272
chapter 14
Electron Transport and Oxidative Phosphorylation
O O H
\
I
\
I
C = c —C— + 0 2->
c = c —c —
/
I
/
I
These hydroperoxides undergo cleavage to give rise to
short-chain aldehydes. Peroxidation can also cause dam-
age to DNA and proteins. In the latter, sulfhydryl groups
give rise to disulfide linkages. Vitamin E functions as an
antioxidant and can prevent oxygen toxicity (Chapter 38).
Glutathione peroxidase, a selenium containing enzyme,
inactivates peroxides:
I
I
H C — 0
HC
2 G S H +
|
|
--------------- ►
G S S G
+
|| + H20 2
H C — O
HC
I
I
O xid ized
G lu ta th io n e
g lu ta th io n e
Glutathione, which protects sulfhydryl groups of proteins,
is regenerated by glutathione reductase, which uses reduc-
ing equivalents from NADPH.
GSSG + NADPH + H+ -> 2GSH + NADP+
The hydrogen peroxide formed above is decomposed by
catalase:
Unsaturated fatty acid residues of membrane lipids form
a-hydroperoxyalkenes by reacting with oxygen:
2H
2
0
2
-* 2H20 + 0
2
Aerobic organisms are protected from oxygen toxicity
by three enzymes: glutathione peroxidase, catalase, and
superoxide dismutase. Superoxide dismutases are metal-
loenzymes (the cytoplasmic enzyme contains Cu2+ and
Zn2+, whereas the mitochondrial enzyme contains Mn2+)
widely distributed in aerobic cells. The role of superoxide
dismutases in preventing oxygen toxicity is still controver-
sial. For example, some aerobic cells (e.g., adipocytes and
some bacteria) lack superoxide dismutase, whereas some
strict anaerobes possess this enzyme.
Human superoxide dismutase has been prepared in large
quantities by recombinant DNA methods in
Escherichia
coli.
It has potential clinical use in preventing oxygen tox-
icity, for example, during the reestablishment of blood
flow through dissolution of a blood clot by thrombolytic
agents after a myocardial infarction, during reperfusion af-
ter kidney transplant, and in the lungs of premature infants.
Allopurinol, a xanthine oxidase inhibitor (Chapter 27), is
potentially useful in preventing the tissue injury brought
about by ischemia followed by reperfusion. During is-
chemia, hypoxanthine production increases by enhanced
adenine nucleotide catabolism (ATP
—>
ADP —»• AMP -»
adenosine —»■
inosine -» hypoxanthine; see Chapter 27),
providing a larger supply of substrate for xanthine oxi-
dase and thus increased formation of superoxide anions.
Complete reduction of 0
2
by single-electron transfer re-
actions (the univalent pathway) yields superoxide anion,
hydrogen peroxide, and hydroxyl radical as intermediates:
02- ^ 0 2- e- ^ H 202^ y l-0 H
l2!^H20
h 2o
In contrast, most 0
2
reduction in aerobic cells occurs by
cytochrome c oxidase, which prevents the release of toxic
oxygen intermediates:
0
2
+ 4H+ + 4 e" -»■ 2H20
Mitochondrial superoxide dismutase maintains intramito-
chondrial superoxide anion at very low steady-state con-
centrations.
The overall process of reducing oxygen to water can be
depicted as follows:
r
3
2
C y to c h ro m e c o x id a s e
------ ►
H
C a ta la s e ,
p e ro x id a s e
—
» » ,
0
,
I
S u p e ro x id e d is m u ta s e
Paraquat, a herbicide that is highly toxic to humans,
causes respiratory distress that can lead to death. Damage
to membranes of the epithelial cells lining the bronchi-
oles and alveoli that occurs with paraquat poisoning has
been ascribed to excessive production of superoxide anion.
Paraquat readily accepts electrons from reduced substrates
of high negative potential, while the reduced paraquat re-
acts with molecular oxygen to form superoxide anion and
an oxidized paraquat molecule:
O x id ized
R e d u c e d
e le c tro n -d o n o r
e le c tro n -d o n o r
O
;
0 2
R e d u c e d p a r a q u a t
O x id ized p a r a q u a t
