Chemistry Reference
In-Depth Information
1.2 Iron
Iron (Fe) is an essential metal whose regulation is
controlled by both uptake and export proteins. Both
iron defi ciency and excess iron can be potentially
toxic to cells, so its transport is stringently control-
led. One of the major proteins involved in the cellular
uptake of iron is transferrin. Transferrin is capable
of binding two molecules of ferric iron. In addition
to binding ferric iron, transferrin is also able to bind
nickel, vanadium, and other metals (Boffi
et al.
, 2003;
Harris, 1986; Sun
et al.
, 1999). One may speculate
that other metals may interfere with iron transport
by occupying sites on transferrin molecules. Difer-
ric transferrin gets internalized into an acidic endo-
some via transferrin receptor-mediated endocytosis.
Iron is subsequently released from the transferrin
receptor, reduced, and transported out of the endo-
some into the cell via the divalent metal transporter-
1 (DMT1/DCT1/NRAMP2). DMT1 is also involved
in the transferrin receptor's independent transport of
iron. Interestingly, DMT1 is able to transport a mul-
titude of other metals including nickel (Ni), manga-
nese (Mn), cobalt (Co), copper (Cu), and zinc (Zn)
(Chen
et al.
, 2005; Garrick
et al.
, 2003). The transport
of metals into the cell by DMT1 is one example of
how nonspecifi c transport of toxic metals like Ni
may interfere with the transport of essential metals.
Indeed, it has been shown that Ni and other toxic
metals can compete with iron for entry into the cell
at DMT1 (Chen
et al.
, 2005; Garrick
et al.
, 2003).
1.4 Phosphate and Sulfate Mimics
Phosphate and sulfate are carried across the cell
membrane by various transport proteins (Clarkson,
1993). Some metal oxyanions resemble these com-
pounds and compete for transport with phosphate and
sulfate through their respective carriers. For example,
selenate, molybdate, and chromate resemble sulfate
and can be transported by sulfate transporters. The
transport of sulfate has been shown to be inhibited
by these mimics (Cardin and Mason, 1975; Mason
and Cardin, 1977; Shennan, 1988). Likewise, vanad-
ate and arsenate are structurally similar to phosphate,
and, as a result, they are substrates for phophate car-
riers. Arsenate has been shown to compete with phos-
phate transport in a number of cell lines and tissue
systems (Clarkson, 1993). Vanadate has also been
shown to inhibit the uptake of phosphate at the NaPi-3
cotransporter (Timmer and Gunn, 1998). In addition,
phosphate can be mimicked in nontransport-related
reactions like the synthesis of ATP (arsenate) or inhi-
bition of ATPase (vanadate) (DeMaster and Mitchell,
1973; Karlish
et al.
, 1979).
1.5 Organic Complexes
Toxic metals are often transported into cells com-
plexed to organic solutes. Methionine is an amino acid
that can be transported into the cell via the L-type
neural amino acid carrier (Ballatori, 2002). Unfortu-
nately, the toxic metal methylmercury can bind to the
amino acid cysteine, forming a complex that resem-
bles the amino acid methionine, which can then be
transported into the cell by this amino acid carrier
(Aschner and Clarkson, 1988; Kerper
et al.
, 1992). In
addition, glutathione carriers can transport meth-
ylmercury complexed with glutathione (Ballatori
and Clarkson, 1984a; 1984b; Dutczak and Ballatori,
1994). Other metals (Cu, Zn, Cd, Cr, and Pb) have
been reported to form complexes that mimic glutath-
ione and are transported by glutathione transporters
(Aaseth
et al.
, 1982; Alexander
et al.
, 1981; Ballatori and
Clarkson, 1985; Cherian and Vostal, 1977; Gyurasics
et al.
, 1991; Norseth
et al.
, 1982). In addition, uptake
of zinc-histidine and copper-histidine complexes by
amino acid transporters has been reported (Aiken
et al.
, 1992; Horn
et al.
, 1995; Horn and Thomas, 1996;
Oakley
et al.
, 2004). Arsenite can be transported by
glucose transporters and by the water transporter,
aquaglyceroporin (Liu
et al.
, 2002). The ability to
directly bear a resemblance to organic compounds or
form complexes that mimic endogenous compounds
is an important mechanism by which toxic metals can
be transported by cells.
1.3 Zinc
Zinc is an essential component of many metalloen-
zymes and transcription factors that are involved in
various cellular processes such as gene expression,
signal transduction, transcription, and replication
(Berg and Shi, 1996). The movement of zinc across
cellular membranes in humans involves various zinc
transporters, including the ZnT family of proteins
and the Zip proteins, both members of the trans-
porter super family known as the ZIP (ZRT1, IRT1-
like protein) family. The ZnT family of transporters
is involved in the sequestration and release of zinc,
whereas DMT1 and Zip proteins are believed to be
responsible for importing Zn into the cells (Harris,
2002). Similarly to DMT1, the ZIP proteins are not
specifi c for Zn transport and can also likely transport
other transition metals into the cell. It has been shown
that Mn, Cd, and Cu can compete with Zn for uptake
by hZIP2, a human zinc transporter, suggesting that
these metals are also substrates for the transporter
(Gaither and Eide, 2000).
