What is metallothionein?

Description of metallothionein and definition of metallothionein.

Metallothioneins belong to a family of cysteine-rich low molecular weight metal-binding proteins (MW 3500 - 14000 Da). Cysteine residues represent about 30% of the amino acid content of metallothioneins. Metallothioneins form complexes with heavy metal ions. Metallothioneins bind physiological metals such as zinc and copper, but also xenobiotic heavy metals such as cadmium, mercury and silver. The binding occurs via the thiol groups of the cysteine residues.

Metallothioneins are present in almost all forms of life [1,2]. Genomes of higher organisms contain multiple metallothionein genes, which encode different metallothionein  isoforms. All mammals express at least four types of metallothioneins, assigned metallothionein-1, metallothionein-2, metallothionein-3, and metallothionein-4 [1]. Metallothionein-1 and metallothionein-2 are expressed in almost all tissues, whereas metallothionein-3 and metallothionein-4 are tissue-specific [1]. In the body, large quantities of metallothionein are synthesised primarily in the liver and kidneys. Their production is dependent on availability of the dietary minerals  such as zinc, copper and selenium, and the amino acids histidine and cysteine. Metallothioneins bind physiological metals such as zinc and copper and participate in the regulation of cellular metabolism of these metals. The function of metallothioneins is not fully clear, but experimental data support participation of metallothioneins in regulation of Zn and Cu, detoxification of toxic metals like cadmium, silver, copper and mercury, and in protection of cells against reactive oxygen species and alkylating agents [3].

Metallothionein-3 is brain-specific metallothionein expressed mainly in the hippocampus, amygdala and cortex [4]. Metallothionein-3 mRNA has been detected in zinc-enriched neurons [4] and in astrocytes [5]. In contrast to other metallothioneins, metallothionein-3 inhibits the growth of cultured neurons and has been therefore denoted as a growth inhibitory factor (GIF) [6]. However, further studies have demonstrated that the growth-inhibitory activity of metallothionein-3 is related to specific hydroxyl radical scavenging properties of metallothionein-3 [7]. Metallothionein-3 knockout mice are more sensitive to kainate-induced epileptic seizures, compatible with a role of metallothionein-3 in regulation of zinc during neural stimulation of glutamate-ergic zinc-enriched neurons [8]. The metallothionein-3 gene is differently regulated than that of metallothionein-1 and metallothionein-2 and its transcription is not metal-induced [9]. Metallothionein-3 mRNA and protein levels are up-regulated after brain injury [10] and down-regulated in Alzheimer’s disease [11,6,12], suggesting that metallothioneins may be associated with brain repair [10,13] and that its down-regulation may be associated with the neuropathology of Alzheimer’s disease [11,6,12].

References.

[1] J.H.R. Kägi, in: K.T. Suzuki, N. Imura, M. Kimura (Eds.), Metallothionein, vol. III, Birkhäuser Verlag, Basel, 1993, pp. 29– 56.
[2] M. Vasak, J.H.R. Kägi, in: R.B. King (Ed.), Encyclopedia of Inorganic Chemistry, J Wiley and Sons Ltd, New York, 1994, pp. 2229– 2241.
[3] M. Nordberg, Metallothioneins: historical review and state of knowledge, Talanta 46 (1998) 243– 254.
[4] B.A. Masters, C.J. Quaife, J.C. Erickson, E.J. Kelly, G.J. Froelick, B.P. Zambrowicz, R.L. Brinster, R.D. Palmiter, Metallothionein-III is expressed in neurons that sequester zinc in synaptic vesicles, J. Neurosci. 14 (1994) 5844– 5857.
[5] I. Hozumi, T. Inuzuka, H. Ishiguro, M. Hiraiwa, Y. Uchida, S. Tsuji, Immunoreactivity of growth inhibitory factor in normal rat brain and after stab wounds—An immunocytochemical study using confocal laser scan microscope, Brain Res. 741 (1996) 197– 204.
[6] Y. Uchida, K. Takio, K. Titani, Y. Ihara, M. Tomonaga, The growth inhibitory factor that is deficient in the Alzheimer’s-disease brain is a 68-amino acid metallothionein-like protein, Neuron 7 (1991) 337–347.
[7] Y. Uchida, F. Gomi, T. Masumizu, Y. Miura, Growth inhibitory factor prevents neurite extension and the death of cortical neurons caused by high oxygen exposure through hydroxyl radical scavenging, J. Biol. Chem. 277 (2002) 32353– 32359.
[8] J.C. Erickson, G. Hollopeter, S.A. Thomas, G.J. Froelick, R.D. Palmiter, Disruption of the metallothionein-III gene in mice: analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures, J. Neurosci. 17 (1997) 1271– 1281.
[9] R.D. Palmiter, S.D. Findley, T.E. Whitmore, D.M. Durnam, MT-III, a brain-specific member of the metallothionein gene family, Proc. Natl. Acad. Sci. U. S. A. 89 (1992) 6333–6337.
[10] I. Hozumi, T. Inuzuka, M. Hiraiwa, Y. Uchida, T. Anezaki, H. Ishiguro, H. Kobayashi, Y. Uda, T. Miyatake, S. Tsuji, Changes of growth-inhibitory factor after stab wounds in rat brain, Brain Res. 688 (1995) 143–148.
[11] V. Colangelo, J. Schurr, M.J. Ball, R.P. Pelaez, N.G. Bazan, W.J. Lukiw, Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor downregulation and up-regulation of apoptotic and pro-inflammatory signaling., J. Neurosci. Res. 70 (2002) 462– 473.
[12] W.H. Yu, W.J. Lukiw, C. Bergeron, H.B. Niznik, P.E. Fraser, Metallothionein III is reduced in Alzheimer’s disease, Brain Res. 894 (2001) 37– 45.
[13] I. Hozumi, T. Inuzuka, S. Tsuji, Brain injury and growth inhibitory factor (GIF)—a minireview, Neurochem. Res. 23 (1998) 319– 328.

[14] Fowler, B.A. et al. (1987) Nomenclature of Metallothionein, Metallothionein II: Experimentia Suppl. Vol. 52, p.19.