Human transferrin: An inorganic biochemistry perspective

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. (C) 2021 The Author(s). Published by Elsevier B.V.

Automated summary

Transferrin (Tf) is an essential protein found in all metazoans, responsible for binding and transporting ferric ions, increasing Fe(III) solubility and preventing its pro-oxidant role. In humans, Tf safely transports iron through circulation and delivers it to cells in need. Understanding the factors governing Tf's expression, catabolism, and modifications is crucial for comprehending its role in human pathology and therapeutic potential.