Page 327 - Color Atlas of Biochemistry
P. 327
318 Tissues and organs
Cytochrome P450 systems Only a few examples of the numerous Cyt
P450-dependent reactions are shown here.
During the first phase of biotransformation in Hydroxylation of aromatic rings (a)plays a
the liver, compounds that are weakly chemi- central part in the metabolism of medicines
cally reactive are enzymatically hydroxylated and steroids. Aliphatic methyl groups can also
(see p. 316). This makes it possible for them to be oxidized to hydroxyl groups (b). Epoxi-
be conjugated with polar substances. The hy- dation of aromatics (c)by Cyt P450 yields
droxylating enzymes are generally mono- products that are highly reactive and often
oxygenases that contain a heme as the redox- toxic. For example, the mutagenic effect of
active coenzyme (see p. 106). In the reduced benzo[a]pyrene (see p. 244) is based on this
form, the heme can bind carbon monoxide type of interconversion in the liver. In Cyt
(CO), and it then shows characteristic light P450 dependent dealkylations (d), alkyl sub-
absorption at 450 nm. This was what led to stituents of O, N, or S atoms are released as
this enzyme group being termed cytochrome aldehydes.
P450 (Cyt P450).
Cyt P450 systems are also involved in many
other metabolic processes—e. g., the biosyn- B. Reaction mechanism
thesis of steroid hormones (see p. 172), bile The course of Cyt P450 catalysis is in principle
acids (see p. 314), and eicosanoids (see well understood. The most important func-
p. 390), as well as the formation of unsatu- tion of the heme group consists of converting
rated fatty acids (see p. 409). The liver’s red- molecular oxygen into an especially reactive
dish-brown color is mainly due to the large atomic form, which is responsible for all of the
amountsof P450 enzymesitcontains. reactions described above.
[1] In the resting state, the heme iron is
trivalent. Initially, the substrate binds near the
A. Cytochrome P450-dependent mono oxy-
heme group.
genases: reactions
[2] Transfer of an electron from FADH 2 re-
Cyt P450-dependent monooxygenases cata- duces the iron to the divalent form that is able
lyze reductive cleavage of molecular oxygen to bind an O 2 molecule (2).
(O 2 ). One of the two oxygen atoms is trans- [3] Transfer of a second electron and a
ferred to the substrate, while the other is re- change in the valence of the iron reduce the
leased as a water molecule. The necessary re- bound O 2 to the peroxide.
ducingequivalentsaretransferredtotheactual [4] A hydroxyl ion is now cleaved from this
monooxygenase by an FAD-containing auxili- intermediate. Uptake of a proton gives rise to
+
ary enzyme from the coenzyme NADPH+H . H 2 Oand the reactiveform of oxygen men-
Cyt P450 enzymes occur in numerous tioned above. In this ferryl radical, the iron
forms in the liver, steroid-producing glands, is formally tetravalent.
and other organs. The substrate specificity of [5] The activated oxygen atom inserts itself
liver enzymes is low. Apolar compounds con- into a C–H bond in the substrate, thereby
taining aliphatic or aromatic rings are partic- forming an OH group.
ularly easily converted. These include endog- [6] Dissociation of the product returns the
enoussubstancessuch assteroid hormones, enzyme to its initial state.
as well as medical drugs, which are inacti-
vated by phase I reactions. This is why Cyt
P450 enzymes are of particular interest in
pharmacology. The degradation of ethanol in
the liver is also partly catalyzed by Cyt P450
enzymes (the “microsomal ethanol-oxidizing
system”; see p. 304). As alcohol and drugs are
brokendownby the same enzyme system,
the effects of alcoholic drinks and medical
drugscan sometimesbe mutually en-
hancing—even sometimes to the extent of
becoming life-threatening.
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
