

Keywords

G6PD molecular dynamics simulations mutations

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Grants

  1. INP 034/2022/E022 Program, National Institute of Pediatrics, Mexico City, Mexico (Recursos Fiscales para la Investigaci��n)
  2. HIM/2019/036 SSA. 1595/Program Hospital Infantil de Mexico Federico G��mez, Mexico City, Mexico (Fondos Federales)
  3. TKII-AMVL001/National Supercomputing Center-IPICYT

MeSH Term

Glucosephosphate Dehydrogenase
Humans
Molecular Dynamics Simulation
Mutation
Kinetics
Glucosephosphate Dehydrogenase Deficiency
Codon
NADP
Computer Simulation
Enzyme Stability

Chemicals

Glucosephosphate Dehydrogenase
Codon
NADP
G6PD protein, human
Journal Article

Word Cloud

Created with Highcharts 10.0.0G6PDmutationsvariantsshowedchangessimulationsthreekineticparametersthermalstabilitywellinducedlowerNADPdynamicsbindingGlucose-6-phosphatedehydrogenasedeficiencyenzymopathyaffectsapproximately500millionpeopleworldwidegreatnumbergenedescribedHoweverclassknownTomahC385RKangnamC385GMadridC385WreportedclinicallyimportantdueassociationssevereclinicalmanifestationshemolyticanemiaThereforeworkaimedperformfirsttimebiochemicalfunctionalcharacterizationsclonedpurifiedpurposefollowedanalysessilicostudiesresultsproteinsRegardingobservedaffinitiesG6PcomparedWT-G6PDMolecularC385aroundneighboringaminoacidsMetadynamicsremarkableaccountpocketvolumesparticularlystructuralsiteconcomitantlossaffinitycatalyticprocessesEvaluationThreeMutationsCodon385Glucose-6-PhosphateDehydrogenaseviaBiochemicalSilicoAnalysismolecular

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