Enzymes That Use Metals to Generate Organic Radicals

An organic radical is an organic species that contains one or more unpaired electrons. Chemists often consider organic radicals to be highly reactive species that produce undesirable reactions. For example, they have been implicated in some of the irreversible chemical changes that accompany aging. It is surprising, however, that organic radicals are also essential components of many important enzymes, almost all of which use a metal ion to generate the organic radical within the enzyme. These enzymes are involved in the synthesis of hemoglobin and DNA, among other important biological molecules, and they are the targets of pharmaceuticals for the treatment of diseases such as anemia, sickle-cell anemia, and cancer. In this section, we discuss one class of radical enzymes that use vitamin B₁₂.

Vitamin B₁₂ was discovered in the 1940s as the active agent in the cure of pernicious anemia, which does not respond to increased iron in the diet. Humans need only tiny amounts of vitamin B₁₂, and the average blood concentration in a healthy adult is only about 3.5 × 10⁻⁸ M. The structure of vitamin B₁₂, shown in Figure 1.1, is similar to that of a heme, but it contains cobalt instead of iron, and its structure is much more complex. In fact, vitamin B₁₂ has been called the most complex nonpolymeric biological molecule known and was the first naturally occurring organometallic compound to be isolated. When vitamin B₁₂ (the form present in vitamin tablets) is ingested, the axial cyanide ligand is replaced by a complex organic group.

The cobalt–carbon bond in the enzyme-bound form of vitamin B₁₂ and related compounds is unusually weak, and it is particularly susceptible to homolytic cleavage:

Homolytic cleavage of the Co³⁺–CH₂R bond produces two species, each of which has an unpaired electron: a d⁷ Co²⁺ derivative and an organic radical, ·CH₂R, which is used by vitamin B₁₂-dependent enzymes to catalyze a wide variety of reactions. Virtually all vitamin B₁₂-catalyzed reactions are rearrangements in which an H atom and an adjacent substituent exchange positions:

In the conversion of ethylene glycol to acetaldehyde, the initial product is the hydrated form of acetaldehyde, which rapidly loses water:

The enzyme uses the ·CH₂R radical to temporarily remove a hydrogen atom from the organic substrate, which then rearranges to give a new radical. Transferring the hydrogen atom back to the rearranged radical gives the product and regenerates the ·CH₂R radical.

The metal is not involved in the actual catalytic reaction; it provides the enzyme with a convenient mechanism for generating an organic radical, which does the actual work. Many examples of similar reactions are now known that use metals other than cobalt to generate an enzyme-bound organic radical.

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