Hydrotropic function of ATP in the crystalline lens
Hydrotropic function of ATP in the crystalline lens
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DOI：
10.1016/j.exer.2019.107862
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发表时间：
2020-01-01
影响因子：
3.4
通讯作者：
Glonek, Thomas
中科院分区：
文献类型：
--
作者：
Greiner, Jack, V;Glonek, Thomas
本文提出的假说是为了解释意外高浓度的三磷酸腺苷，并提供证据支持它在用P-31核磁共振测定的晶体中的水生作用。晶状体在历史上被认为是一个代谢静止的器官，具有合成ATP所需的机械，从而使体内平衡水平保持在约3 mm。这种相对较高浓度的ATP已被发现在包括人类在内的多种哺乳动物物种中是一致的。这个毫摩尔量比ATP的其他已知功能所需的微摩尔量大许多倍。最近的假设是，在毫摩尔浓度下，ATP在各种细胞/组织匀浆中起着水力作用，防止蛋白质聚集，与本文中的观察相结合，支持了这样的假设，即ATP不仅在匀浆中起水力作用，而且在一个完整的功能器官--晶体晶状体中起作用。这种浓度的三磷酸腺苷被认为是维持蛋白质溶解度和有效防止蛋白质聚集所必需的。考虑到蛋白质聚集是年龄相关性白内障的病因，这一概念很重要。三磷酸腺苷是一种普遍存在的胞内分子，具有维持胞内蛋白质在流体中的非聚集状态所必需的亲水性。两亲性的三磷酸腺苷分子屏蔽了晶状体内纤维细胞蛋白质分子上的疏水区，并提供了一个由三磷酸腺苷带负电荷的侧链组成的亲水界面。有证据表明，这种侧链暴露于细胞内的间质水中，并被报道为组织细胞内的间质水，以形成界面的动态水层。用P-31核磁共振在体外测量的侧链磷酸盐的ATP线宽上证实了水的这种组织方式。提出了一个新的模型，提出了水层如何分离相邻的晶状体纤维细胞蛋白质，防止它们聚集。这一假说认为，ATP可以防止正常完整晶状体中的蛋白质聚集，并且随着浓度的下降，可能与年龄相关性白内障发生的疾病过程有关，这是一种影响每一个老年人的疾病。
The hypothesis proposed herein is presented to explain the unexpectedly high concentration of ATP and provide evidence to support its hydrotropic function in the crystalline lens determined using P-31 NMR. The lens, historically considered to be a metabolically quiescent organ, has the requisite machinery to synthesize ATP, such that the homeostatic level is maintained at about 3 mM. This relatively high concentration of ATP has been found to be consistent among multiple mammalian species including humans. This millimolar quantity is many times greater than the micromolar amounts required for the other known functions of ATP. The recent postulation that ATP at millimolar concentrations functions as a hydrotrope in various cell/tissue homogenates preventing protein aggregation coupled with observations presented herein, provide support for extending the hypothesis that ATP functions as a hydrotrope not only in homogenates but in an intact functioning organ, the crystalline lens. Concentrations of ATP of this magnitude are hypothesized to be required to maintain protein solubility and effectively prevent protein aggregation. This concept is important considering protein aggregation is the etiology for age-related cataractogenesis. ATP is a common ubiquitous intracellular molecule possessing the requisite hydrotropic properties for maintaining intracellular proteins in a fluid, non-aggregated state. It is proposed that the amphiphilic ATP molecule shields the hydrophobic regions on intralenticular fiber cell protein molecules and provides a hydrophilic interfacial surface comprised of the ATP negatively charged triphosphate side chain. Evidence is presented that this side chain is exposed to and has been reported to organize intracellular interstitial water to form an interfacial Theologically dynamic water layer. Such organization of water is substantiated with the effect of deuterium oxide (heavy water) on ATP line widths of the side chain phosphates measured ex vivo by P-31 NMR. A novel model is presented to propose how this water layer separates adjacent lens fiber cell proteins, keeping them from aggregating. This hypothesis proposes that ATP can prevent protein aggregation in normal intact lenses, and with declining concentrations can be related to the disease process in age related cataractogenesis, an affliction that affects every older human being.