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Metals in Medicine: Research


Transferrin and Metalloantibiotics

We study the metal binding properties of iron transport proteins, such as human transferrin and the bacterial equivalent, ferric-ion-binding protein (Fbp). We have shown that these proteins can accommodate oxo-metal clusters, i.e. small mineral fragments. The proteins prove to be versatile metal-binding scaffolds, as multinuclear oxo-metal clusters of zirconium, hafnium and titanium can be accommodated. These studies provide a model for protein-mediated mineralization.

Efficient iron acquisition is required for the virulence of pathogenic bacteria. Metal compounds that inhibit this iron uptake mechanism carry medicinal potential. The tight binding of Ti(IV) to Fbp, for instance, has promising characteristics ffor consideration as a candidate metalloantibiotic. We recently discovered that transferrin readily forms worm-like fibrils and in so doing gives rise to periodic iron nanomineralization in the fibrils. This process might be related to how iron is deposited in the brain, a process thought to be related to some forms of neurodegerative diseases.


A novel protein-mineral interface: a hafnium cluster bound to Fbp

   Transferrin fibrils


Some selected recent publications on our work on transferrin and metalloantibiotics:

Ghosh, S., Mukherjee, A., Sadler, P. J., Verma, S.: Periodic Iron Nanomineralization in Human Serum Transferrin Fibrils. Angewandte Chemie-International Edition 2008, 47: 2217-2221

2.     Guo ML, Harvey I, Campopiano DJ, Sadler PJ: Short oxo-titanium(IV) bond in bacterial transferrin: A protein target for metalloantibiotics. Angewandte Chemie-International Edition 2006, 45:2758-2761.
3.     Zhong WQ, Alexeev D, Harvey I, Guo ML, Hunter DJB, Zhu HZ, Campopiano DJ, Sadler PJ: Assembly of an oxo-zirconium(IV) cluster in a protein cleft. Angewandte Chemie-International Edition 2004, 43:5914-5918.
4.     Zhu HZ, Alexeev D, Hunter DJB, Campopiano DJ, Sadler PJ: Oxo-iron clusters in a bacterial iron-trafficking protein: new roles for a conserved motif. Biochemical Journal 2003, 376:35-41.
5.     Guo ML, Harvey I, Yang WP, Coghill L, Campopiano DJ, Parkinson JA, MacGillivray RTA, Harris WR, Sadler PJ: Synergistic anion and metal binding to the ferric ion-binding protein from Neisseria gonorrhoeae. Journal of Biological Chemistry 2003, 278:2490-2502.
6.     Alexeev D, Zhu HZ, Guo ML, Zhong WQ, Hunter DJB, Yang WP, Campopiano DJ, Sadler PJ: A novel protein-mineral interface. Nature Structural Biology 2003, 10:297-302.
7.     Zhong WQ, Parkinson JA, Guo ML, Sadler PJ: Unusual features for zirconium(IV) binding to human serum transferrin. Journal of Biological Inorganic Chemistry 2002, 7:589-599.
8.     Zhang L, Szeto KY, Wong WB, Loh TT, Sadler PJ, Sun HZ: Interactions of bismuth with human lactoferrin and recognition of the Bi-III-lactoferrin complex by intestinal cells. Biochemistry 2001, 40:13281-13287.