Chemistry Reference
In-Depth Information
urine (Chan and Cherian, 1993; Nordberg
et al.
, 1971a;
1971b). Lead has wide-ranging effects on processes
that use zinc. Lead is known to increase zinc excretion
in rats (Victery
et al.
, 1987). The activity of zinc-contain-
ing heme enzymes like
levels (Chen
et al.
, 2005). Aluminum has been reported
to increase the stability of IRP2, another iron regulatory
protein (Ward
et al.
, 2001).
Toxic metals also affect iron-dependent enzymes.
The 4Fe-4S enzyme aconitase loses its enzymatic
activity when cells are exposed to nickel or cobalt. It
has also been shown that toxic metals can affect vari-
ous iron-dependent enzymes involved in the hypoxic
response. The hypoxia inducible factor (HIF)-1
-aminolevulinic acid dehy-
dratase can be decreased by lead, suggesting that lead
may substitute for zinc in some zinc-containing heme
enzymes (Meredith
et al.
, 1977; Tomokuni
et al.
, 1991).
In addition, lead, arsenite, and selenium may disrupt
zinc fi nger proteins. By disturbing zinc fi nger proteins
(approximately 3% of identifi ed genes in the human
genome code for proteins with zinc fi nger domains),
these metals may have widespread effects on transcrip-
tion factors, DNA damage signaling, and DNA repair
proteins (Hartwig
et al.
, 2003; Maret, 2004).
δ
is con-
trolled by two enzyme groups that are members of the
iron and 2-oxoglutarate-dependent dioxygenase fam-
ily of enzymes, the HIF-prolyl hydroxylases and an
asparagine hydroxylase. It has been reported that the
activity of both of these enzymes can be inhibited by
toxic transition metals such as cobalt and nickel (Ivan
et al.
, 2001; Hewitson
et al.
, 2002; Hewitson
et al.
, 2003;
Jaakkola
et al.
, 2001; Schofi eld and Ratcliffe, 2004; Ward
et al.
, 2001).
α
2.4 Magnesium
Magnesium can be found attached to phosphate on
the backbone of DNA. One model suggests that nickel
can replace magnesium, leading to increased chroma-
tin condensation and subsequent DNA methylation
(Lee
et al.
, 1995). This model provides an interesting
link between the interaction of toxic metals with essen-
tial metals and epigenetics.
2.6 Copper
Copper (Cu) is an essential metal for living systems
and is found in an assortment of enzymes, includ-
ing superoxide dismutase (SOD), ferroxidases, and
cytochrome oxidase. Its transport is highly regulated,
and various metals, including zinc, cadmium, and
molybdenum, have been reported to interfere with its
transport or availability in biological systems. It has
also been shown in rodents that lead can alter copper
metabolism, leading to decreases in plasma copper
levels (Klauder and Petering, 1979; Skoczynska
et al.
,
1994).
2.5 Iron
Iron (Fe) is an important essential metal used in many
enzymes and cellular redox reactions. Low cellular iron
levels can be detrimental to a healthy cell, whereas
excess free iron can lead to the production of reactive
oxygen species (ROS) via the Fenton reaction. Cellular
iron levels are tightly regulated by homeostatic mecha-
nisms to maintain the appropriate amount of iron in the
cell. Disruption of iron homeostasis by toxic metals is
a newly emerging area, with many aspects currently
under investigation. We previously mentioned that
nickel and other divalent metals could compete with
iron for entry into the cell at DMT1. One reason why
nickel may be able to compete for iron-binding sites is
because they have similar ionic radii. Metals can inter-
fere with many other iron-dependent processes as well.
Iron homeostasis is maintained by the iron regulatory
protein-1 (IRP1)/iron response element (IRE) system.
When iron levels are low, the 4Fe-4S cluster protein
aconitase loses its cluster and is converted into IRP1.
IRP1 can alter the regulation of mRNAs that have IREs
in their sequence. These IREs can be found in the 3' or
5' untranslated region of mRNAs that encodes for pro-
teins involved in iron uptake, storage, and use (For a
complete review of eukaryotic iron regulation systems,
see Aisen
et al.
(2001). Nickel has been shown to increase
the binding of IRP1 to IRE by lowering cellular iron
3 T
OXIC METAL-BINDING MOLECU
LES
3.1 Introduction
Because metals are generally indestructible, the
accessibility of metals in biological solutions plays a
crucial role in determining their potential toxicity. Met-
als can bind to many types of macromolecules in the
cell, although this discussion will be limited to mole-
cules involved in the transport and/or storage of toxic
metals. Frequently, the binding of metals to proteins is a
defense to reduce toxicity by preventing availability of
the metals, although there are instances when a metal
bound to a protein can be more toxic than the metal
alone. The ability of low-molecular-weight thiols and
protein sulfhydryl groups to bind metals plays a major
part in determining which proteins/peptides will bind
and transport toxic metals. We have limited considera-
tion to two important metal-binding molecules, MT
and glutathione.
