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Bioinorganic Chemistry 131

coordinated to two carboxylate groups of the protein and There is no enzymatic system to eliminate hydroxyl rad-
one hydroxide that are shared between the two irons. One ical because it reacts so quickly that no enzyme could
of the irons is six coordinate, filling out its coordination remove it fast enough to reduce its toxicity. Another very
sphere with three histidines. The other iron is five coordi- short lived but highly damaging molecule is peroxynitrite
−
nate, with two histidine ligands and one open coordination (ONOO ), which forms by direct reaction of superox-
site. When oxygen binds, it coordinates through this open ide with nitric oxide. Because enzymatic intervention is
•
−
coordination site. As with hemoglobin and myoglobin, essentially futile with OH and ONOO , cells depend on
the oxygen is reduced. However, in this case it is reduced SODs and catalases to prevent the formation of precursors
by two electrons to form peroxide. The Fe O O bond to these toxic molecules.
is bent and the structure is stabilized by a hydrogen bond There are two major types of SODs, those containing a
from the unbound oxygen atom to the bridging hydroxyl copper–zinc (Cu/Zn) center in their active site and those
proton. As with the case of hemoglobin, the change in containing either iron or manganese. In the Cu/Zn SODs
iron oxidation state may result in a cooperative binding (Fig. 9), the Cu and Zn atoms are connected through an
mechanism enabling oxygen to be bound in areas of high imidazole ring from a histidine. During catalysis, the Cu
oxygen concentration and released in areas of low oxygen binds superoxide and cycles between the +1 and +2 oxi-
concentration. dation states. Conversion of superoxide to oxygen occurs
Hemocyanin is different than hemoglobin, myoglobin, when the Cu is reduced from +2to +1, and conversion
and hemerythrin in that it is a copper enzyme. In fact, it of superoxide to hydrogen peroxide occurs when Cu is
contains two copper atoms both trigonally ligated to three oxidized from +1to +2. Zinc is present to ensure that the
histidine ligands. In the deoxy form, the oxidation state of copper has the correct electronic properties to carry out
both of these coppers is one. Oxygen binds hemocyanin these transformations. A series of mutations in the Cu/Zn
symmetrically, with each oxygen atom bound to both cop- SODs has been implicated as the cause of the familial form
pers. Like hemerythrin, both metals are oxidized, in this of amylotropic lateral schelorosis (fALS) known as Lou
case to Cu(II), and the dioxygen is reduced by two elec- Gehrig’s disease. Manganese (human mitochondria) and
trons to form peroxide. Hemocyanin is the largest of the iron (bacteria) SODs do not contain a second metal. These
four oxygen transport proteins; it contains many subunits SODs carry out the same reaction by cycling between the
each outweighing hemoglobin. This complexity probably +2 and +3 oxidation states.
plays a role in cooperative oxygen binding similar to that As with the SODs, there are two major types of cata-
of hemoglobin. lases: one contains a heme group in the active site and

F. Protection from Oxidative Stress
Oxygen when it is used as an energy source in biological
systems is ultimately reduced to water and excreted. While
respiration is extremely efficient, it is not infallible, and
occasionally reduced forms of dioxygen are released in
cells. This usually occurs via release of superoxide from
hemoglobin or as a result of reductants that accumulate
after cells have been starved for oxygen for some time
(such as after a stroke or heart attack).
Either directly or indirectly, the intermediates of dioxy-
gen reduction—superoxide, hydrogen peroxide, and hy-
droxyl radical—can be toxic. Two classes of enzymes, the
superoxide dismutases (SODs) and the catalases, work in
tandem to eliminate superoxide and hydrogen peroxide.
SODs catalyze the dismutation of superoxide to oxygen
and hydrogen peroxide. Catalases then convert hydrogen
peroxide to oxygen and water:
+
+
e − 2H ,e − H ,e − H ,e −
+
O 2 −→ O − −−−→ H 2 O 2 −→ H 2 O +HO −→ 2H 2 O
2
Oxygen Hydrogen Hydroxyl Water
superoxide peroxide redical FIGURE 9 Metal center of Cu/Zn superoxide dismutase.