Roles of hemoglobin Allostery in hypoxia-induced metabolic alterations in erythrocytes: simulation and its verification by metabolome analysis.

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.

• Authors: Ayako Kinoshita, Kosuke Tsukada, Tomoyoshi Soga, Takako Hishiki, Yuki Ueno, Yoichi Nakayama, Masaru Tomita, Makoto Suematsu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 14 Pg. 10731-41 (Apr 06 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17289676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hemoglobins
• Proteome
• Carbon Monoxide
• Oxygen

Topics

• Carbon Monoxide (metabolism)
• Cell Hypoxia
• Erythrocytes (enzymology)
• Glycolysis
• Hemoglobins (metabolism)
• Humans
• Models, Biological
• Oxygen (metabolism)
• Proteome (metabolism)