reductase (NADPH-cytochrome P-450 reductase) and one
of at least six molecular species of cytochrome P-450. The
overall reaction is initiated by combining the substrate
(XH) with the ferric form of P-450 to produce the ferrous
form by accepting electrons from NADPH-cytochrome
P-450 reductase (steps a and b, Figure 14-24). The re-
ductase contains one molecule each of FMN and FAD.
The reduced P-450-substrate complex binds molecular
oxygen, which becomes activated upon acceptance of an
electron from the heme iron (steps c and d). The P-450-
substrate-oxygen complex accepts a second electron from
either NADPH-cytochrome-P-450 reductase (step e) or
cytochrome b
5
(step f). In the final steps (g-j), one oxy-
gen atom receives two protons to form a water molecule,
and the other oxygen forms the hydroxyl group of the sub-
strate. The regenerated ferric form of P-450 initiates'the
next cycle. Supply of the second electron pair is via the
cytochrome b
5
electron transport system, which is a mi-
nor pathway used principally for the desaturation of fatty
acids. Cytochrome b5, a microsomal membrane-heme pro-
tein, receives electrons from NADH via the flavoprotein
NADH-cytochrome bs reductase. Superoxide anion can
also be formed as a byproduct in the cytochrome P-450
system.
The hepatic cytochrome P-450 system exhibits a broad
substrate specificity, and many lipophilic compounds in-
cluding drugs, chemicals, and endogenous metabolites are
oxidized by it (Table 14-8). The hydroxylated compounds
are converted to more polar metabolites by conjugation
with glucuronate, sulfate, amino acids, or acetate that is
catalyzed by appropriate transferases. The polar metabo-
lites are excreted by either the biliary-intestinal or the renal
system.
274
Occasionally, the cytochrome P-450 system converts
some chemicals to reactive species with carcinogenic
potential (e.g., polycyclic hydrocarbons). The hepatic mi-
crosomal cytochrome P-450 system is inducible by many
of its substrates. The cytochrome P-450 of adrenal cortical
mitochondria is involved in steroid hydroxylase reactions,
and this system contains iron-sulfur (Fe
2
S
2
) proteins.
Supplemental Readings and References
T. E. Andreoli: Free radicals and oxidative stress.
A m e rica n J o u rn a l o f
M ed ic in e
108,650 (2000).
B. M. Babior: NADPH oxidase: An update.
B lo o d
93, 1464 (1999).
B. M. Babior: Phagocytes and oxidative stress.
A m e rica n Jo u rn a l o f
M e d icin e
109, 33 (2000).
H. Beinert, R. H. Holon, and E. Munck. Iron-sulfur clusters: Nature’s mod-
ulator, multipurpose structures.
S cien ce
277, 653 (1997).
P. D. Boyer: The ATP synthase—a splendid molecular machine.
A n n u a l
R eview o f B io ch em istry
66
, 717 (1997).
S. Iwata, J. W. Lee, K. Okada, et at: Complete structure of the 11 sub-
unit bovine mitochondrial cytochrome bcj complex.
S cien ce
281, 64
(1998).
N. G. Larsson and D. A. Clayton: Molecular genetic aspects of human mi-
tochondrial disorders.
A n n u a l R eview o f G en etics
29, 151 (1995).
G. S. Shadel and D. A. Clayton: Mitochondrial DNA maintenance in verte-
brates.
A n n u a l R eview o f B io ch em istry
66,409 (1997).
B. L. Trumpower: The proton motive Q cycle.
J o u rn a l o f B io lo g ica l C h em -
istry
265, 1409(1990).
L. H. Underhill: Mitochondrial DNA and Disease.
N ew E n g la n d Jo u rn a l o f
M ed icin e
333, 638 (1995)
D. Xi, C. A. Chang, H. Kim, et ah: Crystal structure of the cytochrome bci
complex from bovine heart mitochondria.
S cien ce
277,60 (1997).
M. Zeviani, V. Tiranti, and C. Piantadosi: Mitochondrial disorders.
M edicine
77, 59(1998).
Y. Zhou, T. M. Duncan, and R. L. Cross: Subunit rotation in
E sch erich ia C oli
FqFi-ATP synthase during oxidative phosphorylaton.
Proc. N a tl A cad.
S ci.
94, 10583 (1997).
chapter 14
Electron Transport and Oxidative Phosphorylation
