ATP and Other Nucleoside Triphosphates or: Bonds Rich in Energy

BIOLOGICAL OXIDATION. ENERGY METABOLISM. SUBSTRATE AND OXIDATIVE PHOSPHORYLATION

 

Bioenergetic

 

Bioenergetics is the part of biochemistry concerned with the energy involved in making and breaking of chemical bonds in the molecules found in biological organisms.

Living organisms produce ATP from energy sources via oxidative phosphorylation. The terminal phosphate bonds of ATP are relatively weak compared with the stronger bonds formed when ATP is broken down to adenosine monophosphate and phosphate, dissolved in water. Here it is the energy of hydration that results in energy release. This hydrolysis of ATP is used as a battery to store energy in cells, for intermediate metabolism. Utilization of chemical energy from such molecular bond rearrangement powers biological processes in every biological organism.

 

Exergonic and endergonic processes. Mechanism of energy releasing and storage in the organism.

Exergonic refers to chemical reactions that proceed spontaneously from reactants to products with the release of energy. Endergonic reactions require energy input to proceed. Although the terms are often used rather loosely, they are precisely defined thermodynamic concepts based on changes in an entity called Gibbs free energy (G) accompanying reactions. Reactions in which -G decreases are exergonic, and those in which -G increases are endergonic. Exergonic reactions often involve the breakdown of organic compounds found in food, whereas endergonic reactions frequently entail synthesis of complicated molecules.

Biological metabolism contains many examples of both types, and living organisms have developed elaborate techniques for coupling the two.

By coupling exergonic and endergonic reactions, organisms are able to use the available energy in food they consume to construct complex proteins, lipids, nucleic acids and carbohydrates needed for their growth and development. A well-known example involves coupling the formation of energy-rich adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate (an endergonic reaction), with the transfer of hydrogen, removed from organic food materials, to oxygen (an exergonic reaction). The process is called oxidative phosphorylation. Energy stored in ATP may be used subsequently when the exergonic conversion of ATP back to ADP and phosphate is coupled with the endergonic synthesis of a needed cellular component.

 

What is macroergic bond? Examples of high energy compounds.

A bond in chemical compounds, which acts as an energy accumulator. Macroergic bond  is present in some phosphorus-containing compounds in living organisms, e. g.* adenosinetriphosphate. Macroergic bonds  are formed as a result of complex biochemical processes and break up when energy is released. The processes are reversible and can be repeated.

High-energy phosphate can mean one of two things:

·         The phosphate-phosphate bonds formed when compounds such as adenosine diphosphate and adenosine triphosphate are created.

·                                 The compounds that contain these bonds, which include the nucleoside diphosphates and nucleoside triphosphates, and the high-energy storage compounds of the muscle, the phosphagens. When people speak of a high-energy phosphate pool, they speak of the total concentration of these compounds with these high-energy bonds.

ATP is often called a high energy compound and its phosphoanhydride bonds are referred to as high-energy bonds. There is nothing special about the bonds themselves. They are high-energy bonds in the sense that free energy is released when they are hydrolyzed, for the reasons given above.

The term 'high energy' with respect to these bonds can be misleading because the negative free energy change is not due directly to the breaking of the bonds themselves. The breaking of these bonds, as with the breaking of most bonds, is an endergonic step (i.e., it absorbs energy, not releases it). The negative free energy change comes instead from the fact that the bonds formed after hydrolysis-or the phosphorylation of a residue by ATP-are lower in energy than the bonds present before hydrolysis (this includes all of the bonds involved in the reaction, not just the phosphate bonds themselves). This effect is due to a number of factors including increased resonance stabilization and solvation of the products relative to the reactants.

ATP formation

The ATP is used for many cell functions including transport work moving substances across cell membranes. It is also used for mechanical work, supplying the energy needed for muscle contraction. It supplies energy not only to heart muscle (for blood circulation) and skeletal muscle (such as for gross body movement), but also to the chromosomes and flagella to enable them to carry out their many functions. A major role of ATP is in chemical work, supplying the needed energy to synthesize the multi-thousands of types of macromolecules that the cell needs to exist.

Adenosine triphosphate (ATP) is an organic molecule which stores energy used to carry out life processes. ATP is made of an adenine nucleoside, ribose sugar, and three phosphate groups. The high energy bonds between phosphate groups are broken when hydrolyzed, thus releasing energy in the system. Either one or two phosphate groups can break off, releasing Gibb's free energy, which can then be used to drive other reactions.

Substrate-level and oxidative phosphorylation

Substrate-level phosphorylation is a type of metabolic reaction that results in the formation of adenosine triphosphate (ATP) or guanosine triphosphate (GTP) by the direct transfer and donation of a phosphoryl (PO3) group to adenosine diphosphate (ADP) or guanosine diphosphate (GDP) from a phosphorylated reactive intermediate. Note that the phosphate group does not have to come directly from the substrate. By convention, the phosphoryl group that is transferred is referred to as a phosphate group.

An alternative way to create ATP is through oxidative phosphorylation, which takes place during the process of cellular respiration, in addition to the substrate-level phosphorylation that occurs during glycolysis and the Krebs cycle. During oxidative phosphorylation, NADH is oxidized to NAD+, yielding 2.5 ATPs, and FADH2 yields 1.5 ATPs when it is oxidized. Oxidative phosphorylation uses an electrochemical or chemiosmotic gradient of protons (H+) across the inner mitochondrial membrane to generate ATP from ADP, which is a key difference from substrate-level phosphorylation.

 

The main part of substrate-level phosphorylation occurs in the cytoplasm of cells as part of glycolysis and in mitochondria as part of the Krebs Cycle under both aerobic and anaerobic conditions. In the pay-off phase of glycolysis, two ATP are produced by substrate-level phosphorylation: two and only two 1,3-bisphosphoglycerate are converted to 3-phosphoglycerate by transferring a phosphate group to ADP by a kinase; two phosphoenolpyruvate are converted to pyruvate by the transfer of their phosphate groups to ADP by another kinase. The first reaction occurs after the generation of 1,3-bisphosphoglycerate from 3-phosphoglyceraldehyde and an organic phosphate via a dehydrogenase. ATP is generated in a following separate step (key difference from oxidative phosphorylation) by transfer of the high-energy phosphate on 1,3-bisphosphoglycerate to ADP via the enzyme phosphoglycerate kinase, generating 3-phosphoglycerate. As ATP is formed of a former inorganic phosphate group, this step leads to the energy yield of glycolysis. The second substrate-level phosphorylation occurs later by means of the reaction of phosphenolpyruvate (PEP) to pyruvate via the pyruvate kinase. This reaction regenerates the ATP that has been used in the preparatory phase of glycolysis to activate glucose to glucose-6-phosphate and fructose-6-phosphate to fructose-1,6-bisphosphate, respectively.

ATP can be generated by substrate-level phosphorylation in the mitochondrial matrix, a pathway that is independent from the protonmotive force, pmf. In the mitochondrial matrix there are two reactions capable of substrate-level phosphorylation: the mitochondrial phosphoenolpyruvate carboxykinase (PEPCK), and the succinate-CoA ligase (SUCL or succinate thiokinase or succinyl-CoA synthetase).

Another form of substrate-level phosphorylation is also seen in working skeletal muscles and the brain. Phosphocreatine is stored as a readily available high-energy phosphate supply, and the enzyme creatine phosphokinase transfers a phosphate from phosphocreatine to ADP to produce ATP. Then the ATP releases giving chemical energy. Apart from this substrate-level phosphorylation can also be observed in fermentation, for example, heterolactic fermentation, butyric acid fermentation, and propanoic acid fermentation.

The modern views on the biological oxidation

Biological oxidation is that oxidation which occurs in biological systems to produce energy.

Oxidation can occur by:

1-Addition of oxygen (less common)

2-Removal of hydrogen (common)

3-Removal of electrons (most common)

Electrons are not stable in the free state, so their removal form a substance (oxidation) must be accompanied by their acceptance by another substance (reduction) hence the reaction is called oxidation-reduction reaction or redox reaction and the involved enzymes are called oxido-reductases

Composition of respiratory chain

NADH dehydrogenase (EC 1.6.5.3) (also referred to as "NADH:quinone reductase" or "Complex I") is an enzyme located in the inner mitochondrial membrane that catalyzes the transfer of electrons from NADH to coenzyme Q (CoQ). It is the "entry enzyme" of oxidative phosphorylation in the mitochondria. [1]

Function

NADH Dehydrogenase is the first enzyme (Complex I) of the mitochondrial electron transport chain. There are three energy-transducing enzymes in the electron transport chain - NADH dehydrogenase (Complex I), Coenzyme Q – cytochrome c reductase (Complex III), and cytochrome c oxidase (Complex IV). [2] NADH dehydrogenase is the largest and most complicated enzyme of the electron transport chain.[3].

FADH dehydrogenase

In biochemistry, flavin adenine dinucleotide (FAD) is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety (vitamin B2) bound to the phosphate group of an ADP molecule. The flavin group is bound to ribitol, a sugar alcohol, by a carbon-nitrogen bond, not a glycosidic bond. Thus, riboflavin is not technically a nucleotide; the name flavin adenine dinucleotide is a misnomer.[1]

FAD can be reduced to FADH2, whereby it accepts two hydrogen atoms (a net gain of two electrons):

Ubiquinones

These molecules are also known as coenzyme Q or mitoquinones. They are involved in electron transport in mitochondrial preparations playing an essential role in the oxidation of succinate or NADH via the cytochrome system. They serves not only as a coenzyme but also, in their reduced forms, as antioxidants. They are synthesized de novo in all animal tissues and cannot thus be regarded as vitamins. Ubiquinones are present in all aerobic organisms, plants, animals (the name ubiquinone was proposed with reference to their ubiquitous occurrence) and bacteria, but are absent from Gram-positive eubacteria and the archaebacteria. They were discovered by the Morton's group in animal fat but their quinonoid structure was revealed by Crane two years later in extracts from beef heart mitochondria. The compound had a 2,3-dimethoxy-5-methylbenzoquinone nucleus and a side chain of 10 isoprenoid units and was referred to as coenzyme Q 10 .

Cytochromes are, in general, membrane-bound (i.e. inner mitochondrial membrane) hemeproteins containing heme groups and are primarily responsible for the generation of ATP via electron transport.

They are found either as monomeric proteins (e.g., cytochrome c) or as subunits of bigger enzymatic complexes that catalyze redox reactions.

In the process of oxidative phosphorylation, which is the principal energy-generating process undertaken by organisms, other membrane-bound and -soluble complexes and cofactors are involved in the chain of redox reactions, with the additional net effect that protons (H+) are transported across the mitochondrial inner membrane. The resulting transmembrane proton gradient ([protonmotive force]) is used to generate ATP, which is the universal chemical energy currency of life. ATP is consumed to drive cellular processes that require energy (such as synthesis of macromolecules, active transport of molecules across the membrane, and assembly of flagella).

Respiratory chain

 

The system of mitochondrial enzymes and redox carrier molecules which ferry reducing equivalents from substrates to oxygen are collectively known as the electron transport system, or the respiratory chain. This system captures the free energy available from substrate oxidation so that it may later be applied to the synthesis of ATP.

Complex I and Complex II

Complex I and Complex II direct electrons to coenzyme Q. Complex I, also called NADH-coenzyme Q reductase, accepts electrons from NADH. The NADH releases a proton and two electrons. The electrons flow through a flavoprotein containing FMN and an iron-sulfur protein. First, the flavin coenzyme (flavin mononucleotide) and then the iron-sulfur center undergo cycles of reduction and then oxidation, transferring their electrons to a quinone molecule, coenzyme Q . Complex I is capable of transferring protons from the matrix to the intermembrane space while undergoing these redox cycles. One possible source of the protons is the release of a proton from NADH as it is oxidized to NAD, although this is not the only explanation. Apparently, conformational changes in the proteins of Complex I also are involved in the mechanism of proton translocation during electron transport.

Complex II, also known as succinate-coenzyme Q reductase, accepts electrons from succinate formed during the TCA cycle. Electrons flow from succinate to FAD (the flavin-adenine dinucleotide) coenzyme, through an iron-sulfur protein and a cytochrome b550 protein (the number refers to the wavelength where the protein absorbs), and to coenzyme Q. No protons are translocated by Complex II. Because translocated protons are the source of the energy for ATP synthesis, this means that the oxidation of a molecule of FADH2 inherently leads to less ATP synthesized than does the oxidation of a molecule of NADH. This experimental observation also fits with the difference in the standard reduction potentials of the two molecules. The reduction potential of FAD is -0.22 V, as opposed to -0.32 V for NAD.

Coenzyme Q is capable of accepting either one or two electrons to form either a semiquinone or hydroquinone form. Coenzyme Q is not bound to a protein; instead it is a mobile electron carrier and can float within the inner membrane, where it can transfer electrons from Complex I and Complex II to Complex III.

Complex III is also known as coenzyme Q-cytochrome c reductase. It accepts electrons from reduced coenzyme Q, moves them within the complex through two cytochromes b, an iron-sulfur protein, and cytochrome c1. Electron flow through Complex II transfers proton(s) through the membrane into the intermembrane space. Again, this supplies energy for ATP synthesis. Complex III transfers its electrons to the heme group of a small, mobile electron transport protein, cytochrome c.

Cytochrome c transfers its electrons to the final electron transport component, Complex IV, or cytochrome oxidase. Cytochrome oxidase transfers electrons through a copper-containing protein, cytochrome a, and cytochrome a3, and finally to molecular oxygen. The overall pathway for electron transport is therefore:

The number n is a fudge factor to account for the fact that the exact stoichiometry of proton transfer isn't really known. The important point is that more proton transfer occurs from NADH oxidation than from FADH2 oxidation.

Chemiosmotic hypothesis

A theory postulated by the biochemist Peter Mitchell in 1961 to describe ATP synthesis by way of a proton electrochemical coupling is called chemiosmotic hypothesis.

In the 1960s, ATP was known to be the energy currency of life, but the mechanism by which ATP was created in the mitochondria was assumed to be by substrate-level phosphorylation. Mitchell's chemiosmotic hypothesis was the basis for understanding the actual process of oxidative phosphorylation. At the time, the biochemical mechanism of ATP synthesis by oxidative phosphorylation was unknown.

Mitchell realised that the movement of ions across an electrochemical membrane potential could provide the energy needed to produce ATP. His hypothesis was derived from information that was well known in the 1960s. He knew that living cells had a membrane potential; interior negative to the environment. The movement of charged ions across a membrane is thus affected by the electrical forces (the attraction of positive to negative charges). Their movement is also affected by thermodynamic forces, the tendency of substances to diffuse from regions of higher concentration. He went on to show that ATP synthesis was coupled to this electrochemical gradient.

Because the structures seen in EM, the subunit composition, and the sequences of the subunits appeared to be so similar, it had been assumed that the mechanisms, and hence the stoichiometries, would be the same. In this context, the evidence suggesting that the stoichiometry of H+/ATP (n above) varied depending on system was surprising. Values based on measure ATP/2e- ratios, and H+/2e- ratios had suggested that n was 3 for mitochondria, and 4 for chloroplasts, but these values were based on the assumption of integer stoichiometries. Although all the F1F0-type ATP-synthases likely had a common origin, both the assumption that the stoichiometries are the same, and that n is integer, are called into question by emerging structural data (see below).

Mechanism of the F1 ATP-ase

The ATP synthase operates through a mechanism in which the three active sites undergo a change in binding affinity for the reactants of the ATP-ase reaction, ATP, ADP and phosphate, as originally predicted by Paul Boyer. The change in affinity accompanies a change in the position of the g-subunit relative to the a, b-ring, which involves a rotation of the one relative to the other. In the direction of ATP synthesis, the rotation is driven by a flux of H+ down the proton gradient, through a coupling between the g-subunit, and the c-subunit of FO. This rotation has now been demonstrated experimentally.

Respiratory control

The dependence of oxidative phosphorylation on ADP reveals an important general feature of this process: Respiration is tightly coupled to the synthesis of ATP. Not only is ATP synthesis absolutely dependent on continued electron flow from substrates to oxygen, but electron flow in normal mitochondria occurs only when ATP is being synthesized as well. This regulatory phenomenon, called respiratory control, makes biological sense, because it ensures that substrates will not be oxidized wastefully. Instead, their utilization is controlled by the physiological need for ATP.

In most aerobic cells the level of ATP exceeds that of ADP by 4- to 10-fold. Respiration depends on ADP as a substrate for phosphorylation. When ATP is consumed at high rates, accumulation of ADP stimulates respiration, with concomitant activation of ATP resynthesis. Conversely, in a relaxed and well-nourished cell, ATP accumulates at the expense of ADP, and the depletion of ADP limits the rate of both electron transport and its own phosphorylation to ATP. Thus, the energy-generating capacity of the cell is closely attuned to its energy demands.

Inhibitors of tissue respiration

Chemiosmosis can be disrupted by a variety of chemicals. In oxidative phosphorylation, some of these inhibitors are quite infamous:

The electron transport chain was determined by studying the effects of particular inhibitors.

Rotenone is a common insecticide that strongly inhibits the electron transport of complex I.

Rotenone is a natural product obtained from the roots of several species of plants. Tribes in cert

ain parts of the world beat the roots of trees along riverbanks to release rotenone into the water which paralyzes fish and makes them easy prey.

 

Amytal is a barbiturate that inhibits the electron transport of complex I. Demerol is painkiller that also inhibits complex I. Amytal is a barbiturate drug that blocks electron transport from NADH to coenzyme Q. Amytal blocks electron transport at the same point as the insecticide rotenone.

Antibiotic. Induces apoptosis, which is not prevented by the presence of Bcl-2. Inhibits mitochondrial electron transport specifically between cytochromes b and c1.

All three of these complex I inhibitors block the oxidation of the Fe-S clusters of complex I.

2-Thenoyltrifluoroacetone and carboxin specifically block electron transport in Complex II

 

Antimycin A is an antibiotic that inhibits electron transfer in complex III by blocking the transfer of electrons between Cyt bH and coenzyme Q bound at the QN site. Antibiotic. Induces apoptosis, which is not prevented by the presence of Bcl-2. Inhibits mitochondrial electron transport specifically between cytochromes b and c1.

 

Cyanide, azide and carbon monoxide all inhibit electron transport in Complex IV. The all inhibit

electron transfer by binding tightly with the iron coordinated in Cyt a

The coupling between electron transport and oxidative phosphorylation depends on the impermeability of the inner mitochondrial membrane to H+translocation. The only way for protons to go from the intermembrane space to the matrix is through ATP synthase. Uncouplers uncouple electron transport from oxidative phosphorylation. They collapse the chemiosmotic gradient by dissipating protons across the inner mitochondrial membrane. All of the uncouplers shown to the left, collapse the pH gradient by binding a proton on the acidic side of the membrane, diffusing through the inner mitochondrial membrane and releasing the proton on the membranes alkaline side.

Uncouplers of oxidative phosphorylation stimulate the rate of electron flow but not

ATP synthesis.

(a)At relatively low levels of an uncoupling agent, P/O ratios drop somewhat, but the cell can compensate for this by increasing the rate of electron flow; ATP levels can be kept relatively normal. At high levels of uncoupler, P/O ratios approach zero and the cell cannot maintain ATP levels.

(b) As amounts of an uncoupler increase, the P/O ratio decreases and the body struggles to make sufficient ATP by oxidizing more fuel. The heat produced by this increased rate of oxidation raises the body temperature. The P/O ratio is affected as noted in  (a).

(c) Increased activity of the respiratory chain in the presence of an uncoupler requires the degradation of additional energy stores (glycogen and fat). By oxidizing more fuel in an attempt to produce the same amount of ATP, the organism loses weight. If the P/O ratio nears zero, the lack of ATP will be lethal

2,4-Dinitrophenol, dicumarol and carbonyl cyanide-p-trifluorocarbonyl-cyanide methoxyphenyl hydrazone (FCCP) all have hydrophobic character making them soluble in the bilipid membrane. All of these decouplers also have dissociable protons allowing them to carry protons from the intermembrane space to the matrix which collapses the pH gradient. The potential energy of the proton gradient is lost as heat DNP is a chemical uncoupler of electron transport and oxidative phosphorylation.

 

DNP permeabilizes the inner mitochondrial membrane to protons, destroying the proton gradient and, in doing so, uncouples the electron transport system from the oxidative phosphorylation. In this situation, electrons continue to pass through the electron transport system and reduce oxygen to water, but ATP is not synthesized in the process. The compound, trifluorocarbonylcyanide phenylhydrazone (FCCP), is also an uncoupler.

The link between electron transport and ATP synthesis is below. (a) In the presence of excess phosphate and substrate and intact mitochondria, oxygen is consumed only when ADP is added. When all of the added ADP has been converted into ATP, electron transport stops and oxygen consumption ceases. (b) The addition of 2,4-dintrophenol uncouples electron transfer from ATP synthesis.

An uncoupling protein (also called thermogenin) is produced in brown adipose tissue of newborn mammals and hibernating mammals.

Valinomycin combines with K ions to form a complex that passes through the inner mito chondrial membrane. So, as a proton is translocated out by electron transfer, a K ion moves in, and the potential across the membrane is lost. This reduces the yield of ATP per mole of protons flowing through ATP synthase (FoF1). In other words, electron transfer and phosphorrylation become uncoupled. In response to the decreased efficiency of ATP synthesis, the rate of electron transfer increases markedly. This results in an increase in the H gradient, in oxygen consumption, and in the amount of heat released.

Valinomycin is a potent antibiotic which acts as a potassium (K+) ionophore. Induces K+ conductivity in cell membranes. Also active in vitro against Mycobacterium Tuberculosis, and as an apoptosis inducer.

Oligomycin is a natural antibiotic isolated from Streptomyces diastatochromogenes which inhibits mitochondrial H+-ATP synthase. It is primarily found to act as an inhibitor of mitochondrial respiration and swelling. This antibiotic is widely used as an inhibitor of oxidative phosphorylation.1-2
Oligomycin inhibits the H+- ATP-synthase by binding to the Oligomycin sensitivity-conferring protein (OSCP) at the F(o) subunits 6 and 9  which are found in the stalk of the F1F0-ATPase complex. This binding blocks the proton conductance and inhibits the synthesis of mitochondrial ATP. Because of its activity, it can also be used to reduce the number of parameters (such as ER Ca2+ release, exocytotoxicity and apopotosis) which are affected by mitochondrial depolarization.

Cytochrome P450

The active site of cytochrome P450 contains a heme iron center. The iron is tethered to the P450 protein via a thiolate ligand derived from a cysteine residue. This cysteine and several flanking residues are highly conserved in known CYPs and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD].[7] Because of the vast variety of reactions catalyzed by CYPs, the activities and properties of the many CYPs differ in many aspects. In general, the P450 catalytic cycle proceeds as follows:

1.     The substrate binds to the active site of the enzyme, in close proximity to the heme group, on the side opposite to the peptide chain. The bound substrate induces a change in the conformation of the active site, often displacing a water molecule from the distal axial coordination position of the heme iron, and sometimes changing the state of the heme iron from low-spin to high-spin.[9] This gives rise to a change in the spectral properties of the enzyme, with an increase in absorbance at 390 nm and a decrease at 420 nm. This can be measured by difference spectrometry and is referred to as the "type I" difference spectrum. Some substrates cause an opposite change in spectral properties, a "reverse type I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type II difference spectrum, with a maximum at 430 nm and a minimum at 390 nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements in vitro/ The change in the electronic state of the active site favors the transfer of an electron from NAD(P)H via cytochrome P450 reductase or another associated reductase. This takes place by way of the electron transfer chain, as described above, reducing the ferric heme iron to the ferrous state.

2.     Molecular oxygen binds covalently to the distal axial coordination position of the heme iron. The cysteine ligand is a better electron donor than histidine, which is normally found in heme-containing proteins. As a consequence, the oxygen is activated to a greater extent than in other heme proteins. However, this sometimes allows the iron-oxygen bond to dissociate, causing the so-called "uncoupling reaction", which releases a reactive superoxide radical and interrupts the catalytic cycle.

3.      A second electron is transferred via the electron-transport system, from either cytochrome

Free Radicals: Atoms contain a nucleus, and electrons move around the nucleus, usually in pairs. A free radical is any atom or molecule that contains one or more unpaired electrons.  The unpaired electrons alter the chemical reactivity of an atom or molecule, usually making it more reactive than the corresponding non-radical. However, the actual chemical reactivity of radicals varies enormously. 
Free radicals and diseases: Free radicals are capable of damage biomolecules, provoke immune response, activate oncogens, cause atherogenesis and enhance ageing process.

Free radicals with pollutants: Highly reactive molecules called free radicals can cause tissue damage by reacting with polyunsaturated fatty acids in cellular membranes, nucleotides in DNA, and critical sulfhydryl bonds in proteins. Free radicals can originate endogenously from normal metabolic reactions or exogenously as components of tobacco smoke and air pollutants and indirectly through the metabolism of certain solvents, drugs, and pesticides as well as through exposure to radiation. There is some evidence that free radical damage contributes to the etiology of many chronic health problems such as emphysema, cardiovascular and inflammatory diseases, cataracts, and cancer. Defenses against free radical damage include tocopherol (vitamin E), ascorbic acid (vitamin C), beta-carotene, glutathione, uric acid, bilirubin, and several metalloenzymes including glutathione peroxidase (selenium), catalase (iron), and superoxide dismutase (copper, zinc, manganese) and proteins such as ceruloplasmin (copper).