section 14.7
Other Reducing-Equivalent Transport and Oxygen-Consuming Systems
273
Oxygenases catalyze reactions in which an oxygen atom
or molecule is incorporated into organic substrates. They
may therefore be
monooxygenases
or
dioxygenases.
An
example of a dioxygenase is tryptophan-
2
,3-dioxygenase
(a heme enzyme), which participates in the catabolism of
tryptophan (Chapter 17):
TABLE 14-8
Cytochrome P-450-Dependent Oxidations
Oxidation of carbon atoms
Aliphatic hydroxylation
R —C H 3 ----- -R C H 2O H
NH3
Jj
-----CH2— CH— COO" + 0 2
H
Tryptophan
Formylkynurertine
Monooxygenases, also called hydroxylases or mixed-
function oxidases, catalyze the incorporation of one atom
of an oxygen molecule into the substrate, while the other
atom is reduced to water. A second reductant is required
(e.g., NADH, NADPH or tetrahydrobiopterin); the overall
reaction is
RH + AH
2
+ O
2
—>
ROH + A -(- H
2
O
where AH
2
is the second reductant.
There are many classes of hydroxylases, depending
upon the nature of the second reductant. One group, which
O H
R - C H 2- C H 3
R —C H —C H 3
Epoxidation
R 1 \
I
\
/
IX
C H
a
II
-
C H
c
/
r 2
r 2
h
Aromatic hydroxylation
O-, N-, S-dealkylation
R -O -C H 3 ----- ► ROH + HCHO
FIGURE 14-24
Cytochrome P-450 monooxygenase system in the hepatic endoplasmic
reticulum. P-450-Fe(III) = ferricytochrome P-450; P-450-Fe(II) =
ferrocytochrome P-450; bs = cytochrome bs ; Fpa = NADPH-cytochrome
P-450 reductase; Fpt, = NADH-cytochrome bs reductase; XH = substrate.
[Reproduced with permission from G. Mannering. K. W. Renton,
R. el Azhary, and L. B. Delor, Effects of interferon-inducing agents on
the hepa cytochrome P-450 drug metabolizing systems.
A n n . N. Y. A ca d .
Sci.
350,314(1980).]
H
R -N —CH
3
----- RNH
2
+ HCHO
R—S —CH
3
--- ►
RSH + HCHO
Oxidation of nitrogen atom
N-Hydroxylation
H O
OHO
1
II
I
II
R.,—N—C—R
2
— >Ri—N—C—R
2
acts on a variety of substrates including foreign com-
pounds (xenobiotics), contains
cytochrome P-450.
The
latter derives its name from the absorption maximum at
450 nm of its carbon monoxide adduct, the P standing for
pigment. The cytochrome P-450 monooxygenase system
is widely distributed in nature. In humans, it is present
in most organs, but the highest concentrations are found
in the liver. It is found in membranes of the endoplasmic
reticulum (microsomal fraction of the cell), mitochondria,
and nucleus.
The hepatic microsomal cytochrome P-450 system
has been extensively investigated. It consists of a flavin
