Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity.
Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity.
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DOI：
10.1021/jacs.6b01966
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发表时间：
2016-05-04
影响因子：
15
通讯作者：
Parks TB
中科院分区：
文献类型：
--
作者：
Tinoco AD;Saxena M;Sharma S;Noinaj N;Delgado Y;Quiñones González EP;Conklin SE;Zambrana N;Loza-Rosas SA;Parks TB
人血清转铁蛋白 (sTf) 是一种介导铁从血液转运至细胞的蛋白质。在协同阴离子碳酸根的协助下，sTf 通过将金属离子结合在闭合构象中来运输 Fe(III)。先前的研究表明 sTf 具有作为钛等其他金属的潜在转运体的作用。钛是一种广泛用于着色剂、食品和植入物的金属。大量的钛从这些植入物中渗入血液中。然而，浸出的钛的命运及其转运到细胞中的情况尚不清楚。随着我们不断增加以植入物形式接触钛，了解钛与 sTf 的相互作用变得更加重要。根据体外研究，推测转铁蛋白可以在协同阴离子的帮助下结合 Ti(IV)。然而，协同阴离子的作用和身份以及 sTf 结合 Ti(IV) 的构象状态尚不清楚。在这里，我们解决了 Ti(IV) 结合 sTf 的第一个 X 射线晶体结构。我们发现 sTf 以开放构象与碳酸盐和柠檬酸盐作为金属结合位点的协同阴离子结合 Ti(IV)，这对柠檬酸盐来说是前所未有的作用。对细胞系的研究表明，Ti(IV)-sTf 被转运到细胞中，并且 sTf 和柠檬酸盐调节金属的血液形态并减弱其细胞毒性。我们的研究结果首次揭示了柠檬酸-转铁蛋白在 Ti(IV) 生物活性调节中的协同作用，并为 Ti(IV) 基抗癌药物的未来设计提供了见解。
Human serum transferrin (sTf) is a protein that mediates the transport of iron from blood to cells. Assisted by the synergistic anion carbonate sTf transports Fe(III) by binding the metal ion in a closed conformation. Previous studies suggest sTf’s role as a potential transporter of other metals like titanium. Ti is a widely used metal in colorants, foods, and implants. A substantial amount of Ti is leached into blood from these implants. However, the fate of the leached Ti and its transport into the cells is not known. Understanding Ti interaction with sTf assumes a greater significance with our ever increasing exposure to Ti in the form of implants. Based on in vitro studies it was speculated that transferrin can bind Ti(IV) assisted by a synergistic anion. However, the role and identity of the synergistic anion(s) and the conformational state in which sTf binds Ti(IV) are not known. Here we have solved the first X-ray crystal structure of a Ti(IV)-bound sTf. We find that sTf binds Ti(IV) in an open conformation with both carbonate and citrate as synergistic anions at the metal binding sites, an unprecedented role for citrate. Studies with cell lines suggest that Ti(IV)-sTf is transported into cells and that sTf and citrate regulate the metal’s blood speciation and attenuate its cytotoxic property. Our results provide the first glimpse into the citrate-transferrin synergism in the regulation of Ti(IV) bioactivity and offers insight into the future design of Ti(IV)-based anticancer drugs.