Iron regulation

New Role For Transferrin

Blood protein forms fibers, releases rust

Rachel Petkewich

Transferrin, the blood protein responsible for transporting iron throughout the body, can assemble into fibers that release bits of rust (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200705723). These unexpected findings from in vitro studies may help researchers decipher iron's role in various neurodegenerative diseases.

Howard Lightfoot and Arindam Mukherjee

Transferrin's Fe³⁺-binding site grips the metal (small orange ball) with a carbonate anion, two tyrosinates, an aspartate, and a histidine.

Diseases such as Parkinson's, Alzheimer's, and Huntington's have been associated with the defective regulation of iron in the brain. "If transferrin plays a role in accumulation of iron in brain tissue, then understanding the mechanism of this process will allow the design of drugs that could disrupt transferrin aggregation," says Peter J. Sadler, a chemistry professor at the University of Warwick, in England. Sadler carried out the work in collaboration with chemistry professor Sandeep Verma of the Indian Institute of Technology, Kanpur, and colleagues.

Their findings have intrigued other researchers. "Transferrin has never been shown to form fibrils, let alone ones with pockets of mineralized iron," says N. Dennis Chasteen, a chemistry professor at the University of New Hampshire. "Until this paper, human serum transferrin had been universally thought of simply as a transport protein for iron and other metals in blood circulation."

Transferrin is best known for transporting two Fe³⁺ ions. Each ion is tightly bound to four amino acid side chains that form a compartment and a carbonate anion that acts as a synergistic keystone.

Sadler and his colleagues deposited dehydrated transferrin on various surfaces under conditions that mimic living systems. They used microscopy techniques to show that the protein assembles into fibers and forms metal nanocrystals. Diffraction patterns indicate similarities in composition between the crystals and an iron oxide mineral called lepidocrocite. The researchers plan further experiments to see whether transferrin fibers form and iron minerals accumulate in vivo.

Researchers from the Universities of Warwick, Edinburgh, Dundee and the Czech Republic’s Institute of Biophysics have discovered a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use "light activation" to kill cancer cells in much more targeted way than similar treatments.

The platinum-based compound known as "trans, trans, trans- [Pt(N3)2(OH)2(NH3)(py)]", or a light activated PtIV complex, is highly stable and non-toxic if left in the dark but if light falls upon it becomes much less stable and highly toxic to cancer cells. In fact it is between 13 and 80 times more toxic (depending on how and on which cells it is used) to cancer cells than the current platinum based anti-cancer drug Cisplatin. Moreover it kills the cells by a different mechanism of action, so it can also kill cisplatin-resistant cells.

Professor Peter Sadler, Chairman of the Chemistry Department of the University of Warwick, who led the research project said:

"Light activation provides its massive toxic power and also allows treatment to be targeted much more accurately against cancer cells."

The compound could be used in particular to treat surface cancers. Patients could be treated in a darkened environment with light directed specifically at cancer cells containing the compound activating the compound’s toxicity and killing those cells. Normal cells exposed to the compound would be protected by keeping the patient in darkness until the compound has passed through and out of the patient.

The new light activated PtIV complex is also more efficient in its toxic action on cancer cells in that, unlike other compounds currently used in photodynamic therapy, it does not require the presence of significant amounts of oxygen within a cancer cell to become toxic. Cancer cells tend to have less oxygen present than normal cells.

Although this work is in its early stages, the researches are hopeful that, in a few years time, the new platinum compound could be used in a new type of photoactivated chemotherapy for cancer.

Peter Dunn, Press and Media Relations Manager,
University of Warwick, 024 76 523708
mobile 07767 655860 p.j.dunn@warwick.ac.uk

PR112 PJD 21st December 2007

The University Of Warwick has just been awarded £4 Million under the government’s Science and Innovation scheme to develop a new Centre in Analytical Science.  The Centre will develop new analytical approaches and use the very latest technology and techniques in scientific measurement and data analysis. The Centre will bring together scientists from broadly across the University to pool their expertise being led from Chemistry, but including computer scientists, physicists, life scientists, medical researchers, statisticians, and engineers.

For more information please contact:           

Professor Mark Smith, University of Warwick
Tel: 024 76 522380

Peter Dunn, Press and Media Relations Manager,
University of Warwick,  024 76 523708 or 007767 655860  
p.j.dunn@warwick.ac.uk

Giovanni Costantini  transfers to Warwick Chemistry being the former group leader of the Self-organized Growth and Quantum Structures Group in the Nanoscale Science Department headed by Prof. Klaus Kern at the Max-Planck-Institute für Festkörperforschung in Stuttgart. He will take up his position full-time from January 2008. 

Recent work under Warwick Chemistry affiliation already includes: 

Ordering of Dipeptide Chains on Cu Surfaces through 2D Cocrystallization
Wang, Y.; Lingenfelder, M.; Classen, T.; Costantini, G.; Kern, K.
J. Am. Chem. Soc.; (Communication); 2007; ASAP Article;  DOI:
10.1021/ja075118v

Structure and Energetics of Diphenylalanine Self-Assembling on Cu(110)
Tomba, G.; Lingenfelder, M.; Costantini, G.; Kern, K.; Klappenberger,
F.; Barth, J. V.; Ciacchi, L. C.; De Vita, A.
J. Phys. Chem. A.; (Article); 2007; 111(49); 12740-12748. 

Hydrogen and Coordination Bonding Supramolecular Structures of Trimesic
Acid on Cu(110)
Classen, T.; Lingenfelder, M.; Wang, Y.; Chopra, R.; Virojanadara, C.;
Starke, U.; Costantini, G.; Fratesi, G.; Fabris, S.; de Gironcoli, S.;
Baroni, S.; Haq, S.; Raval, R.; Kern, K.
J. Phys. Chem. A.; (Article); 2007; 111(49); 12589-12603. 

A review on Metals in Membranes by the Peter Sadler  team was the most downloaded paper in Chem.Soc.Rev. in November 2007.

In this critical review we discuss recent advances in understanding the modes of interaction of metal ions with membrane proteins, including channels, pumps, transporters, ATP-binding cassette proteins, G-protein coupled receptors, kinases and respiratory enzymes. Such knowledge provides a basis for elucidating the mechanism of action of some classes of metallodrugs, and a stimulus for the further exploration of the coordination chemistry of metal ions in membranes. Such research offers promise for the discovery of new drugs with unusual modes of action. The article will be of interest to bioinorganic chemists, chemical biologists, biochemists, pharmacologists and medicinal chemists. (247 references)

Pickering Miniemulsion Polymerization using Laponite Clay as a Stabilizer by Stefan Bon's research team is in the top 20 summer 2007 downloads in Langmuir.

Abstract:

Solid-stabilized, or Pickering, miniemulsion polymerizations using Laponite clay discs as stabilizer are investigated. Free radical polymerizations are carried out using a variety of hydrophobic monomers (i.e., styrene, lauryl (meth)acrylate, butyl (meth)acrylate, octyl acrylate, and 2-ethyl hexyl acrylate). Armored latexes, of which the surfaces of the particles are covered with clay discs, are obtained, as confirmed by scanning electron microscopy (FE-SEM) and atomic force microscopy (AFM). Overall polymerization kinetics of the Pickering miniemulsion polymerizations of styrene were investigated via gravimetry. Comparison with the bulk polymerization analogue clearly shows compartmentalization. Moreover, retardation effects up to intermediate monomer conversions are observed; they are more prominent for the smaller particles and are ascribed to the Laponite clay. A model is presented that allows for the prediction of the average particle size of the latexes produced as a function of the amounts of monomer and Pickering stabilizers used. It shows that under specific generic conditions the number of clay discs used correlates in a linear fashion with the total surface area of the latex particles. This is a direct result of the reversibility of the Laponite clay disc adhesion process under the emulsification conditions (i.e., sonication) used.

¹⁰⁶Ru radiolabelling of the antitumour complex [(⁶-fluorene)Ru(en)Cl]PF₆
James D. Hoeschele, Abraha Habtemariam, Jeanette Muir and Peter J. Sadler, Dalton Trans., 2007
DOI: 10.1039/b706246j

The organometallic half-sandwich Ru^II arene anticancer complex [(⁶-fluorene)Ru(en)Cl]PF₆ (1) has been synthesized in high yield and purity on a micromole scale with incorporation of the -emitting radioisotope ¹⁰⁶Ru (half-life = 1.01 y) using a refined procedure involving conversion of RuCl₃ into [(⁶-fluorene)RuCl₂]₂, and then [(⁶-fluorene)Ru(CH₃CN)₂Cl]PF₆ as intermediates. Distribution studies 0.25 h post i.v. injection of ¹⁰⁶Ru-1 at a dose of 25 mg 1 kg^–1 show that ¹⁰⁶Ru is well distributed throughout the tissues of a rat. This appears to be the first report of the radiolabelling of a potential ruthenium antitumour agent for distribution/biological studies.

Template directed synthesis of nanostructured phthalocyanine thin films by Tim Jones' team in top 10 downloads in J.Mater.Chem. (September 2007)

Link to journal article

Towards a continuous dynamic kinetic resolution of 1-phenylethylamine using a membrane assisted, two vessel process
Chayaporn Roengpithya, Darrell A. Patterson, Andrew G. Livingston, Paul C. Taylor, Jacob L. Irwin and Mark R. Parrett, Chem. Commun., 2007, 3462
DOI: 10.1039/b709035h