Exploring Serum Transferrin Regulation of Nonferric Metal Therapeutic Function and Toxicity

Abstract

Serum transferrin (sTf) plays a pivotal role in regulating iron biodistribution and homeostasis within the body. The molecular details of sTf Fe(III) binding blood transport, and cellular delivery through transferrin receptor-mediated endocytosis are generally well-understood. Emerging interest exists in exploring sTf complexation of nonferric metals as it facilitates the therapeutic potential and toxicity of several of them. This review explores recent X-ray structural and physiologically relevant metal speciation studies to understand how sTf partakes in the bioactivity of key non-redox active hard Lewis acidic metals. It challenges preconceived notions of sTf structure function correlations that were based exclusively on the Fe(III) model by revealing distinct coordination modalities that nonferric metal ions can adopt and different modes of binding to metal-free and Fe(III)-bound sTf that can directly influence how they enter into cells and, ultimately, how they may impact human health. This knowledge informs on biomedical strategies to engineer sTf as a delivery vehicle for metal-based diagnostic and therapeutic agents in the cancer field. It is the intention of this work to open new avenues for characterizing the functionality and medical utility of nonferric-bound sTf and to expand the significance of this protein in the context of bioinorganic chemistry.

A possible way to relate the effects of SARS-CoV-2 induced changes in transferrin to severe COVID-19 associated diseases

“…It binds iron with very high affinity, which gives its main function as to reduce the free iron content of the blood. Moreover, transferrin prevents the reduction of the bound Fe 3+ and thus Fe 2+ caused toxicity (23). One transferrin can bind two Fe 3+ ions in a strict order.…”

Urea Gel Electrophoresis in Studies of Conformational Changes of Transferrin on Binding and Transport of Non-Ferric Metal Ions

“…For most non-Fe metal ions and medicinal metal complexes, there is a strong competition for metal binding in blood serum between Tf and other serum proteins, particularly albumin [ 10 , 11 , 13 , 21 , 43 ]. In our preliminary experiments, undiluted human serum was reacted with 50 μM of metal complexes, which is within the range of concentrations observed for anticancer metal complexes in clinical use [ 44 ], for 4 h at 310 K. This was followed by the removal of most albumin using affinity columns (see Section 4 ) and loading the samples into urea gels ( Figure 6 ; see Figure S2 in Supplementary Material for data processing).…”

“…The ability of Tf to bind many other (particularly trivalent) metal ions at the Fe(III) binding site [ 5 ] and the fact that human blood Tf is normally only ~30% Fe(III) saturated [ 6 ] resulted in the hypothesis that Tf can act as a carrier of other biological and non-biological metal ions into the cells [ 5 , 7 , 8 ]. However, growing evidence suggests that, in most cases, binding of metals other than Fe(III) to Tf results in changes in Tf conformation that disrupt the Tf cycle and prevent their cellular uptake so that Tf is more likely to protect cells from toxicity of these metal ions [ 9 , 10 , 11 ]. Essentiality of some transition metal ions, particularly V and Cr, for human nutrition and the role of Tf in their metabolism remain as topics of hot debate [ 9 , 10 , 12 , 13 ].…”

“…Although urea-PAGE has been used occasionally to study the binding of non-Fe metal ions to Tf [ 10 , 17 , 18 , 19 , 20 ], the scope of this technique for elucidation of the roles of Tf in ‘alternative’ metal metabolism [ 8 , 11 ] has not been explored systematically. This communication demonstrates the ability of this technique to test how various metal ions binding to Tf in a Fe(III)-like manner change the conformation of metalloprotein.…”

Solution speciation and human serum protein binding of indium(III) complexes of 8-hydroxyquinoline, deferiprone and maltol

“…Transferrin (Tf) is the most significant In(III) binding protein in blood serum and it is thought to compete effectively with chelate forming ligands like citrate, nitrilotriacetic acid (NTA), thioglycolic acid or HQ for the binding of In(III) ions [1,[18][19][20][21]. Ga(III) can bind to Tf as well, at the same time in vitro investigations conducted in our research group pointed out the impact of the chelate forming ligand on the competition between the ligand an this protein for Ga(III).…”