Page 32 - Academic Press Encyclopedia of Physical Science and Technology 3rd InOrganic Chemistry

P1: ZBU Final Pages
Encyclopedia of Physical Science and Technology EN002F-55 May 22, 2001 21:6

120 Bioinorganic Chemistry

acidic and iron is released. Then, the iron is shuttled to enhance the growth of some marine diatoms in the absence
sites of utilization (e.g., myoglobin) or storage (ferritin). of a sufficient supply of zinc.) Below are examples of two
In contrast to the analogous bacterial receptors that are different types of biochemical resistance to the toxic ions.
regulated transcriptionally, both the transferrin receptor The first example is from a prokaryote (Hg 2+ detoxifica-
protein and the storage protein ferritin are regulated trans- tion), the second from a eukaryote (Cd 2+ detoxification).
lationally. After the genes for the proteins are transcribed
to mRNA, a section of the mRNA is used to regulate
1. Prokaryotic Hg(II) Detoxification
the synthesis of the protein. This region is termed the
IRE (iron-responsive element). The IREs associated with Bacterial mercury regulation and resistance is the classic
transferrin receptor are rich in adenine and uracil bases. example of regulated metal resistance. It is accomplished
These bases do not stabilize RNA structure as well as by the mer gene. Mercury is a metal that is not essential
guanine and cytosine. For ferritin, the IRE is found in for life, but is highly toxic. Interestingly, the mechanism
the region of mRNA preceding the protein-coding region, for detoxification is through uptake. The explanation for
whereas the IRE follows the protein-coding region for the this is that Hg(II) is extremely thiophilic and will bind to
transferrin receptor protein. The placement of the IRE is available cysteines voraciously. In order to prohibit envi-
essential for the proper regulation of iron. ronmental Hg(II) from binding and disrupting the function
The control mechanism for this system is a cytoplas- of membrane proteins, Hg(II) must be controlled by being
mic protein called the IRP (iron regulatory protein). At brought into the cell and reduced to Hg(0).
low intracellular iron levels, the IRP does not bind iron. The expression of proteins involved in Hg(II) detoxifi-
Without the iron bound, the protein has a high affinity cation is regulated by the MerR protein. The MerR protein
for the IRE. Under these conditions, the ferritin mRNA is always bound as a dimer adjacent to the RNA poly-
is blocked from binding the ribosome and protein is not merase binding site of the mer gene. In the absence of
produced. At the same time, the unstable mRNA for the Hg, MerR holds the DNA in a conformation so that the
transferrin receptor protein is stabilized by binding the RNApolymerasebindingisblockedandtranscriptioncan-
IRP, which allows protein synthesis to occur for longer not occur. When the mercury binds to MerR, it changes
periods. As a consequence more iron is brought into the the conformation of the MerR protein–DNA complex and
cell and less storage protein is made at low levels of in- allows RNA polymerase to bind and transcribe the mer
tracellular iron. At high iron levels, the IRP binds four Fe operon, creating mRNA for the series of enzymes that
atoms in an “iron–sulfur” cluster. This causes the protein carry out mercury resistance.
to change its three-dimensional structure to a form that has These proteins are MerA, MerT, and MerP. MerP is
low affinity for the IRE. Now ferritin mRNA binding to the responsible for scavenging Hg(II) from the environment
ribosome is no longer blocked, allowing protein synthesis and bringing it to the cell surface. MerT then transports
and, ultimately, iron storage. Concurrently, the transferrin the Hg(II) across the cell membrane. The Hg(II) is then
receptor mRNA, now less stable, is rapidly degraded, lim- reduced to Hg(0) by MerA, which uses NADPH as a re-
iting the iron entering the cell. As a consequence less iron ductant. The Hg(0) is much less toxic than Hg(II) and is
is brought into the cell and more storage protein is made also volatile. Therefore, it is able to diffuse through the
at high levels of intracellular iron. membrane out of the cell where it will evaporate out of
It is thought that the IRE/IRP system of regulation is the surrounding solution.
very ancient and may represent how the earliest genes
were regulated in an RNA world. Other metals such
2. Eukaryotic Cd(II) detoxification
as copper and nickel have separate sets of proteins and
genes that regulate the homeostasis of these necessary Cadmium is released into the environment by power sta-
metals. tions, heating systems, metal-working industries, waste
incinerators, and urban traffic and as a by-product of some
fertilizers. Its primary mode of toxicity is as an inhibitor
C. Regulation of Toxic Inorganic Ions
to enzymes. For example, by binding to nitrate reductase
Some inorganic ions are not necessary to the survival of it inhibits the transport of nitrate and blocks energy flow
an organism. In many of these cases, the presence of the in plants. In other plants, Cd(II) inhibits Fe(III) reductase
metal ion at any concentration is detrimental to that organ- leadingtoFe(II)deficiency,hencedisruptingphotosynthe-
ism. These inorganic ions are purely toxic. For example, sis (see below). In addition, Cd(II) can act as a carcinogen.
mercury, cadmium, and arsenic are toxic to most organ- Unlike iron, however, the cadmium does not produce oxy-
isms. It should be noted, however, that these elements are gen radicals. Instead, it inhibits the enzymes responsible
not necessarily toxic to all organisms (e.g., cadmium can for protection against oxygen radicals.