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Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, MA 02115
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ABSTRACT |
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 TOP ABSTRACT A homeostatic zinc systemMetallothionein structureRedox functions of...Oxidative zinc release from...Metallothionein/ligand...REFERENCES |
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KEY WORDS: • zinc • metallothionein • redox regulation • ATP • glutathione
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A homeostatic zinc system |
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TOPABSTRACTA homeostatic zinc systemMetallothionein structureRedox functions of...Oxidative zinc release from...Metallothionein/ligand...REFERENCES |
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) reviewed the
coordination environments of zinc in proteins and their variability
that is now well established through X-ray diffraction and NMR
spectroscopic studies of > 100 entities. Zinc coordination motifs
have been defined that demonstrate characteristic spacings of
particular amino acid zinc ligands. Such motifs predict
zinc-binding sites from sequence data of proteins (Vallee and Auld 1990
). Within the past decade, these efforts have led
to the discovery and definition of large families of zinc proteins. As
a consequence, the number of different zinc proteins has increased so
that a conservative estimate minimally recognizes in the order of a few
thousand of them. The full impact of the biochemistry of such a large
number of zinc proteins on physiology, pathology and medicine is now
amply apparent (Vallee and Falchuk 1993
).
However, the dynamics of zinc binding to and release from proteins, the
cellular distribution of zinc, the hierarchy of distribution, the
homeostatic control of zinc and its regulatory roles remain enigmatic.
It must be emphasized that the proposition that zinc is readily
available inside the cell as the "free" ion has no merit. Zinc is
firmly bound to proteins with picomolar binding constants, and the
concentration of the "free" ion would be expected to be in the
picomolar or nanomolar range; this has been confirmed experimentally
(Atar et al. 1995
, Peck and Ray 1971
,
Simons 1991
). The regulation of zinc distribution
remains a critical, unanswered question. The manner in which zinc is
released from its tight binding sites in proteins and its transfer from
one site to another are also unknown. Moreover and significantly, zinc
in biology is redox inert, in contrast to copper or iron. If its
concentration rises excessively, zinc will interfere with other
metal-dependent processes, particularly calcium (Csermely et al. 1989
), or inhibit other proteins (or both). Zinc
homeostasis must balance zinc utilization, precluding pathological
consequences.
Our work demonstrates that the metallothionein
(MT)3
/thionein(T) couple safeguards zinc and acts as a remarkable biochemical device
that controls the concentration of readily available zinc. The
activation of metal-responsive element–binding transcription
factors induces T when the concentration of available zinc reaches a
critical, but thus far undefined, value, followed by the sequestration
of zinc in MT. Based on the overall zinc binding constant of mammalian
MT [2 x 1012
M-1 at pH 7.0
(Va
ák and Kägi 1994
)], MT binds zinc
more tightly than most other zinc proteins and constitutes a
thermodynamic "sink" for zinc, in particular because the zinc
concentration of MT is relatively high in comparison with other zinc
proteins, i.e., zinc bound to MT represents 5–10% of the total zinc
in a human hepatocyte (Bühler and Kägi 1974
). Consequently, zinc cannot move freely from its tight
binding sites in MT to those of lower affinity without the assistance
of effectors that enhance its release and transfer. MT exchanges zinc
relatively quickly in intramolecular and intermolecular reactions with
other zinc/sulfur clusters despite this relatively high thermodynamic
stability (Maret et al. 1997
). The MT/T system has at
least two functions, i.e., to sequester zinc, a consequence of gene
regulation (Fig. 1
, left), and to release it by events that signal its
requirement (Fig. 1
, right). This regulatory process is a
direct function of the cluster structure of MT, which was detected only
recently (Vaák and Kägi 1994
).
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Metallothionein structure |
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TOPABSTRACTA homeostatic zinc systemMetallothionein structureRedox functions of...Oxidative zinc release from...Metallothionein/ligand...REFERENCES |
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, Robbins et al. 1991
). In one domain, three zinc atoms are bound to nine
cysteines, whereas in the other domain, four zinc atoms are bound to 11
cysteines. In this way, each zinc atom is bound tetrahedrally to
four cysteines, but overall there are fewer than the maximum
number of possible ligands for the seven metals; hence, some of the
cysteines form ligand bridges, creating an extensive zinc/sulfur
network. The protein envelops the zinc atoms in a manner that
effectively shields them from the environment and leaves only a few of
the sulfur ligands partially exposed to solvent. Because both protein
structure and tetrahedral zinc coordination preclude access of ligands
to zinc, it would seem that a conformational change of the protein is
necessary to release zinc. |
Redox functions of metallothionein |
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TOPABSTRACTA homeostatic zinc systemMetallothionein structureRedox functions of...Oxidative zinc release from...Metallothionein/ligand...REFERENCES |
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). The cluster unit operates via a novel mechanism,
which allows the cysteine sulfur ligands to zinc to be oxidized and
reduced with concomitant release and binding of zinc. This results in
an oxidoreductive mechanism exercised by the ligands of the otherwise
redox-inert zinc atom (Fig. 2
). Thus, MT can become a redox protein, in which the redox chemistry
originates not from the metal atom but rather from its coordination
environment. In this principle of modulating zinc affinity lies the
significance of the sulfur coordination chemistry of zinc in the
cluster structure of MT.
|
). This allows biochemical
coupling of reactions between zinc/sulfur centers and redox-active
compounds such that the coordination state of zinc becomes part of the
redox environment of the cell. The change of the cellular redox state
supplies the driving force for zinc distribution in such a way that a
shift to more oxidizing conditions releases zinc, whereas a shift to
more reducing conditions leads to its binding. We have identified
cellular redox agents that oxidize MT and release zinc and could
therefore serve as regulators of zinc distribution under physiological
conditions. Among them are both sulfur and selenium compounds as redox
partners. |
Oxidative zinc release from metallothionein: the relation of zinc/sulfur coordination to the biological redox chemistry of sulfur and selenium |
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TOPABSTRACTA homeostatic zinc systemMetallothionein structureRedox functions of...Oxidative zinc release from...Metallothionein/ligand...REFERENCES |
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Initially, we used 65Zn-MT to screen for
biological compounds that would release zinc from MT. In this process,
we found glutathione disulfide (GSSG) and other biological disulfides
to be "releasing factors" (Maret 1994
). The reaction
of MT with GSSG is relatively slow (k = 5 x 10-3 s-1
M-1 at pH 8.6) but
eventually mobilizes all seven zinc atoms. This zinc-thiol/disulfide
interchange has also been observed when GSSG activates matrix
metalloproteases (Tyagi et al. 1996
), as well as when
zinc is ejected from viral zinc finger proteins by means of disulfide
drugs (Rice et al. 1995
, Tummino et al. 1996
). We have hypothesized that such a metal release mechanism
would link the control of the zinc content in MT to the cellular
glutathione (GSH) redox state. A relation between MT and the GSH system
has gained further support from the observation that GSH binds to MT
(Brouwer et al. 1993
). In this regard, we studied the
release and transfer of zinc from MT to both apoenzymes and
chromophoric zinc-chelating agents such as
4-(2-pyridylazo)resorcinol serving as zinc acceptors. In the absence of
any effector, only one zinc atom is transferred from MT to the
acceptor, indicating that one particular zinc atom in MT is more labile
than are the remainder (Jacob et al. 1998a
, Jiang et al. 1998a
). However, the binding of GSH inhibits the release
of this zinc atom in MT (Jiang et al. 1998a
), and
therefore it may not be released in vivo at a cellular concentration of
0.1–10 mmol/L GSH (Meister 1988
). In contrast, when
present together with GSSG, GSH enhances zinc transfer to the
apoenzymes. The GSH/GSSG couple modulates zinc transfer in a range of
concentrations and redox ratios that are attained in the cell
(Jiang et al. 1998a
). These experiments further support
a link between cellular zinc distribution and the GSH/GSSG redox state
and suggest that zinc distribution might be controlled by intermediary
metabolism (Maret 1998
) because the GSH/GSSG couple is
controlled by the NADP+/NADPH redox state through
the oxidation of glucose in the pentose phosphate pathway. It is
perhaps revealing that in addition to GSSG, enzymes with active site
disulfides react with MT and release zinc (Maret and Vallee 1998
). Thus, members of the large family of thiol/disulfide
oxidoreductases are oxidants toward MT and could provide specific
interactions with MT or link zinc distribution to specific cellular
signals. It has now been shown that a protein disulfide acts as a
cellular oxidant, at least in bacterial cells (Zheng et al. 1998
).
Selenium.
Like sulfur, selenium also undergoes redox reactions in biology and is
used as a cellular oxidant toward thiols. Thus, in the selenium enzyme
GSH peroxidase, the selenol of the active site selenocysteine is first
oxidized by peroxide to a selenenic acid derivative that then serves as
an oxidant toward the thiol of GSH. This biological chemistry motivated
us to investigate selenium compounds with regard to their potential to
release zinc from MT. Ebselen
[2-phenyl-1,2-benzisoselenazol-3(2H)-one], a
selenium-containing redox drug that mimics GSH peroxidase
(Sies 1993
), releases zinc from MT within seconds in a
reaction that follows a 1:1 stoichiometry with respect to thiols and
takes place even in the presence of an excess of GSH (Jacob et al. 1998b
). Moreover, selenocystamine reacts with MT at much
lower concentrations than does cystamine (Jacob et al. 1998a
, Maret 1995
). This demonstrates an
interaction between selenium and zinc/sulfur centers, raising the
possibility that a selenium compound of low molecular weight or
selenium as a component of an enzyme might act as an oxidant of MT in
vivo even in the presence of a large excess of thiols in the form
either of GSH or other protein thiols. Furthermore, this invites the
investigation of an interaction between these two essential elements,
i.e., sulfur and selenium. In particular, the question arises of
whether a compromised selenium status might adversely affect the zinc
status.
|
Metallothionein/ligand interactions |
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TOPABSTRACTA homeostatic zinc systemMetallothionein structureRedox functions of...Oxidative zinc release from...Metallothionein/ligand...REFERENCES |
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175 µmol/L at pH 7.4 (Jiang et al. 1998b
). This binding is abolished by chemical modification of
the eight highly conserved lysine residues of MT, indicating that they
participate in this process. The binding is sufficiently strong to
saturate MT in the presence of typical cellular ATP concentrations.
This further suggests that MT is present in the cytosol as an MT/ATP
complex and that at least two important effectors, i.e., GSH and ATP,
are lost when MT is isolated. The functional consequences of ATP
binding include an altered redox behavior as demonstrated by the
increased rate of reaction with disulfides, an enhancement of zinc
transfer to zinc-depleted sorbitol dehydrogenase and a drastically
altered conformation of the molecule. Based on gel filtration
experiments, ATP alters the dumb-bell shape of MT to that of a more
globular protein. Although Brouwer et al. (1993
) propose
that GSH binds to the N-terminal ß-domain, we have postulated
that ATP binds to the C-terminal 
-domain. Both effectors
increase the reactivity of MT toward disulfides. We further speculated
that GSH and ATP might be the two substances required to open the
domains so the zinc atoms will be released in the presence of
acceptors.
The binding of ATP to MT could also be an intermediate step in the
formation of a Zn-ATP complex as a specific cofactor required by
certain enzymes. Thus, both pyridoxal (PL) kinase and flavokinase
exhibit specificity for a Zn-ATP complex (Churchich et al. 1989
, Nakano and McCormick 1991
). Both enzymes
supply critical cofactors from their vitamin precursors for energy
metabolism.
Explications and implications.
It would seem to be an inescapable conclusion that a protein like MT
that has so many genes and transcriptional regulators must have an
important function. Indeed, MT-3 turns out to be an inhibitor of nerve
growth (Uchida et al. 1991
), even though mechanistic
insights regarding this function do not yet exist. Research on the
function of MT has long had the bias that MT might be an antioxidant
and participate in the detoxification of cadmium and mercury. However,
either displaced by these metals or released from MT, zinc would likely
be as harmful as the action of other metals or oxidants of other
systems. Genetic knockouts of MT-1 and MT-2 were interpreted to
demonstrate that MT-1 and MT-2 are not necessary for the growth and
reproduction of mice (Masters et al. 1994
,
Michalska and Choo 1993
). Because it has been shown that
such transgenic animals become obese (Beattie et al. 1998
), the interpretation of such MT knockout experiments has
been questioned. In fact, an important lesson of these experiments is
that "biochemistry and genetics are both required to elucidate the
function of macromolecules" (Palmiter 1998
). The
obesity of the transgenic animals clearly demonstrates that the absence
of MT affects a critical, zinc-dependent step. This step likely is
the control of the available, metabolically active pool of cellular
zinc. In this regard, MT is not just a buffer but rather a rheostat
that is ligand and redox regulated at the protein level in addition to
its extensive gene regulation and regulation during the cell cycle
(Nagel and Vallee 1995
), just what is needed for such an
important element as zinc (Vallee 1995
).
With the identification of its characteristic protein functions, the
specificity of the MT/T system is slowly becoming unraveled, and the
next challenge is to understand the signaling systems with which it
interacts. Thus, there is growing appreciation that oxidant signals are
used as critical switches in cellular proliferation, where a need for
zinc in newly synthesized proteins arises (Burdon 1995
),
and that they operate in the relatively strong reducing environment of
the cytosol. This is achieved by compartmentalization of redox
reactions and by keeping different redox couples at different
potentials. A classic example is the ratio
NAD+/NADH, which is 105 times higher than that of the
NADP+/NADPH couple. The latter is held at
-394 mV, which is much more reducing than the GSH/GSSG couple
with a redox potential of -239 mV in the cytosol (for a 100:1 ratio at
a concentration of 1 mmol/L total GSH) or -165 mV in the endoplasmic
reticulum (for a 3:1 ratio) (Hwang et al. 1992
). Very
small changes in the redox potential affect critical biochemical steps.
Thus, in apoptosis a change occurs of 72 mV to more oxidizing
conditions for the GSH/GSSG couple (Cai and Jones 1998
);
the difference in redox potential between proliferating and confluent
fibroblasts is 34 mV (Hutter et al. 1997
). A difference
as small as 15 mV abolishes the binding of redox-sensitive
transcription factors to DNA (Clive and Greene 1996
).
These changes of the cellular redox state are exactly in the range of
those required to release zinc from MT in vitro. Moreover,
thiol-reactive oxidants increase the concentration of "free"
zinc in whole cells (Turan et al. 1997
). Thus, there is
no question that oxidative zinc release from zinc/sulfur centers does
occur, but when and where and which general or specific oxidants
participate in this process are unknown. Oxidative stress is one
example in which an imbalance of the antioxidant status elicits a
perturbation of cellular zinc homeostasis and constitutes a
pathophysiological mechanism for neurodegenerative (Maret 1995
) and other chronic (Maret 1998
) diseases.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 This work was supported by the Endowment for Research in Human Biology, Inc.
3 Abbreviations used: GSH, glutathione; GSSG, glutathione disulfide; MT, metallothionein; T, thionein.
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 C. Duggan, W. B. MacLeod, N. F. Krebs, J. L. Westcott, W. W. Fawzi, Z. G. Premji, V. Mwanakasale, J. L. Simon, K. Yeboah-Antwi, D. H. Hamer, et al. Plasma Zinc Concentrations Are Depressed during the Acute Phase Response in Children with Falciparum Malaria J. Nutr., April 1, 2005; 135(4): 802 - 807. [Abstract] [Full Text] [PDF]
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R. R. Starzynski, P. Lipinski, J.-C. Drapier, A. Diet, E. Smuda, T. Bartlomiejczyk, M. A. Gralak, and M. Kruszewski Down-regulation of Iron Regulatory Protein 1 Activities and Expression in Superoxide Dismutase 1 Knock-out Mice Is Not Associated with Alterations in Iron Metabolism J. Biol. Chem., February 11, 2005; 280(6): 4207 - 4212. [Abstract] [Full Text] [PDF]
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 A. Martinez-Ruiz and S. Lamas S-nitrosylation: a potential new paradigm in signal transduction Cardiovasc Res, April 1, 2004; 62(1): 43 - 52. [Abstract] [Full Text] [PDF]
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B. Kindermann, F. Doring, M. Pfaffl, and H. Daniel Identification of Genes Responsive to Intracellular Zinc Depletion in the Human Colon Adenocarcinoma Cell Line HT-29 J. Nutr., January 1, 2004; 134(1): 57 - 62. [Abstract] [Full Text] [PDF]
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D. U. Spahl, D. Berendji-Grun, C. V. Suschek, V. Kolb-Bachofen, and K.-D. Kroncke Regulation of zinc homeostasis by inducible NO synthase-derived NO: Nuclear metallothionein translocation and intranuclear Zn2+ release PNAS, November 25, 2003; 100(24): 13952 - 13957. [Abstract] [Full Text] [PDF]
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 U. P. Kodavanti, A. D. Ledbetter, M. C. Schladweiler, D. L. Costa, C. F. Moyer, R. Hauser, D. C. Christiani, and A. Nyska Reply Toxicol. Sci., July 1, 2003; 74(1): 228 - 229. [Full Text] [PDF]
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S. L. Sensi, D. Ton-That, P. G. Sullivan, E. A. Jonas, K. R. Gee, L. K. Kaczmarek, and J. H. Weiss Modulation of mitochondrial function by endogenous Zn2+ pools PNAS, May 13, 2003; 100(10): 6157 - 6162. [Abstract] [Full Text] [PDF]
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Abstract Section: 11th International Symposium on Trace Elements in Man and Animals Abstracts J. Nutr., May 1, 2003; 133(5): 203E - 282. [Full Text] [PDF]
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 L.L. Espey, T. Ujioka, H. Okamura, and J.S. Richards Metallothionein-1 Messenger RNA Transcription in Steroid-Secreting Cells of the Rat Ovary During the Periovulatory Period Biol Reprod, May 1, 2003; 68(5): 1895 - 1902. [Abstract] [Full Text] [PDF]
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M. P. Richards, S. M. Poch, C. N. Coon, R. W. Rosebrough, C. M. Ashwell, and J. P. McMurtry Feed Restriction Significantly Alters Lipogenic Gene Expression in Broiler Breeder Chickens J. Nutr., March 1, 2003; 133(3): 707 - 715. [Abstract] [Full Text] [PDF]
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D. K. Lee, J. Geiser, J. Dufner-Beattie, and G. K. Andrews Pancreatic Metallothionein-I May Play a Role in Zinc Homeostasis during Maternal Dietary Zinc Deficiency in Mice J. Nutr., January 1, 2003; 133(1): 45 - 50. [Abstract] [Full Text] [PDF]
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R. Rousset, K. A. Wharton Jr., G. Zimmermann, and M. P. Scott Zinc-dependent Interaction between Dishevelled and the Drosophila Wnt Antagonist Naked Cuticle J. Biol. Chem., December 6, 2002; 277(50): 49019 - 49026. [Abstract] [Full Text] [PDF]
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A. Daiber, D. Frein, D. Namgaladze, and V. Ullrich Oxidation and Nitrosation in the Nitrogen Monoxide/Superoxide System J. Biol. Chem., March 29, 2002; 277(14): 11882 - 11888. [Abstract] [Full Text] [PDF]
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 K. Ghoshal, S. Majumder, Q. Zhu, J. Hunzeker, J. Datta, M. Shah, J. F. Sheridan, and S. T. Jacob Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and Lung by Overlapping but Distinct Molecular Mechanisms Mol. Cell. Biol., December 15, 2001; 21(24): 8301 - 8317. [Abstract] [Full Text] [PDF]
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R. K. Blanchard, J. B. Moore, C. L. Green, and R. J. Cousins Inaugural Article: Modulation of intestinal gene expression by dietary zinc status: Effectiveness of cDNA arrays for expression profiling of a single nutrient deficiency PNAS, November 20, 2001; 98(24): 13507 - 13513. [Abstract] [Full Text] [PDF]
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Y. Yang, W. Maret, and B. L. Vallee Differential fluorescence labeling of cysteinyl clusters uncovers high tissue levels of thionein PNAS, April 25, 2001; (2001) 101123298. [Abstract] [Full Text]
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B. Ye, W. Maret, and B. L. Vallee Zinc metallothionein imported into liver mitochondria modulates respiration PNAS, February 8, 2001; (2001) 41619198. [Abstract] [Full Text]
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B. Ye, W. Maret, and B. L. Vallee Zinc metallothionein imported into liver mitochondria modulates respiration PNAS, February 27, 2001; 98(5): 2317 - 2322. [Abstract] [Full Text] [PDF]
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Y. Yang, W. Maret, and B. L. Vallee Differential fluorescence labeling of cysteinyl clusters uncovers high tissue levels of thionein PNAS, May 8, 2001; 98(10): 5556 - 5559. [Abstract] [Full Text] [PDF]
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