Abstract
When erythrocytes are exposed to hypoxia, hemoglobin (Hb) stabilizes in the T-state by capturing 2,3-bisphosphoglycerate. This process could reduce the intracellular pool of glycolytic substrates, jeopardizing cellular energetics. Recent observations suggest that hypoxia-induced activation of glycolytic enzymes is correlated with their release from Band III (BIII) on the cell membrane. Based on these data, we developed a mathematical model of erythrocyte metabolism and compared hypoxia-induced differences in predicted activities of the enzymes, their products, and cellular energetics between models with and without the interaction of Hb with BIII. The models predicted that the allostery-dependent Hb interaction with BIII accelerates consumption of upstream glycolytic substrates such as glucose 6-phosphate and increases downstream products such as phosphoenolpyruvate. This prediction was consistent with metabolomic data from capillary electrophoresis mass spectrometry. The hypoxia-induced alterations in the metabolites resulted from acceleration of glycolysis, as judged by increased conversion of [(13)C]glucose to [(13)C]lactate. The allostery-dependent interaction of Hb with BIII appeared to contribute not only to maintenance of energy charge but also to further synthesis of 2,3-bisphosphoglycerate, which could help sustain stabilization of T-state Hb during hypoxia. Furthermore, such an activation of glycolysis was not observed when Hb was stabilized in R-state by treating the cells with CO. These results suggest that Hb allostery in erythrocytes serves as an O(2)-sensing trigger that drives glycolytic acceleration to stabilize intracellular energetics and promote the ability to release O(2) from the cells.
Highlights
When erythrocytes are exposed to hypoxia, hemoglobin (Hb) stabilizes in the T-state by capturing 2,3-bisphosphoglycerate
We developed a mathematical model of erythrocyte metabolism and compared hypoxia-induced differences in predicted activities of the enzymes, their products, and cellular energetics between models with and without the interaction of Hb with Band III (BIII)
The Model Including BIII-Hb Interaction Predicts Sustained Energy Charge and Accelerated O2 Release—Using the dynamic mathematical model validated by CE-MS analysis, we examined the roles of the BIII-Hb interaction in regulation of cellular energetics and O2 delivery
Summary
When erythrocytes are exposed to hypoxia, hemoglobin (Hb) stabilizes in the T-state by capturing 2,3-bisphosphoglycerate. The allostery-dependent interaction of Hb with BIII appeared to contribute to maintenance of energy charge and to further synthesis of 2,3bisphosphoglycerate, which could help sustain stabilization of T-state Hb during hypoxia Such an activation of glycolysis was not observed when Hb was stabilized in R-state by treating the cells with CO. When exposed to hypoxic conditions, erythrocytes are known to accelerate glucose consumption [1] This event appears to result from acceleration of glycolysis, as judged by the increase in 2,3-BPG [2], a metabolite stabilizing the T-state of Hb. Because T-state Hb has a higher affinity to 2,3BPG and ATP than the R-state Hb, stabilization of the former structure would reduce amounts of free ATP available for maintenance of cellular homeostasis. Tion was unable to reproduce actual alterations in the metabolites, suggesting a pivotal role for this molecular interaction in the maintenance of erythrocyte energetics
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