In Silico Modeling of Glucokinase Mutation Effect on Thermodynamics and Enzymatic Kinetics in Diabetes Mechanism
DOI:
https://doi.org/10.18196/mmjkk.v25i2.27011Keywords:
Diabetes Melitus, Enzyme Kinetics, Glucokinase, MODY2, ThermodynamicsAbstract
Mutations in the glucokinase (GCK) enzyme can disrupt the glucose metabolism pathway, potentially increasing the risk of diabetes mellitus. This study attempts to examine the impact of GCK mutations in silico, focusing on thermodynamic and kinetic aspects. Four specific GCK mutations (43 R→H, 131 S→P, 160 D→N, 182 V→L) were analyzed at physiologically temperatures (298-313K) and pH 7.4. Computational analysis revealed that all mutations significantly altered Gibbs free energy (ΔG) values, with the wild-type enzyme showing -14.39J compared to substantially reduced negative values (-1.23J to -2.94J) in mutant forms. Enthalpy changes (ΔH) demonstrated significant linear regression relationships (p<0.05) for most mutations, indicating thermodynamic destabilization of the enzyme structure. Reaction rate constants showed decreased catalytic efficiency across all mutations (wild-type: 1.614×1027 s-1 vs. mutants: 1.606 - 1.607×1027 s-1). Three-dimensional visualizations confirmed structural perturbations at mutation sites. These findings suggest that GCK mutations impair glucose-sensing capabilities through dual mechanisms: reduced catalytic efficiency and thermodynamic instability, potentially the altered insulin secretion thresholds observed in Maturity-Onset Diabetes of the Young type 2 (MODY2) and other diabetes subtypes. Integrating kinetic and thermodynamic parameters provides valuable insights for developing targeted therapeutics such as glucokinase activators (GKAs), offering a ray of hope for diabetes treatment.
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