KINETICS AND MECHANISM OF DEOXYHEMOGLOBIN-S GELATION - NEW APPROACH TO UNDERSTANDING SICKLE-CELL DISEASE
KINETICS AND MECHANISM OF DEOXYHEMOGLOBIN-S GELATION - NEW APPROACH TO UNDERSTANDING SICKLE-CELL DISEASE
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DOI：
10.1073/pnas.71.12.4864
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发表时间：
1974-01-01
影响因子：
11.1
通讯作者：
EATON, WA
中科院分区：
文献类型：
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作者：
HOFRICHTER, J;ROSS, PD;EATON, WA
我们报告了纯化脱氧血红蛋白 S 凝胶化的动力学研究结果。凝胶化是通过升高温度来诱导的，并通过使用微热量计测量吸收的热量和使用显微分光光度计测量线性双折射的出现来监测凝胶化。动力学是不寻常的。凝胶化开始之前有一段延迟期，随后是 S 形进度曲线。延迟时间在形式上取决于脱氧血红蛋白 S 浓度的大约 30 次方；浓度从 23 g/dl 降低至 22 g/dl 会使延迟时间增加四倍。它还非常依赖于温度； 20-30°C 范围内温度升高 1°C 几乎使延迟时间减半。从这些结果我们得出结论，初始速率是由单个纤维的成核控制的。我们提出了一个动力学模型，该模型解释了凝胶反应初始阶段的浓度、温度和时间依赖性。将我们的数据外推到生理条件预测，体内可实现的细胞内血红蛋白浓度和氧饱和度的变化会产生延迟时间的巨大变化。延迟时间的范围涵盖平均毛细血管通过时间和总循环时间。这一结果表明延迟时间是决定镰状细胞病病程的一个极其重要的变量，并提出了一种新的治疗方法。
We report the results of a kinetic investigation on the gelation of purified deoxyhemoglobin S. Gelation was induced by raising the temperature and was monitored by measuring both the heat absorbed, with a microcalorimeter, and the appearance of linear birefringence, with a microspectrophotometer. The kinetics are unusual. Prior to the onset of gelation there is a delay period, followed by a sigmoidal progress curve. The delay time is formally dependent on approximately the 30th power of the deoxyhemoglobin S concentration; a decrease in concentration from 23 to 22 g/dl increases the delay time by a factor of four. It is also extremely temperature dependent; a 1°C temperature rise in the range 20-30°C almost halves the delay time. From these results we conclude that the initial rate is controlled by the nucleation of individual fibers. We present a kinetic model that accounts for the concentration, temperature, and time dependence of the initial phase of the gelation reaction. Extrapolation of our data to physiological conditions predicts that changes in intracellular hemoglobin concentration and oxygen saturation, realizablein vivo, produce enormous changes in the delay time. The range of delay times spans both the mean capillary transit and total circulation times. This result points to the delay time as an extremely important variable in determining the course of sickle cell disease, and suggests a new approach to therapy.