influences of natural abundance and thermodynamic properties do not determine the cellular content and function of a specific metal (da Silva and Williams, 1991). Nevertheless, these mechanisms can be overwhelmed by very high intakes of a trace metal.
There are three ways trace metals can be involved in gene expression. One is structural, where metals facilitate interaction among various binding groups to provide the altered conformation necessary for interactions such as between specific proteins and DNA (Cousins, 1995). The second type of involvement is catalytic, where the metal is required for the activity of an enzyme associated with gene expression. The third class involves specific regulation, where metal occupancy of a transacting protein modulates transcription of a specific gene. This type of involvement is different from the first in that it is much more specific, being more interactive than structural in function. Since the catalytic role appears to be relatively unalterable in humans except, perhaps, in extreme deficiency situations during development, this chapter will concentrate on the structural and regulatory aspects of metals in gene expression.
The best examples of the regulation of gene expression by metals are iron and zinc. In the case of iron, metal occupancy decreases the binding of a metal-regulatory binding protein to ferritin mRNA, allowing the translation of ferritin mRNA to increase while simultaneously increasing binding to transferrin receptor mRNA, which increases the degradation of mRNA (O'Halloran, 1993). Because iron exhibits oxidation-reduction (redox) chemistry, rapid control of ferritin synthesis at the level of translation is necessary to provide rapid control of free iron levels within cells.
Far more is known about the involvement of zinc in gene expression than that of other elements. The intracellular binding affinity is greater for zinc than for virtually all other metals found in cells, with the exception of copper. However, unlike iron, zinc does not exhibit redox chemistry but has the properties of a Lewis acid and exhibits fast ligand exchange, which is important for its catalytic role (da Silva and Williams, 1991). A principal example of this catalytic role in gene expression is exhibited by the family of RNA nucleotidyl transferases (RNA polymerases I, II, and III). Zinc also plays a structural role in the zinc-finger motif of proteins that are involved in DNA binding, as is discussed below. Finally, as an activator of trans-acting factors,2 zinc is responsible for regulating the expression of specific genes. The latter is discussed below.