Exploring titanium(IV) chemical proximity to iron(III) to elucidate a function for Ti(IV) in the human body.
Exploring titanium(IV) chemical proximity to iron(III) to elucidate a function for Ti(IV) in the human body.
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DOI：
10.1016/j.ccr.2018.03.006
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发表时间：
2018-05-15
影响因子：
20.6
通讯作者：
Tinoco AD
中科院分区：
文献类型：
--
作者：
Saxena M;Loza-Rosas SA;Gaur K;Sharma S;Pérez Otero SC;Tinoco AD
尽管其天然丰富且广泛用作食品、涂料添加剂和骨植入物，但钛在人体中没有特定的生物学功能。高浓度的Ti（IV）可能导致细胞毒性，然而，植入钛骨植入物的患者血液中没有Ti毒性表明存在一种或多种减轻毒性的生物学机制。与Fe（III）类似，血液中的Ti（IV）与铁转运蛋白血清转铁蛋白（sTf）1结合，这证明了其通过转铁蛋白定向内吞作用的细胞摄取机制的可能性。然而，一旦进入细胞内，sTf结合的Ti（IV）如何被释放到细胞质中、利用或储存仍然在很大程度上未知。为了解释Ti在细胞中的使用所涉及的分子机制，我们将其与Fe（III）的分子机制进行了比较。基于其与Fe（III）的化学相似性，我们比较了Fe（III）和Ti（IV）的生物配位化学，并假设Ti（IV）可以结合到类似的细胞内生物分子。可比较的配体亲和力曲线表明，在高Ti（IV）浓度下，Ti（IV）可以与Fe（III）竞争结合生物分子，并抑制Fe的生物利用度。在体内典型的Ti浓度下，Ti可能以Ti（IV）的不稳定池存在于细胞中，类似于Fe。Ti可以表现出不同类型的特性，这些特性将决定其细胞功能。我们预测这些功能中的一些模仿那些在细胞中的Fe和其他特定的Ti。骨和细胞形态和定位研究提示了Ti的各种细胞内靶点，如磷蛋白、DNA、核糖核苷酸还原酶和铁蛋白。然而，为了破译钛如何介导这些作用的确切机制，需要开发创新和更灵敏的方法来跟踪这种难以在体内追踪的金属。
Despite its natural abundance and widespread use as food, paint additive, and in bone implants, no specific biological function of titanium is known in the human body. High concentrations of Ti(IV) could result in cellular toxicity, however, the absence of Ti toxicity in the blood of patients with titanium bone implants indicates the presence of one or more biological mechanisms to mitigate toxicity. Similar to Fe(III), Ti(IV) in blood binds to the iron transport protein serum transferrin (sTf)1, which gives credence to the possibility of its cellular uptake mechanism by transferrin-directed endocytosis. However, once inside the cell, how sTf bound Ti(IV) is released into the cytoplasm, utilized, or stored remain largely unknown. To explain the molecular mechanisms involved in Ti use in cells we have drawn parallels with those for Fe(III). Based on its chemical similarities with Fe(III), we compare the biological coordination chemistry of Fe(III) and Ti(IV) and hypothesize that Ti(IV) can bind to similar intracellular biomolecules. The comparable ligand affinity profiles suggest that at high Ti(IV) concentrations, Ti(IV) could compete with Fe(III) to bind to biomolecules and would inhibit Fe bioavailability. At the typical Ti concentrations in the body, Ti might exist as a labile pool of Ti(IV) in cells, similar to Fe. Ti could exhibit different types of properties that would determine its cellular functions. We predict some of these functions to mimic those of Fe in the cell and others to be specific to Ti. Bone and cellular speciation and localization studies hint toward various intracellular targets of Ti like phosphoproteins, DNA, ribonucleotide reductase, and ferritin. However, to decipher the exact mechanisms of how Ti might mediate these roles, development of innovative and more sensitive methods are required to track this difficult to trace metal in vivo.
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