Contact Information:

1^st floor, S.G. Mudd Bldg., room 112

Telephone: (617) 432-5685

e-mail: [email protected]

 

Research Interests:

Molecular Mechanisms of Cellular Metal Homeostasis

Sulfur Redox Biochemistry

Structure and Function of Metalloenzymes

 

Key words: Metallothionein, Alcohol Dehydrogenases, Zinc, Transition Metals, Selenium, Glutathione, Polyols, Carotenoids and Retinoids

  

Research Activities: Molecular Mechanisms of 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 and protein-nucleic acid 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.  It is a 6 kD zinc-rich protein that was discovered in this laboratory in 1957.  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 bond 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 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 a regulatory function.  With a new differential fluorescence labeling procedure we now find almost as much thionein as metallothionein in many tissues.  Jointly, this suggests 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.

 

Our research is at the interface of cell biology and inorganic chemistry.  Present interests focus on: i) identification of proteins that are targeted by thionein and metallothionein, ii) exploration of a possible role of zinc as a signaling ion, iii) mapping pathways and mechanisms of translocation of MT/T, iv) attempts to integrate the zinc/MT/T system into signal transduction networks that control energy metabolism and cell fate, and v) delineation of the steps that lead from defects in this system to the development of degenerative and chronic diseases.

    

Representative Recent 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. (1995) Metallothionein and the Acute Phase Response, J. Lab. Clin. Med. 126, 106-107.

Maret, W., Larsen, K.S., & Vallee, B.L. (1997) Coordination Dynamics of Biological Zinc “Clusters” in Metalloproteins and in the DNA-binding Domain of the Transcription Factor Gal4, Proc. Natl. Acad. Sci. USA 94, 2233-2237.

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.

Jiang, L-J., Maret, W. & Vallee, B.L. (1998) The Glutathione Redox Couple Modulates Zinc Transfer from Metallothionein to Zinc-Depleted Sorbitol Dehydrogenase, Proc. Natl. Acad. Sci. USA 95, 3483-3488.

Jacob, C., Maret, W. & Vallee, B.L. (1998) Control of Zinc Transfer Between Thionein, Metallothionein and Zinc Proteins, Proc. Natl. Acad. Sci. USA 95, 3489-3494.

Jiang, L-J., Maret, W. & Vallee, B.L. (1998) The ATP-Metallothionein Complex, Proc. Natl. Acad. Sci. USA 95, 9146-9149.

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.