M.S.       Chemistry, Universität des Saarlandes, Saarbrücken, Germany

Ph.D.      Natural Sciences, summa cum laude, Universität des Saarlandes, Saarbrücken, Germany

Postdoctoral Fellow Department of Biophysics & Theoretical Biology, The University of Chicago

Active Research:

Zinc Metalloregulation and Cellular Zinc Distribution

Zinc is essential for growth and development in all phyla of life.  It is a constituent of well over 300 enzymes and an even larger number of zinc-binding proteins that are involved in protein-protein, protein-nucleic acid, and protein-lipid interactions.  In many cases the coordination environment of zinc in proteins is known in great detail.  In contrast, considerable uncertainty exists regarding the molecules and mechanisms that regulate uptake, distribution and storage of zinc – or even the processes by which zinc is inserted into proteins in the first place.

One molecule that participates in the cellular trafficking and distribution of zinc is metallothionein.  At the center of its action are two zinc/thiolate cluster networks, in which seven zinc ions are bound to twenty cysteines.  The clusters are thermodynamically stable, but their inherent coordination dynamics result in zinc transfer potentials that allow delivery of zinc to appropriate acceptors.  The cluster structure provides the chemical basis by which cysteine ligands can induce redox properties.  Specifically, redox-active zinc-sulfur bonds allow oxidants to release zinc from metallothionein and reductants to support binding of zinc to thionein, the apoprotein of metallothionein.  In this manner, metallothionein links cellular zinc and redox metabolism.  Oxidants that mediate zinc release include biological disulfides, S-nitrosothiols, and selenium compounds that act catalytically and couple the metallothionein and glutathione systems.  Furthermore, zinc metallothionein is translocated to liver mitochondria, where released zinc inhibits mitochondrial respiration.  Zinc also inhibits several enzymes in energy metabolism and in signaling transduction cascades at nanomolar concentrations.  Thionein activates these zinc-inhibited processes, thus demonstrating an action as an endogenous chelating agent that removes zinc either from unspecific sites or from sites where zinc has regulatory functions.  Jointly, these findings suggest a reversible system where metallothionein is a zinc donor and thionein a zinc acceptor, and where both direct cellular zinc fluxes under the control of the cellular redox state.

Selected Publications:

Maret, W. (1994) Oxidative Metal Release from Metallothionein via Zinc-Thiol/Disulfide Interchange, Proc. Natl. Acad. Sci. USA 91, 237-241.

Maret, W. (1995) Metallothionein/Disulfide Interactions, Oxidative Stress, and the Mobilization of Cellular Zinc, Neurochem. Int. 27, 111-117.

Maret, W. (1998) The Glutathione Redox State and Zinc Mobilization from Metallothionein and other Proteins with Zinc/Sulfur Coordination Sites, in: Shaw, C. A., ed., Glutathione in the Nervous System, pp. 257-273, Taylor and Francis, Washington D.C.

Maret, W. & Vallee, B.L. (1998) Thiolate Ligands in Metallothionein Confer Redox Activity on Zinc Clusters, Proc. Natl. Acad. Sci. USA 95, 3478-3482.

Davis, J.J., Hill, H.A.O., Kurz, A., Jacob, C., Maret, W. & Vallee, B.L. (1998) A Scanning Tunnelling Microscopy Study of Rabbit Metallothionein, Phys. Chem. Comm. 2 (electronic publication, http://www.rsc.org/ej/qu/1998/F9806057/index.htm)

Jacob, C., Maret, W. & Vallee, B.L. (1999) Selenium Redox Biochemistry of Zinc/Sulfur Coordination Sites in Proteins and Enzymes, Proc. Natl. Acad. Sci. USA 96, 1910-1914. Maret, W., Jacob, C., Vallee, B.L. & Fischer, E.H. (1999) Inhibitory Sites in Enzymes: Zinc Removal and Reactivation by Thionein, Proc. Natl. Acad. Sci. USA 96, 1936-1940.

Maret, W. (2000) The Function of Zinc Metallothionein: A Link between Cellular Zinc and Redox State, J. Nutr. 130, 1455S-1458S.

Hong, S-H., Toyoma, M., Maret, W. & Murooka, Y. (2001) High Yield Expression and Single Step Purification of Human Thionein:  Preparation of Metallothionein from Thionein generated in situ, Protein Express. Purif. 21, 243-250.

Ye, B., Maret, W. & Vallee, B.L. (2001) Zinc Metallothionein Imported into Liver Mitochondria Modulates Respiration, Proc. Natl. Acad. Sci. USA 98, 2503-2508.

Maret, W., Heffron, G., Hill, H.A.O., Djuricic, D., Jiang, L-J., & Vallee, B.L. (2002) The ATP/Metallothionein Interaction: NMR and STM, Biochemistry 41, 1689-1694.

Chen, Y., Irie, Y., Keung, W.M., & Maret, W. (2002) S-Nitrosothiols React Preferentially with Zinc Thiolate Clusters of Metallothionein III through Transnitrosation,  Biochemistry 41, 8360-8367.

Maret, W. (2003) The Cellular Zinc and Redox States Converge in the Metallothionein/Thionein Pair, J. Nutr. 133, 1460S-1462S.

Hong, S-H. & Maret, W. (2003) A Fluorescence Resonance Energy Transfer Sensor for the ß-Domain of Metallothionein, Proc. Natl. Acad. Sci. USA 100, 2255-2260.

Haase, H. & Maret, W. (2003) Intracellular Zinc Fluctuations Modulate Protein Tyrosine Phosphatase Activity in Insulin/Insulin-like Growth Factor-1 Signaling, Exp. Cell Res. 291, 289-298.

Maret, W. (2004) Exploring the Zinc Proteome, J. Anal. At. Spectrom. 19, 15-19.

Maret, W.  (2004) Zinc and Sulfur: A Critical Biological Partnership, Biochemistry 43, in press (published on web: March 2, 2004).