Abstract
We have recently demonstrated that the rate-limiting enzymes in human glucose metabolism organize into cytoplasmic clusters to form a multienzyme complex, the glucosome, in at least three different sizes. Quantitative high-content imaging data support a hypothesis that the glucosome clusters regulate the direction of glucose flux between energy metabolism and building block biosynthesis in a cluster size-dependent manner. However, direct measurement of their functional contributions to cellular metabolism at subcellular levels has remained challenging. In this work, we develop a mathematical model using a system of ordinary differential equations, in which the association of the rate-limiting enzymes into multienzyme complexes is included as an essential element. We then demonstrate that our mathematical model provides a quantitative principle to simulate glucose flux at both subcellular and population levels in human cancer cells. Lastly, we use the model to simulate 2-deoxyglucose-mediated alteration of glucose flux in a population level based on subcellular high-content imaging data. Collectively, we introduce a new mathematical model for human glucose metabolism, which promotes our understanding of functional roles of differently sized multienzyme complexes in both single-cell and population levels.
Highlights
IntroductionGlucose metabolism consists of glycolysis and gluconeogenesis. Glycolysis converts glucose into pyruvate, whereas gluconeogenesis reverses the sequential reactions to produce glucose[1]
Glucose metabolism consists of glycolysis and gluconeogenesis where three irreversible reactions are involved in glycolysis, four irreversible reactions in gluconeogenesis, and seven reversible reactions in both pathways
We constructed a simple mathematical model to understand the cluster size-dependent functional contributions of metabolic enzymes and their multienzyme complexes to cancer cell metabolism
Summary
Glucose metabolism consists of glycolysis and gluconeogenesis. Glycolysis converts glucose into pyruvate, whereas gluconeogenesis reverses the sequential reactions to produce glucose[1]. Understanding the mechanism of glucose flux regulation between energy metabolism and building block biosynthesis is important to address altered metabolic phenotypes in human cancer as well as other chronic diseases, including but not limited to diabetes and obesity[2]. Recent mathematical models for human liver or cancer cells cover a complicated network beyond glycolysis by including the pentose phosphate pathway, serine biosynthesis, glutamine metabolism, and/or mitochondrial metabolism[13,14]. Our mathematical model includes enzyme kinetics and their allosteric regulation and spatial compartmentalization of the rate-limiting enzymes of the pathway, allowing us to understand the metabolic contributions of glucose flux at both single-cell and population levels
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