104
Cytochrome P450
ferredoxin reductase:
NADPH
−−−→
NADPH P450 reductase
(FAD + FMN containing)
−−−→
P450
where FAD is flavin adenine dinucleotide
and FMN is flavin mononucleotide. A
small number of variations in the reduc-
tase systems do exist amongst the P450
superfamily. In at least one case, a soluble
bacterial P450 utilizes the microsomal type
of reductase system that is attached to the
C-terminus of the P450 domain to form a
fusion protein. Another type of P450 fu-
sion protein having a ferredoxin domain
attached to the P450 domain is also found
in bacteria. In another example found in
fungi, reduced pyridine nucleotide inter-
acts directly with the P450.
In summary then, P450s are protoheme-
containing, mixed-function oxidases in
which a cysteine thiolate ligand coordi-
nates the polypeptide chain to the heme
iron. In bacteria, these proteins are soluble,
while in higher life-forms they are integral
membrane proteins. Virtually all P450s
require additional proteins to transfer elec-
trons from reduced pyridine nucleotides to
their heme iron.
2
P450 Functions
P450s metabolize a wide range of both
endogenous and exogenous (foreign from
the environment) compounds. These com-
pounds generally are lipophilic, and it
is predicted that the P450 superfamily
can metabolize more than 10,000 known
compounds. Endogenous substrates in-
clude steroids, fatty acids, prostaglandins,
leukotrienes,
bile
acids,
and
biogenic
amines, while exogenous substrates in-
clude environmental pollutants and phar-
maceuticals. P450s catalyze the oxidative,
peroxidative, and reductive metabolism of
such compounds. In the broadest sense
then, we can group P450s into two classes:
those that metabolize endogenous com-
pounds and those that metabolize ex-
ogenous substrates (Table 1). The general
catalytic mechanism for oxygenation by
P450s of both types of substrate can be
represented by the cycle shown in Fig. 1.
Binding of substrate in the P450 active site
has been shown in some cases to raise the
redox potential of the heme iron to about
180 mV, making it more susceptible to
reduction by NADPH.
In animals, the forms involved in en-
dogenous substrate metabolism tend to
be localized in speci±c functional sites
such as steroidogenic tissues (adrenal,
gonads, placenta) or a speci±c organ
(kidney, liver) in which they participate
in key endogenous pathways such as
steroid hormone biosynthesis (mineralo-
corticoids, glucocorticoids, sex hormones),
bile acid biosynthesis, vitamin D
3
acti-
vation and inactivation, and synthesis of
key metabolites from arachidonic acid.
These reactions lead to the production of
regulators of many biological processes
such as reproduction and vascular activity,
to name only two. Other potential roles
for P450s include biosynthesis of neuros-
teroids and activation or inactivation of
important compounds for growth and de-
velopment including derivatives of vitamin
A. Certain P450-dependent endogenous
functions such as cholesterol biosynthesis
are widely distributed. Cholesterol biosyn-
thesis is important in most, if not all, ani-
mal cells for membrane biogenesis and is
dependent on lanosterol 14
α
-demethylase
cytochrome P450. A key developmen-
tal role for P450-dependent activities is
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