Scrima Rosella, Fugetto Sabino, Capitanio Nazzareno, Gatti Domenico L
Department of Clinical and Experimental Medicine, University of Foggia, Via L. Pinto 1, Foggia, Italy.
Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI, USA.
Discoveries (Craiova). 2022 Jun 30;10(2):e146. doi: 10.15190/d.2022.5. eCollection 2022 Apr-Jun.
Abnormal hemoglobins can have major consequences for tissue delivery of oxygen. Correct diagnosis of hemoglobinopathies with altered oxygen affinity requires a determination of hemoglobin oxygen dissociation curve, which relates the hemoglobin oxygen saturation to the partial pressure of oxygen in the blood. Determination of the oxygen dissociation curve of human hemoglobin is typically carried out under conditions in which hemoglobin is in equilibrium with O2 at each partial pressure. However, in the human body due to the fast transit of red blood cells through tissues hemoglobin oxygen exchanges occur under non-equilibrium conditions. We describe the determination of non-equilibrium oxygen dissociation curve and show that under these conditions the true nature of hemoglobin cooperativity is revealed as emerging solely from the consecutive binding of oxygen to each one of the four subunits of hemoglobin until the entire tetramer is saturated. We call this form of cooperativity the sequential cooperativity of hemoglobin and define the simplest model that includes it as the minimalist model of hemoglobin. A single instantiation of this model accounts for ~70% of hemoglobin cooperativity under non-equilibrium conditions. The total cooperativity of hemoglobin can be viewed more correctly as the summation of two instantiations of the minimalist model (each one corresponding to a tetramer of low and high affinity for O2, respectively) in equilibrium with each other, as in the Monod-Wyman-Changeux model of hemoglobin. In addition to offering new insights on the nature of hemoglobin reaction with oxygen, the methodology described here for the determination of hemoglobin non-equilibrium oxygen dissociation curve provides a simple, fast, low-cost alternative to complex spectrophotometric methods, which is expected to be particularly valuable in regions where hemoglobinopathies are a significant public health problem, but where highly specialized laboratories capable of determining a traditional oxygen dissociation curve are not easily accessible.
异常血红蛋白可对组织的氧气输送产生重大影响。要正确诊断氧亲和力改变的血红蛋白病，需要测定血红蛋白氧解离曲线，该曲线将血红蛋白氧饱和度与血液中的氧分压联系起来。人体血红蛋白氧解离曲线的测定通常是在血红蛋白与每个分压下的O₂处于平衡的条件下进行的。然而，在人体中，由于红细胞在组织中的快速通过，血红蛋白氧交换是在非平衡条件下发生的。我们描述了非平衡氧解离曲线的测定，并表明在这些条件下，血红蛋白协同性的真正本质表现为仅源于氧气与血红蛋白四个亚基中的每一个依次结合，直到整个四聚体饱和。我们将这种协同形式称为血红蛋白的顺序协同性，并将包含它的最简单模型定义为血红蛋白的极简模型。在非平衡条件下，该模型的单个实例占血红蛋白协同性的约70%。血红蛋白的总协同性可以更准确地看作是极简模型的两个实例（分别对应于对O₂具有低亲和力和高亲和力的四聚体）相互平衡的总和，就像血红蛋白的莫诺德 - 怀曼 - 尚热模型一样。除了为血红蛋白与氧反应的本质提供新见解外，这里描述的测定血红蛋白非平衡氧解离曲线的方法为复杂的分光光度法提供了一种简单、快速、低成本的替代方法，预计在血红蛋白病是重大公共卫生问题，但难以获得能够测定传统氧解离曲线的高度专业化实验室的地区尤其有价值。
