Duncan E. K. Sutherland and Martin J. Stillman Department of Chemistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7

Metallothioneins (MTs), first discovered in 1957 (Margoshes and Vallee, 1957), are a family of small cysteine rich proteins found in all organisms. MTs have been implicated in toxic metal detoxification (Liu et al., 2000), protection against oxidative stress (Kang, 2006) and as metallochaperones (Tapia et al., 2004; Maret, 2008a), supplying both Zn2+ and Cu+ to their respective apo-enzymes. Zinc and copper are essential for the normal function of the brain and significant amounts are present in both the normal and diseased state. Zinc levels are critical for normal physical and mental development with numerous symptoms being reported in the cases of zinc deficiency. Copper is essential in the redox-based enzyme chemistry, for example the superoxide dismutases. Metallothionein is widely considered to play a significant role in the homeostasis of both these metals in other organs, particularly, in the liver, and in vitro studies show well-defined metallation chemistry. Metallothioneins are also implicated in the redox balance of cells as a result of the 20 cysteine thiols present and the variable metallation status possible. Therefore, the metallation of MT is intimately connected with both the concentrations of these metals and the ability to act as a metalchaperone, aiding in cellular metal buffering. Further, MT is most likely a key component in the mechanistic pathways that describe

absorption, function and excretion of zinc and copper. Mammals produce four metallothionein isoforms (MT-1 to MT-4), of which MT-1 and MT-2 are expressed in all organs, MT-3 is found predominantly in the central nervous system, and MT-4 is present in some stratified tissues. However, despite 50 years of intense research, the exact function(s) remain unknown and the mechanistic details of the metallation reactions and subsequent metal transfer reactions are poorly understood.