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Chemistry of Oxidation

What is the chemistry behind biological oxidation?

RADICALS

A radical (sometimes called a " free radical " ) is a molecule that has

an unpaired electron (represented by a dot next to the chemical

structure, e. g. A.). Some radicals are stable and long-lived (the

most common example is O2, the oxygen in the air we breath, which is

a " biradical " as it has two unpaired electrons), but most radicals

are highly reactive and thus unstable.

As a rule, a radical needs to pair its unpaired electron with

another, and will react with another molecule in order to obtain this

missing electron. If a radical achieves this by " stealing " an

electron from another molecule, that other molecule itself becomes a

radical (Reaction 1), and a self-propagating chain reaction is begun

(Reaction 2).

If a radical pairs its unpaired electron by reacting with a second

radical, then the chain reaction is terminated, and both

radicals " neutralize " each other (Reaction 3).

Radicals are produced by normal aerobic (oxygen-requiring) metabolism

and are necessary to life. However, excess amounts of radicals are

harmful because of their reactivity. Radicals can be formed easily by

compounds that readily give up a single electron (for example,

polyunsaturated fatty acids). Radicals are also produced by processes

other than normal metabolism-by ionizing radiation, smoking and other

pollutants, herbicides and pesticides, and are even found in certain

types of food (e. g., deep-fat fried foods). Radicals can damage

lipids (fats, which make up cell membranes), proteins, and DNA.

Radical damage can be significant because it can proceed as a chain

reaction. An example of radical damage is that caused by the hydroxyl

radical (described in more detail below).

SINGLET OXYGEN

Oxygen in the air we breathe is in its " ground " (not energetically

excited) state and is symbolized by the abbreviation 3O2. It is a

free radical-in fact it is a diradical, as it has two unpaired

electrons. Electrons " spin " (that is, rotate about an axis passing

through the electron). Molecules whose outermost pair of electrons

have parallel spins (symbolized by ) are in the " triplet " state;

molecules whose outermost pair of electrons have antiparallel spins

(symbolized by ) are in the " singlet " state. Ground-state oxygen is

in the triplet state (indicated by the superscripted " 3 " in 3O2) -

its two unpaired electrons have parallel spins, a characteristic

that, according to rules of physical chemistry, does not allow them

to react with most molecules. Thus, ground-state or triplet oxygen is

not very reactive. However, triplet oxygen can be activated by the

addition of energy, and transformed into reactive oxygen species.

If triplet oxygen absorbs sufficient energy to reverse the spin of

one of its unpaired electrons, it forms the singlet state. Singlet

oxygen, abbreviated 1O2*, has a pair of electrons with opposite

spins; though not a free radical it is highly reactive. (The * symbol

is used to indicate that this is an excited state with excess energy.

It should be emphasized that neither triplet- nor singlet-state

molecules are necessarily in the excited state; the designation

of " triplet " or " singlet " refers only to the spin state. For example,

carotenoids exist in an unexcited, ground singlet state S0 and can be

excited by light absorption to a higher-energy singlet state S1, with

no change in spin state (sen et al. 1991).)

This reaction can also be written in this form:

Singlet oxygen is produced as a result of natural biological

reactions and by photosensitization by the absorption of light

energy. According to rules of physical chemistry, the " relaxation "

(excess energy loss) of singlet oxygen back to the triplet state

is " spin forbidden " and thus singlet oxygen has a long lifetime for

an energetically excited molecule, and must transfer its excess

energy to another molecule in order to relax to the triplet state.

SUPEROXIDE

Triplet oxygen can also be transformed into a reactive state if it is

accepts a single electron. This process of accepting an electron is

called reduction, and in this case, is " monovalent " reduction because

only one electron is involved. The molecule that gave up the electron

is oxidized. The result of monovalent reduction of triplet oxygen is

called superoxide, abbreviated O2.-. Superoxide is a radical. It is

usually shown with a negative sign, indicating that it carries a

negative charge of -1 (due to the extra electron, e-, it gained).

This reaction can also be written in this form:

Superoxide can act both as an oxidant (by accepting electrons) or as

a reductant (by donating electrons). However, superoxide is not

particularly reactive in biological systems and does not by itself

cause much oxidative damage. It is a precursor to other oxidizing

agents, including singlet oxygen, peroxynitrite, and other highly

reactive molecules. However, superoxide is not all bad-in fact it is

necessary for health. For example, certain cells in the human body

produce superoxide (and the reactive molecules derived from it) as a

antibiotic " weapon " used to kill invading microorganisms. Superoxide

also acts as a signaling molecule needed to regulate cellular

processes.

Under biological conditions, the main reaction of superoxide is to

react with itself to produce hydrogen peroxide and oxygen, a reaction

known as " dismutation " . Superoxide dismutation can be spontaneous or

can be catalyzed by the enzyme superoxide dismutase ( " SOD " ).

Superoxide is also important in the production of the highly reactive

hydroxyl radical (HO.) (discussed in more detail below). In this

process, superoxide actually acts as a reducing agent, not as an

oxidizing agent. This is because superoxide donates one electron to

reduce the metal ions (ferric iron or Fe3+ in the example below) that

act as the catalyst to convert hydrogen peroxide (H2O2) into the

hydroxyl radical (HO.).

The reduced metal (ferrous iron or Fe2+ in this example) then

catalyzes the breaking of the oxygen-oxygen bond of hydrogen peroxide

to produce a hydroxyl radical (HO.) and a hydroxide ion (HO-):

Superoxide can react with the hydroxyl radical (HO.) to form singlet

oxygen (1O2*) (not a radical but reactive nonetheless):

Superoxide can also react with nitric oxide (NO.) (also a radical) to

produce peroxynitrate (OONO-), another highly reactive oxidizing

molecule.

HYDROGEN PEROXIDE

Superoxide (O2.-) can undergo monovalent reduction to produce

peroxide (O2-2), an activated form of oxygen that carries a negative

charge of -2. Usually peroxide is termed " hydrogen peroxide " (H2O2)

since in biological systems the negative charge of -2 is neutralized

by two protons (two hydrogen atoms, each with a positive charge).

Hydrogen peroxide is important in biological systems because it can

pass readily through cell membranes and cannot be excluded from

cells. Hydrogen peroxide is actually necessary for the function of

many enzymes, and thus is required (like oxygen itself) for health.

Hydrogen peroxide is not as reactive as a product it can form, the

hydroxyl radical.

HYDROXYL RADICAL

Hydrogen peroxide, in the presence of metal ions, is converted to a

hydroxyl radical (HO.) and a hydroxide ion (HO-). The metal ion is

required for the breaking of the oxygen-oxygen bond of peroxide. This

reaction is called the Fenton reaction, and was discovered over a

hundred years ago. It is important in biological systems because most

cells have some level of iron, copper, or other metals which can

catalyze this reaction.

This reaction can also be written (with iron as the metal):

A hydroxyl radical can also react with superoxide to produce singlet

oxygen and a hydroxide ion:

Like hydrogen peroxide, the hydroxyl radical passes easily through

membranes and cannot be kept out of cells. Hydroxyl radical damage

is " diffusion rate-limited " . Simply put, the rate at which hydroxyl

radicals can damage other molecules is limited chiefly by how far and

fast it can diffuse (travel) in the cell. This highly reactive

radical can add to an organic (carbon-containing) substrate

(represented by R below)-this could be for example a fatty acid-

forming a hydroxylated adduct that is itself a radical.

This adduct can be further oxidized (e. g. by metal ions or oxygen)

by a one-electron transfer (monovalent reduction), resulting in a

oxidized but stable product. In the first case, the extra electron is

transferred to the metal ion, and in the second case, to oxygen

(forming superoxide).

Two adduct radicals can also react with each other, forming a stable,

crosslinked-but oxidized-product, with water as a byproduct.

The hydroxyl radical can also oxidize the organic substrate

by " stealing " or abstracting an electron from it.

The resulting oxidized substrate is again itself a radical, and can

react with other molecules in a chain reaction. For example, it could

react with ground-state oxygen to produce a peroxyl radical (ROO.).

The peroxyl radical again is highly reactive, and can react with

another organic substrate in a chain reaction.

This type of chain reaction is common in the oxidative damage of

fatty acids and other lipids, and demonstrates why radicals such as

the hydroxyl radical can cause so much more damage than one might

have expected.

Similar damage caused by hydroxyl radicals and other reactive oxygen

species can occur in proteins and with nucleic acids (mainly DNA).

Proteins are highly susceptible to oxidative damage, particularly at

sites where sulfur-containing amino acids are found. DNA can be

oxidatively damaged at both the nucleic bases (the individual

molecules that make up the genetic code) and at the sugars that link

the bases. Oxidative damage of DNA results in degradation of the

bases, breaking of the DNA strands by oxidation of the sugar

linkages, or cross-linking of DNA to protein (a form of damage

particularly difficult for the cell to repair). Although all cells

have some capability of repairing oxidative damage to proteins and

DNA, excess damage can cause mutations or cell death.