Poly-oxo anion chemistry | Bio-inorganic chemistry | Collaborators
Bio-inorganic chemistry
(with Dr. Zhiguang Xiao, Lianyi Zhang, Karrera Djoko, Matthias Zimmermann, Chak Ming Sze and Lee Xin Chong)
The trace metals are essential to life for enzymes but are highly toxic in excess. A balance between deficiency and toxic excess must be maintained. The secrets of their catalytic and structural roles are under intensive scrutiny.
Acquisition of the metals is mediated by molecular membrane pumps and by transport proteins which take the metal to its destinations in biological cells. Figure 1 shows a simplified representation of transport of copper in mammalian cells. Defects in copper metabolism cause Menkes and Wilson diseases in humans and is a component of certain neurodegenerative diseases (Alzheimer, Creutzfeldt-Jakob, mad cow).
Figure 1. Over-simplified model of copper transport in eurykotic cells such as hepatocytes which receive much of the copper absorbed from the small intestine. Membrane pumps Ctr1 and ATP7B and chaperones Ccs and Hah1 transport CuI. Ceruloplasmin transports CuII. Cytochrome c oxidase (cyt ox) and superoxide dismutase are redox enzymes which employ the CuII/CuI couple. As well as loading ceruloplasmin with copper, the trans-Golgi network inserts copper into many enzymes. The ATP7B pump performs two functions: it transports nutrient copper into the trans-Golgi network and excess copper out of the cell (by trafficking to the cell membrane via membrane-bound vesicles).
The molecular pump Ctr1 (Copper Transporter no. 1) is primarily responsible for import of copper into human cells. It appears to interact with the chaperones via a Cu4S6 cluster (Figure 2).[1] We are studying certain chaperones from mammalian and bacterial sources (Figure 3).[2,3]
Figure 2. Cu4S6 cluster (Cu atoms are pink)
Figure 3. Copper chaperone protein. (a) Cu atoms bind at each end; (b) Detail of CuII binding site.
In addition, the cancer drug cis-platin enters certain cells via the Ctr1 pump. Interactions of cis-platin with the copper proteins appears to be a major cause of loss of drug and side effects. We are studying the pumps and chaperones and their interactions with cis-platin.
The proteins are generated via molecular genetics and then purified. The molecular probes needed are provided by techniques such as NMR, ESR, MS, fluorescence, X-ray crystallography, electro-chemistry and quantitative HPLC.
New projects include:-
design and synthesis of new chromophoric ligands to act as quantitative probes of bio-metals, both in vivo and in vitro;
transport of nutrient metals in normal and in hyper-accumulating plants;[4]
zinc and copper transporters in the simple plant Arabidopsis thaliana.
Selected Publications:
Z. Xiao, F. Loughlin, G. N. George, G. Howlett and A.G. Wedd. J. Amer. Chem. Soc. 2004, 126, 3801-3890.
L. Zhang, M. Koay, M. J. Maher, Z. Xiao and A. G. Wedd. J. Am. Chem. Soc. 2006, 128, 5834-5850.
K. Y. Djoko, Z. Xiao, D. L. Huffman,and A. G. Wedd. Inorg. Chem. 2007, in press.
Callahan, D.; Baker, A; Kolev, S. D.; Wedd, A. G. J. Biol. Inorg. Chem., 2006, 11, 2-12.
