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Thionein/metallothionein control Zn(II) availability and the activity of enzymes

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Abstract

Fundamental issues in zinc biology are how proteins control the concentrations of free Zn(II) ions and how tightly they interact with them. Since, basically, the Zn(II) stability constants of only two cytosolic zinc enzymes, carbonic anhydrase and superoxide dismutase, have been reported, the affinity for Zn(II) of another zinc enzyme, sorbitol dehydrogenase (SDH), was determined. Its log K is 11.2 ± 0.1, which is similar to the log K values of carbonic anhydrase and superoxide dismutase despite considerable differences in the coordination environments of Zn(II) in these enzymes. Protein tyrosine phosphatase 1B (PTP 1B), on the other hand, is not classified as a zinc enzyme but is strongly inhibited by Zn(II), with log K = 7.8 ± 0.1. In order to test whether or not metallothionein (MT) can serve as a source for Zn(II) ions, it was used to control free Zn(II) ion concentrations. MT makes Zn(II) available for both PTP 1B and the apoform of SDH. However, whether or not Zn(II) ions are indeed available for interaction with these enzymes depends on the thionein (T) to MT ratio and the redox poise. At ratios [T/(MT + T) = 0.08–0.31] prevailing in tissues and cells, picomolar concentrations of free Zn(II) are available from MT for reconstituting apoenzymes with Zn(II). Under conditions of decreased ratios, nanomolar concentrations of free Zn(II) become available and affect enzymes that are not zinc metalloenzymes. The match between the Zn(II) buffering capacity of MT and the Zn(II) affinity of proteins suggests a function of MT in controlling cellular Zn(II) availability.

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Notes

  1. Free Zn(II) has been referred to as “freely available” or “rapidly exchangeable” Zn(II) that is thermodynamically and kinetically available to chelating agents that are introduced into cells. It is likely not devoid of small ligands, the nature of which is unknown, though glutathione and histidine are likely candidates.

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Acknowledgements

The authors wish to thank Wojciech Bal from the Institute of Biochemistry and Biophysics at the Polish Academy of Sciences in Warsaw for help with potentiometric measurements, V.M. Sadagopa Ramanujam, Associate Professor in the Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, for metal analyses by atomic absorption spectrophotometry (supported by the Human Nutrition Research Facility), and Marinel Ammenheuser for editorial assistance. This work was supported in part by the National Institutes of Health grant GM 065388 to W.M. and by a sponsored research agreement with Neurobiotex Inc, Galveston, TX, USA.

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  1. Artur Krężel

    Present address: Protein Engineering Laboratory, Faculty of Biotechnology, University of Wroclaw, Tamka 2, 50-137, Wroclaw, Poland

Authors and Affiliations

  1. Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX, 77555, USA

    Artur Krężel & Wolfgang Maret

  2. Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, 77555, USA

    Wolfgang Maret

  3. Division of Human Nutrition, Preventive Medicine and Community Health, The University of Texas Medical Branch, 700 Harborside Drive, Galveston, TX, 77555, USA

    Wolfgang Maret

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  1. Artur Krężel
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Correspondence to Wolfgang Maret.

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Krężel, A., Maret, W. Thionein/metallothionein control Zn(II) availability and the activity of enzymes. J Biol Inorg Chem 13, 401–409 (2008). https://doi.org/10.1007/s00775-007-0330-y

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  • DOI: https://doi.org/10.1007/s00775-007-0330-y

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