Competitive Binding of Bismuth to Transferrin and Albumin in Aqueous Solution and in Blood Plasma

Sun, Hongzhe; Li, Hongyan; Mason, Anne B.; Woodworth, Robert C.; Sadler, Peter J.

doi:10.1074/jbc.m004779200

Cited by 55 publications

(31 citation statements)

References 44 publications

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“…These conclusions were based on the similarity of 1 H resonance shifts induced by Bi 3ϩ and Fe 3ϩ binding to hTf [20,21]. The following studies of bismuth-hTf complex using two-dimensional 1 H, 13 C hetero-nuclear singlequantum coherence (HSQC) NMR spectroscopy did reveal some differences in evolution of the resonance peaks for methionine residues (used as reporters of tertiary structural changes) upon titration of the N-lobe of hTf with Fe 3ϩ and Bi 3ϩ [13]. To evaluate the putative structural changes within hTf upon bismuth binding, circular dichroism (CD) spectra of both apo-and metal-saturated forms of the protein have been recorded in the far-and near-UV regions ( Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, only indium accumulates in tissues (hence its use as an imaging agent), while systemic bioavailability of bismuth from its medicinal preparations is usually very low even at high doses [12], suggesting very inefficient cellular uptake via transferrin cycle. Bi 3ϩ binds preferentially to hTf (and not to scavenger proteins, such as albumin [13], or endogenous low molecular weigh organic chelators [11]) both in aqueous solution and in blood plasma. Therefore, its inefficient delivery to tissue may be caused by either (1) …”

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confidence: 99%

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Indirect detection of protein-Metal binding: Interaction of serum transferrin with In³⁺ and Bi³⁺

Zhang

Gumerov

Kaltashov

et al. 2004

J. Am. Soc. Mass Spectrom.

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Transferrins comprise a class of monomeric glycoproteins found in all vertebrates, whose function is iron sequestration and transport. In addition to iron, serum transferrin also binds a variety of other metals and is believed to provide a route for the in vivo delivery of such metals to cells. In the present study, ESI MS is used to investigate interactions between human serum transferrin and two nonferrous metals, indium (a commonly used imaging agent) and bismuth (a component of many antiulcer drugs). While the UV-Vis absorption spectroscopy measurements clearly indicate that both metals bind strongly to transferrin in solution, the metal-protein complex can be detected by ESI MS only for indium, but not for bismuth. Despite the apparently low stability of the transferrin-bismuth complex in the gas phase, presence of such complex in solution can be established by ESI MS indirectly. This is done by monitoring the evolution of charge state distributions of transferrin ions upon acid-induced protein unfolding in the presence and in the absence of the metal in solution. The anomalous instability of the transferrin-bismuth complex in the gas phase is rationalized in terms of conformational differences between this form of transferrin and the holo-forms of this protein produced by binding of metals with smaller ionic radii (e.g., Fe , with only two ligands in the metal coordination sphere provided by the protein itself. This suggestion is corroborated by the results of circular dichroism measurements in the near-UV range. Since the cellular consumption of metals in the transferrin cycle critically depends upon recognition of the holo-protein complex by the transferrin receptor, the noncanonical conformation of the transferrin-bismuth complex may explain very inefficient delivery of bismuth to cells even when a high dosage of bismuth-containing drugs is administered for prolonged periods of

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Indirect detection of protein-Metal binding: Interaction of serum transferrin with In³⁺ and Bi³⁺

Zhang

Gumerov

Kaltashov

et al. 2004

J. Am. Soc. Mass Spectrom.

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“…1 Introduced more than three decades, 67 Ga citrate still remains a clinically useful cost-effective radiopharmaceutical in the management of patients with certain neoplastic processes. The main point of contention has been the role of transferrin receptor (TfR) as the rate-limiting factor governing 67 Ga cellular incorporation.…”

Section: ＋mentioning

confidence: 99%

Common Pathway for K562 Cells Endocytosis and Release of Ga_C‐Tf and Ga₂‐Tf via a Transferrin Receptor

Liu

Zhao

et al. 2010

Chin. J. Chem.

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There has been an increasing interest in the use of gallium in anticancer activity. However, whether the uptakes of two species of transferrin, including digallium transferrin (Ga 2 -Tf) and the C-terminal monogallium transferrin (Ga C -Tf) by cells, are different is not well understood. In this work the mechanism of both species passing in and out K562 cells has been established by using 125 I-labeled transferrin. There were about (1.5±0.08)×10 5 binding sites per cell surface. Both Ga 2 -Tf and Ga C -Tf were recycled to the cell exterior with a protracted endocytic cycle compared to apotransferrin (apoTf). The cycling time from the internalization to release was calculated about t 1/2 ＝ (3.15±0.055) min for apoTf, t 1/2 ＝(4.69±0.09) min for Ga 2 -Tf and t 1/2 ＝(4.78±0.15) min for Ga C -Tf. The result implies that metal dissociating from transferrin in acidic endosomes was likely to be the key step. Both Ga 2 -Tf and Ga C -Tf into K562 cells are transferrin receptor-mediated process with a similar rate of endocytosis and release. Our present observations provide useful information for better targeted drugs in specific therapy.

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“…On the basis of this concentration and the affinity of Ggly for bismuth of 0.29 nM at neutral pH determined above, the occupancy of the two Ggly binding sites can be calculated to be greater than 90%. This figure will of course be modified by the iron status of the patient because bismuth is also known to bind to apotransferrin (28), but in principle a significant proportion of the trivalent metal binding sites of Ggly in serum may be occupied by bismuth. In terms of ulcer disease, inhibition of Ggly activity by bismuth might then modulate the long-term acid stimulatory effects of an increased serum Gamide, because Ggly seems to be required for a sustained Gamide-mediated hyperchlorhydria (24).…”

Section: Fig 6 Bismuth Ions Inhibit Ggly-induced Cell Migrationmentioning

confidence: 99%

“…Because bismuth ions are also trivalent, and have been shown to substitute for ferric ions in binding to lactoferrin (27) and transferrin (28), we hypothesized that gastrins might also bind bismuth ions and that binding might influence biological activity. To investigate this question, we have studied the fluorescence and NMR spectra of gastrins in the presence of bismuth salts.…”

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confidence: 99%

A Novel Effect of Bismuth Ions

Pannequin

Kovac

Tantiongco

et al. 2004

Journal of Biological Chemistry

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Although bismuth salts have been used for over two centuries for the treatment of various gastrointestinal disorders, the mechanism of their therapeutic action remains controversial. Because gastrins bind two trivalent ferric ions with high affinity, and because ferric ions are essential for the biological activity of glycineextended gastrin 17, we have investigated the hypothesis that trivalent bismuth ions influence the biological activity of gastrins. Binding of bismuth ions to gastrins was measured by fluorescence quenching and NMR spectroscopy. The effects of bismuth ions on gastrinstimulated biological activities were measured in inositol phosphate, cell proliferation, and cell migration assays. Fluorescence quenching experiments indicated that both glycine-extended and amidated gastrin 17 bound two bismuth ions. The NMR spectral changes observed on addition of bismuth ions revealed that Glu-7 acted as a ligand at the first bismuth ion binding site. In the presence of bismuth ions the ability of glycine-extended gastrin 17 to stimulate inositol phosphate production, cell proliferation, and cell migration was markedly reduced. In contrast, bismuth ions had little effect on the affinity of the CCK-2 receptor for amidated gastrin 17, or on the stimulation of inositol phosphate production by amidated gastrin 17. We conclude that bismuth ions may act, at least in part, by blocking the effects of glycine-extended gastrin 17 on cell proliferation and cell migration in the gastrointestinal tract. This is the first report of a specific inhibitory effect of bismuth ions on the action of a gastrointestinal hormone.

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Competitive Binding of Bismuth to Transferrin and Albumin in Aqueous Solution and in Blood Plasma

Cited by 55 publications

References 44 publications

Indirect detection of protein-Metal binding: Interaction of serum transferrin with In³⁺ and Bi³⁺

Indirect detection of protein-Metal binding: Interaction of serum transferrin with In³⁺ and Bi³⁺

Common Pathway for K562 Cells Endocytosis and Release of Ga_C‐Tf and Ga₂‐Tf via a Transferrin Receptor

A Novel Effect of Bismuth Ions

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Competitive Binding of Bismuth to Transferrin and Albumin in Aqueous Solution and in Blood Plasma

Cited by 55 publications

References 44 publications

Indirect detection of protein-Metal binding: Interaction of serum transferrin with In3+ and Bi3+

Indirect detection of protein-Metal binding: Interaction of serum transferrin with In3+ and Bi3+

Common Pathway for K562 Cells Endocytosis and Release of GaC‐Tf and Ga2‐Tf via a Transferrin Receptor

A Novel Effect of Bismuth Ions

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Indirect detection of protein-Metal binding: Interaction of serum transferrin with In³⁺ and Bi³⁺

Indirect detection of protein-Metal binding: Interaction of serum transferrin with In³⁺ and Bi³⁺

Common Pathway for K562 Cells Endocytosis and Release of Ga_C‐Tf and Ga₂‐Tf via a Transferrin Receptor