Roles of hemoglobin allostery in hypoxia-induced metabolic alterations in erythrocytes - Simulation and its verification by metabolome analysis
Roles of hemoglobin allostery in hypoxia-induced metabolic alterations in erythrocytes - Simulation and its verification by metabolome analysis
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DOI：
10.1074/jbc.m610717200
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发表时间：
2007-04-06
影响因子：
4.8
通讯作者：
Suematsu, Makoto
中科院分区：
文献类型：
--
作者：
Kinoshita, Ayako;Tsukada, Kosuke;Suematsu, Makoto
当红细胞暴露于缺氧时，血红蛋白（Hb）通过捕获2，3-二磷酸甘油酸稳定在T状态。这一过程可能会减少糖酵解底物的细胞内池，危及细胞能量。最近的观察表明，缺氧诱导的糖酵解酶的激活与它们从细胞膜上的带III（BIII）释放有关。基于这些数据，我们开发了一个数学模型的红细胞代谢和比较缺氧诱导的差异，预测活动的酶，其产品，和细胞能量模型之间的相互作用和没有Hb与BIII。该模型预测，变构依赖性Hb与BIII的相互作用加速了上游糖酵解底物（如葡萄糖6-磷酸）的消耗，并增加了下游产物（如磷酸烯醇丙酮酸）。这一预测与毛细管电泳质谱的代谢组学数据一致。通过[ C-13]葡萄糖转化为[C-13]乳酸的增加来判断，缺氧诱导的代谢物变化是由于糖酵解加速所致。Hb与BIII的变构依赖性相互作用似乎不仅有助于维持能量电荷，而且还有助于进一步合成2，3-二磷酸甘油酸，这有助于维持缺氧期间T状态Hb的稳定。此外，这种激活的糖酵解没有观察到血红蛋白时，稳定在R-状态处理的细胞与CO。这些结果表明，血红蛋白变构在红细胞作为一个O-2传感触发器，驱动糖酵解加速，以稳定细胞内的能量，并促进从细胞释放O-2的能力。
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 [ C-13] glucose to [ C-13] 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.