Transferrin (Tf) is an essential protein, probably ubiquitous to all metazoans. The main function of this family of proteins is to bind and transport ferric ions, increasing Fe(III) solubility under physiological conditions and preventing its deleterious pro-oxidant role in aerobic environments. In humans, Tf is responsible for the safe transport of this essential micronutrient through circulation and its delivery to requiring cells. Cellular uptake occurs through endocytosis mediated by the transferrin receptor (TfR). Although there is a good understanding of the general molecular mechanisms governing Tf iron binding and cellular iron delivery, several aspects of Tf biochemistry remain unclear.

In this review, we provide an overview of the inorganic biochemistry of human Tf (hTf), exploring the available structural information on hTf and the hTf/TfR complex to discuss physiologically relevant aspects, such as iron binding site distribution, mechanism of iron loading and TfR priming of iron release in vivo. In addition, we consider the role of hTf microheterogeneity on its function. Post-translational modifications such as phosphorylation, glycation and oxidation may occur at relevant hTf sites, which will compromise iron binding, inter lobe cooperativity or interaction with the TfR. Furthermore, these modifications may contribute to the deregulation of systemic iron transport and distribution on a disease specific manner. Finally, a brief review of the role of hTf as one of the main blood serum ligands for toxic and therapeutic metal ions is presented.

hTf is a long known and studied protein, but it is essential to understand the factors governing its expression and catabolism and how specific modifications modulate its function, in order to fully comprehend its role in human pathology or to explore its potential as a therapeutic agent.

转铁蛋白 (Tf) 是一种必需蛋白质，可能在所有后生动物中无处不在。该蛋白质家族的主要功能是结合和运输三价铁离子，在生理条件下增加 Fe(III) 的溶解度，并防止其在有氧环境中产生有害的促氧化作用。在人类中，Tf 负责通过循环安全运输这种必需的微量营养素并将其输送到需要的细胞。细胞摄取通过转铁蛋白受体 (TfR) 介导的内吞作用发生。尽管对控制 Tf 铁结合和细胞铁传递的一般分子机制有很好的理解，但 Tf 生物化学的几个方面仍不清楚。

在这篇综述中，我们概述了人类 Tf (hTf) 的无机生物化学，探索了 hTf 和 hTf/TfR 复合物的可用结构信息，以讨论生理相关方面，例如铁结合位点分布、铁负载机制和体内铁释放的 TfR 引发. 此外，我们考虑了 hTf 微异质性对其功能的作用。相关的 hTf 位点可能会发生诸如磷酸化、糖化和氧化等翻译后修饰，这将损害铁结合、叶间协同或与 TfR 的相互作用。此外，这些修饰可能有助于以疾病特定的方式放松全身铁转运和分布。最后，简要回顾了 hTf 作为有毒和治疗性金属离子的主要血清配体之一的作用。

hTf 是一种长期已知和研究的蛋白质，但必须了解控制其表达和分解代谢的因素以及特定修饰如何调节其功能，以便充分理解其在人类病理学中的作用或探索其作为治疗剂的潜力。