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Allosteric control of hemoglobin S fiber formation by oxygen and its relation to the pathophysiology of sickle cell disease.

氧对血红蛋白S纤维形成的变构控制及其与镰状细胞病病理生理学的关系。

  • 影响因子:8.58
  • DOI:10.1073/pnas.1922004117
  • 作者列表:"Henry ER","Cellmer T","Dunkelberger EB","Metaferia B","Hofrichter J","Li Q","Ostrowski D","Ghirlando R","Louis JM","Moutereau S","Galactéros F","Thein SL","Bartolucci P","Eaton WA
  • 发表时间:2020-06-30
Abstract

:The pathology of sickle cell disease is caused by polymerization of the abnormal hemoglobin S upon deoxygenation in the tissues to form fibers in red cells, causing them to deform and occlude the circulation. Drugs that allosterically shift the quaternary equilibrium from the polymerizing T quaternary structure to the nonpolymerizing R quaternary structure are now being developed. Here we update our understanding on the allosteric control of fiber formation at equilibrium by showing how the simplest extension of the classic quaternary two-state allosteric model of Monod, Wyman, and Changeux to include tertiary conformational changes provides a better quantitative description. We also show that if fiber formation is at equilibrium in vivo, the vast majority of cells in most tissues would contain fibers, indicating that it is unlikely that the disease would be survivable once the nonpolymerizing fetal hemoglobin has been replaced by adult hemoglobin S at about 1 y after birth. Calculations of sickling times, based on a recently discovered universal relation between the delay time prior to fiber formation and supersaturation, show that in vivo fiber formation is very far from equilibrium. Our analysis indicates that patients survive because the delay period allows the majority of cells to escape the small vessels of the tissues before fibers form. The enormous sensitivity of the duration of the delay period to intracellular hemoglobin composition also explains why sickle trait, the heterozygous condition, and the compound heterozygous condition of hemoglobin S with pancellular hereditary persistence of fetal hemoglobin are both relatively benign conditions.

摘要

: 镰状细胞病的病理是由于组织中脱氧时异常血红蛋白S聚合,在红细胞中形成纤维,使其变形并阻塞循环。目前正在开发将四元平衡从聚合T四元结构转变为非聚合R四元结构的药物。在这里,我们更新了我们对平衡时纤维形成的变构控制的理解,展示了Monod,Wyman和Changeux的经典四元双态变构模型的最简单扩展如何包括三级构象变化提供了更好的定量描述。我们还表明,如果纤维形成在体内处于平衡状态,大多数组织中的绝大多数细胞将含有纤维,这表明一旦非聚合胎儿血红蛋白在出生后约1岁时被成人血红蛋白S取代,该疾病就不太可能存活。基于最近发现的纤维形成之前的延迟时间和过饱和之间的普遍关系,对镰形时间的计算表明,体内纤维形成非常远离平衡。我们的分析表明,患者存活是因为延迟期允许大多数细胞在纤维形成之前逃离组织的小血管。延迟期的持续时间对细胞内血红蛋白组成的巨大敏感性也解释了为什么镰状性状、杂合状态和血红蛋白S的复合杂合状态与胎儿血红蛋白的pancellular遗传性持续存在都是相对良性的情况。

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影响因子:1.74
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翻译标题与摘要 下载文献
血红蛋白病方向

由于血红蛋白分子结构异常(异常血红蛋白病),或珠蛋白肽链合成速率异常(珠蛋白生成障碍性贫血,又称海洋性贫血)所引起的一组遗传性血液病。

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