The synergistic binding of anions and Fe3+ by transferrin. Implications for the interlocking sites hypothesis.

Schlabach, Michael R.; Bates, George W.

doi:10.1016/s0021-9258(19)41699-2

Cited by 280 publications

(84 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is important to note that as observed within the crystal lattice, there appears to be very low Ti(IV) occupancy at the N-site of this structure. At the C-site of the same structure, Ti(IV) is coordinated in a closed-conformation, canonical manner except that a malonate anion substitutes for the carbonate anion (Figure 11C) as it has been shown to do for Fe(III) binding [6,47]. Accounting for the physiological concentrations of citrate and bicarbonate (27 mM) in blood, it is expected that both anions will jointly serve as synergistic ligands for Ti(IV) coordination within the sTf binding sites producing the (Ti-citrate) 2 (CO 3 ) 2 -sTf complex [8].…”

Section: Stf May Facilitate the Cytotoxic/antiproliferative Properties Of Ti(iv) At High Metal Concentrationmentioning

confidence: 98%

“…The subdomains form two Fe(III) binding sites involving identical coordinating moieties. The Fe(III) binding residues (Figure 1) include two tyrosines (Tyr95 and Tyr188 of N-lobe; Tyr426 and Tyr517 of C-lobe), a histidine (His249 of N-lobe; His585 of C-lobe), and an aspartic acid (Asp63 of N-lobe; Asp392 of C-lobe) in addition to a carbonate ion, which is notoriously known as the synergistic anion [6]. Altogether they coordinate Fe(III) with a coordination number 6 in the canonical modality.…”

Section: Structural Characterization Of Stf and Its Fe(iii) Bindingmentioning

confidence: 99%

“…His585 of C-lobe), and an aspartic acid (Asp63 of N-lobe; Asp392 of C-lobe) in addition to a carbonate ion, which is notoriously known as the synergistic anion [6]. Altogether they coordinate Fe(III) with a coordination number 6 in the canonical modality.…”

Section: Structural Characterization Of Stf and Its Fe(iii) Bindingmentioning

confidence: 99%

“…This physiologically relevant coordination of Fe(III) is referred to as the canonical modality of metal binding (Figure 1A). Several carboxylate containing ligands can substitute for the carbonate and retain the bidentate coordination [6] while still fulfilling the canonical modality. The order of magnitude difference in the Fe(III) affinity to both sites is due to differences in intramolecular interactions within the secondary sphere of coordination.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exploring Serum Transferrin Regulation of Nonferric Metal Therapeutic Function and Toxicity

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Stf May Facilitate the Cytotoxic/antiproliferative Properties Of Ti(iv) At High Metal Concentrationmentioning

confidence: 98%

Section: Structural Characterization Of Stf and Its Fe(iii) Bindingmentioning

confidence: 99%

Section: Structural Characterization Of Stf and Its Fe(iii) Bindingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Exploring Serum Transferrin Regulation of Nonferric Metal Therapeutic Function and Toxicity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…This shift in l max indicates that malate acts as a synergistic anion for Ti(IV) binding, as it does for Fe(III) binding. 55 The molar absorptivity is approximately the same for both Ti sources in the presence of malate. This similarity in binding does not hold when the synergistic anion is carbonate.…”

Section: Titanium Transferrin Studiesmentioning

confidence: 91%

Pharmaceutical formulation affects titanocene transferrin interactions

et al. 2011

View full text Add to dashboard Cite

Since the discovery of the anticancer activity of titanocene dichloride (TDC), many derivatives have been developed and evaluated. MKT4, a soluble, water-stable formulation of TDC, was used for both Phase I and Phase II human clinical trials. This formulation is investigated here by using (1)H and (13)C NMR, FT-ICR mass spectrometry, and UV/vis-detected pH-dependent speciation. DFT calculations are also utilized to assess the likelihood of proposed species. Human serum transferrin has been identified as a potential vehicle for the Ti anticancer drugs; these studies examine whether and how formulation of TDC as MKT4 may influence its interactions, both thermodynamic and kinetic, with human serum transferrin by using UV/vis absorption and fluorescence quenching. MKT4 binds differently than TDC to transferrin, showing different kinetics of binding as well as a different molar absorptivity of binding (7500 M(-1) cm(-1) per site). Malate, used in the buffer for MKT4 administration, acts as a synergistic anion for Ti binding, shifting the tyrosine to Ti charge transfer energy and decreasing the molar absorptivity to 5000 M(-1) cm(-1) per site. These differences may have had consequences after the change from TDC to MKT4 in human clinical trials.

show abstract

Apotransferrin proton dissociation and interactions with hydrogencarbonate in neutral media

Bellounis

Pakdaman

Chahine

1996

J. Phys. Org. Chem.

View full text Add to dashboard Cite

A spectrofluorimetric titration analysis of the proton dissociation and the interactions of human serum transferrin with hydrogencarbonate was performed at pH 7-0-9.0. Apotransferrin loses a single proton probably per binding site with K , = (6.80i0.35) x M. This proton dissociation is independent of the hydrogencarbonate concentration. Apotransferrin does not interact with CO,'-. However, it interacts with two HCO,-, exhibiting two different affinity constants; the dissociation constant presumably for the C-site is K, = (4.4OrtO-15) x M and that for presumably the N-site is K , = (3.60i0.30) x lo-' M. These interactions are independent of pH and occur with the unprotonated and protonated apotransferrin species with the same low affinities. Such affinities are probably induced by ionic interactions involving the side chain of the arginine residues in each of the two binding sites. As for the proton dissociation, it can occur with one of the other sidechains of the amino acid residues of these binding sites.

show abstract

The synergistic binding of anions and Fe3+ by transferrin. Implications for the interlocking sites hypothesis.

Cited by 280 publications

References 13 publications

Exploring Serum Transferrin Regulation of Nonferric Metal Therapeutic Function and Toxicity

Exploring Serum Transferrin Regulation of Nonferric Metal Therapeutic Function and Toxicity

Pharmaceutical formulation affects titanocene transferrin interactions

Apotransferrin proton dissociation and interactions with hydrogencarbonate in neutral media

Contact Info

Product

Resources

About