Binding of ruthenium and osmium at non‑iron sites of transferrin accounts for their iron-independent cellular uptake.

Abstract

Being identified with less toxic and generally showing selective effects for solid tumor metastases, ruthenium and osmium compounds are promising drug candidates for clinical uses. Human serum proteins, such as albumin and transferrin, play vital roles in the transportation and accumulation of ruthenium and osmium agents into target tissues. However, the molecular mechanism of how transferrin transport ruthenium and their osmium analogues at atomic level remains obscure. In this study, we uncovered that the cellular uptake of Os3+ or Ru3+ are not competed by Fe3+. To unveil the molecular mechanism behind the phenomena, we report the first crystal structures of human serum transferrin (hTF) in complex with ruthenium and osmium compounds bound to the non-conserved residues on the surface of hTF without altering its overall conformation. As for Ru3+ and Os3+, these binding sites by descending affinity are: His14/His289, His349-350 ~ His578/Arg581. Ruthenium drugs and their osmium analogues preferentially bind to His14/His289 with bipyridine or imidazole ligands leaving. These binding sites on hTF surface are also available in human lactoferrin and some transferrin family member of other species. The presence of these binding sites makes the cellular uptake of Ru3+ and Os3+ less affected by Fe3+, compare to Zr4+ or Hf4+. Collectively, these findings are critical for our understanding of the role of serum transferrin in cellular delivery of ruthenium and osmium anticancer agents.

• Authors: Minji Wang, Haibo Wang, Xiaohan Xu, Tsz-Pui Lai, Ying Zhou, Quan Hao, Hongyan Li, Hongzhe Sun
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 234 Pg. 111885 (09 2022) ISSN: 1873-3344 [Electronic] United States
• PMID: 35690040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Osmium Compounds
• Transferrin
• Osmium
• Ruthenium

Topics

• Binding Sites
• Humans
• Models, Molecular
• Osmium (chemistry)
• Osmium Compounds (metabolism)
• Ruthenium (chemistry)
• Transferrin (chemistry)