XAFS studies on metal complexes of small biological molecules

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Exposure to heavy metal ions has profound health effects. Only a few are positive, such as the therapeutic effects of some platinum, bismuth and gold compounds, but accumulation of heavy metals in the environment is causing severe problems. Uptake via food, drinking water and the atmosphere of e.g., lead (dust from previous lead-based paint and leaded gasoline), cadmium (smoking and food) and mercury (in fish), can affect the human metabolism by replacing zinc and calcium in enzymes. Most heavy metal ions show high affinity to thiol (-SH) groups, which, in physiological systems, mostly occur in cysteine residues e.g., in enzymes, hormones or cell receptors. The tripeptide glutathione (Glutamyl-Cysteine-Glycine), the most abundant cellular thiol in the body, is important for protection against heavy metal ions. Its metal complexes form part of enzymes with dominant roles in protein metabolism. N-acetyl cysteine (NAC), a natural antioxidant, has long been used in several treatments, from heart diseases to HIV-1 retardation. NAC improves the efficiency of clinical chelating agents and facilitates detoxification of Cr, Cd and Pb. Recent bio-tests on NAC complexes with transition biometals (Zn, Co, Fe) showed significant anti-inflammatory activity. Therefore, the nature of the coordination of metal ions to N-acetyl cysteine and glutathione is needed for better understanding of such reaction mechanisms and also for improving specific cysteine based clinical detoxification agents. We will prepare such complexes with NAC and glutathione in solution and in the solid state, and use synchrotron-based X-ray absorption, vibrational, and NMR spectroscopic methods to study the local structure around the metal atoms for systems where crystallography cannot be applied. By establishing the bonding environment around the metal ions in these complexes as models for in-vivo conditions, and correlating their structures to their clinical properties, more efficient chelating agents for detoxification can be designed. Training of highly qualified researchers in applying synchrotron radiation methods is part of this project, and is required for efficient use of the advanced Canadian Light Source facility, the largest scientific project in Canada.