Abstract
In this paper, we develop a comprehensive mathematical model to describe the phosphorylation of glucose by the enzyme hexokinase I. Glucose phosphorylation is the first step of the glycolytic pathway, and as such, it is carefully regulated in cells. Hexokinase I phosphorylates glucose to produce glucose-6-phosphate, and the cell regulates the phosphorylation rate by inhibiting the action of this enzyme. The cell uses three inhibitory processes to regulate the enzyme: an allosteric product inhibitory process, a competitive product inhibitory process, and a competitive inhibitory process. Surprisingly, the cellular regulation of hexokinase I is not yet fully resolved, and so, in this study, we developed a detailed mathematical model to help unpack the behaviour. Numerical simulations of the model produced results that were consistent with the experimentally determined behaviour of hexokinase I. In addition, the simulations provided biological insights into the abstruse enzymatic behaviour, such as the dependence of the phosphorylation rate on the concentration of inorganic phosphate or the concentration of the product glucose-6-phosphate. A global sensitivity analysis of the model was implemented to help identify the key mechanisms of hexokinase I regulation. The sensitivity analysis also enabled the development of a simpler model that produced an output that was very close to that of the full model. Finally, the potential utility of the model in assisting experimental studies is briefly indicated.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
The mathematical model we developed for the phosphorylation of glucose is necessarily large and complex since it describes multiple binding sites, numerous species, almost 150 chemical reactions, and various inhibitory mechanisms
The Sobol global sensitivity analysis employed in the current study was described in the Methods Section, and it was implemented using the SALib package [59]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Glucose is a major source of energy for most living organisms. Glucose glycolysis is a key pathway for the production of energy in a cell [1], and glycolytic intermediates form precursors for the biosynthesis of other key cellular constituents, such as glycogen, nucleotide sugars, and hyaluronan. The first step of glycolysis is the transformation of glucose into glucose-6-phosphate. This is achieved via a phosphorylation that is catalysed by an enzyme called hexokinase. There are four isozymes of hexokinase found in mammalian tissue [2,3], and these are usually referred to as hexokinase I, II, III, and IV (glucokinase)
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