Cytochrome P450: Radicals in a Biochemical Setting

Uploaded by lamechivanes on 29.12.2010

Much of our body's ability to process
an enormous variety of chemicals
depends on the action of cytochrome enzymes
which transform organic compounds
so that they can be disposed of by the body
or used as building blocks.
In particular, the cytochrome P450 enzymes
catalyze a wide variety of oxidation reactions
through radical intermediates.
We can understand the mechanism of cytochrome enzymes
using the concepts we've already discussed
in this lesson.
The active sites of P450 enzymes contain a heme group,
iron surrounded by a large porphyrin molecule.
Oxidation of the iron results in the formation
of an iron-oxygen double bond.
The unique iron-oxygen double bond
is able to abstract a hydrogen atom
from an organic substrate that fits into the active site.
Although the carbon is drawn as sp3 hybridized here,
aroyl and alkenyl hydrogens may also be abstracted.
This process produces an organic radical
and an iron radical bound to a hydroxyl group.
The hydroxyl group is then able to rebound
onto the organic radical
with the net effects
that the oxygen atom of the Fe-O double bond
has inserted itself into the C-H bond
and the iron has been reduced.
The intrinsic reactivity preferences of the P450s,
that is, how the iron-oxygen double bond would react
in the absence of any orienting effects by the enzyme
are determined by the stability of the possible radicals
that may be formed on the substrate.
This means that we can use the principles
of radical stability we've already learned
as well as bond dissociation energies
to predict the most likely site of oxidation.
For instance, we would expect tertiary C-H bonds
to be oxidized more readily than primary C-H bonds
because the corresponding radical intermediates,
tertiary over primary, are more stable.
The hydroxylation of thujone
provides a nice example of this idea.
As we would expect,
the two unconstrained tertiary positions
are oxidized preferentially by cytochrome P450.
I'll leave it as a problem for you to think about
why the constrained tertiary position,
where the cyclopropane ring meets the cyclopentane ring
is unlikely to undergo oxidation by cytochrome P450.