| In most textbooks, oxygen is shown as a diatomic
molecule with two bonds between the oxygen atoms. This is an attractive
presentation, from the viewpoint of the electron dot structures and
electron pairing to form chemical bonds, but it is incorrect. In fact,
at body temperature, O2 is a biradical, a molecule with two
unpaired electrons (Fig. 35.1). These electrons have parallel
spins and are unpaired. Since most organic oxidation reactions, e.g.
the oxidation of an alkane to an alcohol or an aldehyde to an acid, are
two-electron oxidation reactions, O2 is generally not very
reactive. In fact, O2 is completely stable in the presence
of H2, a strong reducing agent, until enough heat is
provided to flip an O2 electron and initiate the combustion
reaction. Once it is started, the combustion provides the heat needed
to propagate the reaction, sometimes explosively. |
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| page 498 |
| Figure 35.1 Structure of oxygen and reactive
oxygen species (ROS). Oxygen is shown at the far left as the
incorrect double-bonded diatomic form. This form, known as singlet
oxygen, exists to a significant extent only at high temperature or in
response to irradiation. The diradical is the natural, ground-state
form of O2 at body temperature. ROS are partially reduced,
reactive forms of oxygen. The first product is the anion radical,
superoxide (O2•), which is in equilibrium with
the weak acid, hydroperoxyl radical (pKa ≈ 4.5). Reduction of
superoxide yields hydroperoxide O2-2, in the form
of H2O2. Reduction of H2O2
causes a hemolytic cleavage reaction that releases hydroxyl radical (OH•)
and hydroxide ion (OH-). Water is the end product of
complete reduction of O2. |
| RADIOTHERAPY
AND CHEMOTHERAPY |
| Exposure
to radiation from nuclear explosions or accidents, or breathing or
ingestion of radioactive elements, such as Strontium-90 or radon gas,
produces a flux of ROS in the body, causing mutations in DNA. Radiation
therapy uses a focused beam of high-energy electrons or γ-rays from an
X-ray or Cobalt-60 source to destroy tumor tissue. The radiation
produces a flux of hydroxyl radicals (from water) and organic radicals
at the site of the tumor, oxidizing and destroying the DNA of the tumor
cell. Irradiation of food is also used as a method of sterilization to
destroy bacterial and viral contaminants or destroy insect infestations
in order preserve food products during long-term storage. |
|
Metabolic reactions are conducted at body
temperature, far below the temperature required to activate free
oxygen. In biological redox reactions involving O2, the
oxygen is activated by redox active metal ions, such as iron and
copper. All enzymes that use O2 in vivo are
metalloenzymes and, in fact, even the oxygen transport proteins,
hemoglobin and myoglobin, contain iron in the form of heme. These metal
ions provide one electron at a time to oxygen, activating O2
for metabolism. Because iron and copper, and sometimes manganese and other ions, activate oxygen,
these redox-active metal ions are present at very low (sub-micromolar)
free concentrations in vivo. Normally, they are tightly
sequestered in inactive form in storage or transport proteins, and they
are locally activated at the active sites of enzymes where oxidation
chemistry can be contained and focused on a specific substrate. Free
redox-active metal ions are dangerous in biological systems because, in
free form, they activate O2. |
| ISCHEMIA/REPERFUSION
INJURY |
| A patient
suffered a severe myocardial infarction, which was treated with tissue
plasminogen activator, a clot-dissolving (thrombolytic) enzyme. During
the days following hospitalization, the patient experienced
palpitations, irregular rapid heartbeat, associated with weakness and
faintness. The patient was treated with anti-arrhythmic agents. |
| Comment.
Ischemia, meaning limited blood flow, is a condition in which a tissue
is deprived of oxygen and nutrients. There is growing evidence that
damage to heart tissue occurs not during the hypoxic or ischemic phase,
but during reoxygenation of the tissue. This type of damage occurs
following coronary occlusion, transplantation, and cardiovascular
surgery. It is generally accepted that ROS play a major role in
reperfusion injury. When cells are deprived of oxygen, they must rely
on anaerobic glycolysis and glycogen stores for ATP synthesis. NADH and
lactate accumulate, and all of the components of the mitochondrial
electron transport system are saturated with electrons, because they
cannot be transferred to oxygen. The mitochondrial membrane potential
is increased, and when oxygen is reintroduced, great quantities of ROS
are rapidly produced, overwhelming the scavenging mechanisms. ROS flood
throughout the cell, damaging membrane lipids, DNA and other vital
cellular constituents, leading to necrosis. There is considerable
research on the evaluation of antioxidant supplements to protect
tissues prior to transplantation, during surgery and during recovery
from ischemia. |
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| page 499 |
| Figure 35.2 Oxidative stress: an imbalance
between pro-oxidant and antioxidant systems. As described in this
chapter, numerous factors contribute to the enhancement and inhibition
of oxidative stress. AGE, advanced glycation end-product; CAT,
catalase; GPx, glutathione peroxidase; MPO, myeloperoxidase. |
|
