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The Chemistry of Dioxygen

Oxygen may be considered one of the most important elements in chemistry. Not counting hydrocarbons, there is a greater diversity of molecules with oxygen than with carbon. Given its role in the molecular world, very little time is spent on the chemistry of oxygen in undergraduate chemistry classes. Why is oxygen so special?

Oxygen reacts with atoms of all elements except the Noble gases to form molecules. One of the most important from a biological sense is water. It :

  • provides a perfect solvent for biomolecules
  • moderates the earth's climate
  • is the source of almost all the dioxygen in the air.
  • absorbs UV light and allowed life to first develop in the sea

From a chemical point of view, water is a(n):

  • nucleophile and electrophile
  • acid and base
  • oxidizing agent and reducing agent
  • protic solvent that can form H-bonds

The Formation of Earth and the Development of Life

The gaseous and dusty environment from which earth formed contained metals and water, which as you remember from General Chemistry, can react to form hydrogen gas. H2 reacts with nonmetals (under various conditions of temperature and pressure) to form H2S, HCl, CH4, and NH3 which contributed to the reducing nature of the early atmosphere. This kept the transition metals in their lowest oxidation states. Many metals, including the coinage metals (Cu, Ag, and Au) and the platinum group (Ru, Rh, Pd, Pt) were stable in elemental form.

Then, around 2.7-2.8 billion years ago, photosynthetic organisms (blue/green algae or also called cyanobacteria) developed which could oxidize water to form dioxygen. Oxygen was generally unavailable for redox chemistry before then as photosynthesis, the process that would evolve to oxidize water to produce dioxygen, was unavailable. Remember that to oxidize water to dioxygen, itself a strong oxidizing agent, requires a stronger oxidizing agent than dioxygen and lots of energy. Fossilized remains of cyanobacteria are found in stromatolites. Using knowledge of how atmospheric oxygen can alter the chemistry of different sulfur isotopes of SO2, it has been shown that O2 did not exist in the atmosphere as a whole above 1 ppm earlier than 2.4 billion years ago, although there might have been isolated pockets with higher concentrations. After that it rose, presumably as a result of cyanobacteria. Before this time, bacteria oxidized a similar molecule, H2S to form elemental sulfur. It is probable that volcanic gases like H2 might have kept oxygen levels from rising between 2.7 billion year ago and 2.4 billion years ago, when its build-up started. Methane and hydrogen in the form of H2 probably decreased around 2.4 billion years ago as methane with its hydrogen atoms escaped to the upper atmosphere and space. Over the next billion years, dioxygen rose to perhaps 0.2 - 2% (compared to the present levels of 20%). Why? Because the early atmosphere was reducing, the added oxygen combined with a large "sink" of reduced metals (like elemental Cu and Fe) or nonmetals (like C and ammonia), preventing a large buildup. Only after these reduced substances were "titrated" did dioxygen build up to present levels. In addition, the oxygen might have increased weathering of sulfur deposits which can lead to sulfides entering the ocean, where they could precipitate ocean iron ions that are necessary for cyanobacterial chemistry. This would place constraints on cyanobacterial growth until dioxygen levels in the atmosphere increased enough so sulfides were converted to sulfates.

Around 2.3 billion years ago, as trace dioxygen had accumulated in the atmosphere, redox chemistry changed, although isotope evidence suggest that little dioxgen was found in water. Around 1.8 - 1.5 billion years ago, the earth's atmosphere became somewhat oxygenated, which was also coincident with the development of eukaryotic organisms. Until then, life was restricted to the oceans since there was no ozone to absorb dangerous UV radiation. The buildup of dioxygen in the air must have led to a great extinction of anaerobic organisms, since as we shall see, products of oxygen metabolism are very toxic. Some evolved to use dioxygen. Ozone developed, and life could then migrate from the sea to the land. It wasn't until around 600 million years ago that animals arose, however. Was this event associated with the development of a fully oxygenated (20%) atmosphere? Recent evidence, which shows that substantial oxygen wasn't available in the deep sea until about 600 million years, seems to suggest that. Based on analysis of iron compounds in waters in Newfoundland, it appears that oxygen was very low in the sea 580 million years ago, during the Gaskiers glaciation period. Immediately after that it rose to levels consistent with atmospheric dioxygen levels of 15%, levels necessary for large animals. Similar trends in carbon and sulfur isotopes in marine rocks in Oman also suggest large increases in oxygen at the end of the Gaskiers glaciation period. What caused this second great oxygenation event? One possibility is that organic matter was sequestered from reaction with atmospheric dioxygen, as clays bound organic molecules in the ocean and lichens and zooplankton facilitated weather and production of insoluble organic material in the oceans.

Dioxygen is obviously critically important for higher organisms, so an understanding of its chemistry becomes important. This chapter will show that dioxygen is a ground state diradical that has low solubility in aqueous solution, reacts in a kinetically sluggish fashion in oxidation reaction, and forms toxic byproducts as it gets reduced. Life forms hence evolved ways to deal with these problems, including ways to increase its solubility (with dioxygen binding and transport proteins), and enzymes (that could activate it kinetically and also detoxify oxygen by-products). Dioxygen is toxic to many cells. Obligate aerobes die in an oxygen environment as many of their cellular components get oxidized by this excellent oxidizing agent. Several strains of bacteria actually swim away from high levels of dioxygen. A graph showing log of survival vs log pO2 is linear with a negative slope for a variety of organisms, including mice, fish, rats, rabbits, and insects. Pure oxygen can induce chest soreness, coughs, and sore throats in people. Premature infants put in pure dioxygen environments often developed blindness due to retrolental fibroplasia (a build-up of fibrous tissue behind the lens). The trade off for this toxicity is clear. Energy is derived from organic molecules through oxidation. Before dioxygen became available to power aerobic catabolism of reduced molecules like fatty acids and the less reduced sugars, such molecules were only partially oxidized. The glycolytic pathway, found in most organisms, oxidizes glucose (6 Cs) to two molecules of pyruvate (3 Cs). It was only with the availability of dixoygen did pathways evolve (Kreb Cycle, mitochondrial electron transport/oxidative phosphorylation) that allowed pyurvate to be fully oxidized to carbon dioxide, with the release of much more energy.

The Properties of Dioxygen

It is important to understand the properties of dioxygen since oxidation reactions using it power not only our bodies but our entire civilization. We will obviously concentrate on biological reactions, but even these show the same characteristics as non-biological ones.

  • Oxidation of organic molecules by oxygen is thermodynamically favored but kinetically slow.
  • Pure oxygen environments are toxic to cells and organisms.

First we will try to understand these properties of oxygen, and then we will see how organisms overcome these problem to use dioxygen.

We can understand both of these properties by looking at the molecular orbitals of oxygen and its reduction products as shown in the diagrams below. Ground state oxygen is a diradical, which explains the paramagnetic behavior of oxygen. The two unpaired oxygens each have a spin state of 1/2 for a total resultant spin S of 1, making ground state oxygen a triplet (2S+1) = 3. Organic molecules typically undergo 2 electron oxidation steps. Consider the stepwise oxidation of methane below. The oxidation number of C in methane is -4, -2 in methanol, 0 in formaldehyde, +2 in formic acid, and finally +4 in carbon dioxide, indicating two electron losses in each step.

01methtoco2step.gif

The two electrons lost by the organic substrate are added to oxygen, but since the two lost electrons are spin paired, a spin flip must occur to allow the electrons to enter the unfilled oxygen orbitals. Alternatively, energy can be put into ground state dioxygen to produce excited state singlet oxygen (S=0, 2S+1 = 1). The source of the large activation energy required (about 25 kcal or 105 kJ/mol) to flip the electron spin accounts for the kinetic sluggishness of reactions of dioxygen with organic reactants.

A traditional Lewis structure for ground state dioxygen can not be easily written since the electrons are added in pairs, and dioxygen is a diradical. There are 6 electrons in the sigma molecular orbitals from second shell electrons (two each in s2s, s2s*, and s2p,) and 6 electrons in the pi molecular orbitals from second shell electrons (two each in two different p2p orbitals, and one electron each in two different p2p*), so the net number of electrons in bonding orbitals is 4, giving a bond order (or number of 2). In contrast it is easy to write the Lewis structure of singlet, excited state oxygen, since all electrons can be viewed as paired, with two net bonds (1 sigma, 1 pi) connecting the atoms of oxygen. This Lewis structure will be used to represent single, excited oxygen, which should react more quickly with organic molecules. The excited state single on the far right (below) is unstable and decays to the middle singlet state. The middle state is approximately 94.3 kJ/mol higher in energy than the ground state triplet (on the left). In quantum mechanical parlance, the transition from the ground state triplet to the singlet state is forbidden for a number of reasons, making it unlikely that absorption of a photon will induce the transition.

02dioxygenchem2.gif

The Reductions of Dioxygen

When oxygen oxidizes organic molecules, it itself is reduced. By adding electrons one at a time to the molecular orbitals of ground state dioxygen we produce the step-wise reduction products of oxygen. On the addition of one electron, superoxide is formed. A second electron produces peroxide. Two more produces 2 separated oxides since no bonds connect the atoms (the number of electrons in antibonding and bonding orbitals are identical). Each of these species can react with protons to produce species such as HO2, H2O2 (hydrogen peroxide) and H2O. It is the first two reactive reduction products of dioxygen that make it potentially toxic.

03dioxygenreduction2.gif

How Are the Potential Problems in Oxygen Chemistry Dealt With Biologically?

Kinetic sluggishness: Enzymes that utilize dioxygen must activate it in some way, which decreases the activation energy. Enzymes that use dioxygen typically are metalloenzymes, and often heme-containing proteins. Since metals such as Fe2+ and Cu2+ are themselves free radicals (i.e. they have unpaired electons), they react readily with ground state oxygen which itself is a radical. The molecular orbitals of the metal and oxygen combine to produce new orbitals which for oxygen are more singlet-like in nature. Likewise, dioxygen reacts more readily with organic molecules which can themselves form reasonably stable free radicals, such as flavin adenine dinucleotide (FAD), as we shall see later.

Dioxygen toxicity: Since toxicity arises from the reduction products of oxygen, enzymes that use oxygen have evolved to bind oxygen and its reduction products tightly (through metal-oxygen bonds) so they are not released into the cells where they can cause damage. In addition, enzymes which detoxify free dioxygen reduction products are widely found in nature. For example:

  • superoxide dismutase catalyzes the dismutation (self-redox) of 2 superoxides into dioxygen and hydrogen peroxide;
  • catalase converts hydrogen peroxide into water and oxygen;
  • peroxidase catalyzes the reaction of hydrogen peroxide with an alcohol to form water and an aldehyde;
  • peroxiredoxins react with peroxides and thioredoxin (a small electron donor) to form water and oxidized thioredoxin.

Finally free radical scavengers such as vitamins A, C, E, and selenium can react with reactive free radicals to produce more stable free radical derivatives of the vitamins and Se. More on this later.

The Reactions of Dioxygen and Its Reduction Products

1. Triplet O2 - Ground State

Figure: Triplet O2 - Ground State

04o2chem_trip.gif

  • Metals ions - Metal ions are radicals themselves, so can react with dioxygen. Ex:

Fe2+ + O2 ↔ [ Fe2+-- O2 ↔  Fe3+-- O2-.] ↔ Fe3+ + O2-. (superoxide)

  • Autoxidation of organic molecules to produce peroxides. In this free radical reaction, several reactions occur, including

RH → R. (Initiation)
R. + O2→ ROO. (Propagation)
ROO. + RH → R. + ROOH (Propagation)
R. + R. → R--R (Termination)
ROO. + ROO. → ROOR + O2 (Termination)
ROO. + R. → ROOR (Termination)

The initiation step above occurs mostly at C atoms which can produce the most stable free radicals (allylic, benzylic position, and 3o > 2o >> 10 carbons). Hence unsaturated fatty acids are extra reactive at the methylene C that separate the double bonds.


 

05o2chem_pufas.gif


2. Single O2 - Excited State

Figure: Single O2 - Excited State

06o2chem_sing.gif

It can be made from triplet oxygen by photoexcitation. Alternatively, it can be made from triplet oxygen through collision with an excited molecule which relaxes to the ground state after a radiationless transfer of energy to triplet oxygen to form reactive singlet oxygen. This later process accounts for photobleaching of colored clothes when the conjugated dye molecules absorb UV and Vis light, relax by transferring energy to triplet oxygen to form singlet oxygen, which then chemically reacts with the conjugated double bonds in the dye.

  • Alkenes react with oxygen to form hydroperoxides, potentially through a epoxide intermediate
  • Dienes reacts with oxygen in a Diels-Alder like reaction to form endoperoxides

3. Superoxide

Figure: Superoxide

07o2chem_superox.gif

  • Dismutation: O2-. + O2-. → H2O2 + O2
  • Acid/Base: HO2. → O2-. + H+ (pKa = 4.8)
  • With metal ions: Fe3+ (as in heme) + O2-. → O2 + Fe2+

4. Peroxide

In contrast to dioxygen which contains multiple bonds between the O atoms, peroxide has only one bond. In fact, it is quite weak and requires only 38 kcal/mol to break it. Remember, bonds can be broken in a heterolytic way (both electrons in a bond go to one of the atoms), or in a homolytic fashion, in which the one electron goes to each atom.

08o2chem_perox.gif

 

  • Acid/Base: H2O2 → HO2- → O22- (pKa1 = 11.8; pKa2 > 14)
  • Reaction with Fe2+ - The Fenton Reaction: (similar to reaction of triplet O2 with Fe2+ above)
    Fe2+ + OOH- ↔ Fe2+-- OOH ↔ Fe2+-- O + OH- ↔ Fe3+-- O. ↔ Fe3+ + OH. last step a proton is added). In this reaction, a homolytic cleavage of the O--O bond occurs generating OH- and the hydroxy free radical, OH., which will react with any molecule it encounters.
  • Thermal or photochemical homolytic cleavage of peroxide. This forms alkoxide free radicals which react like the hydroxy free radical.
  • Reactions with alkyl groups in the presence of metal ions such as Cu, Co, or Mn:
    RH + R'OOH → ROOR'

5. Hydroxy Free Radical

As mentioned above, this species is extremely reactive. It will react with any molecule it encounters and does so immediately. It can abstract a H atom leaving another free radical. For example, the hydroxy free radical could extract a hydrogen atom from a polyunsaturated fatty acid to from a carbon-centered radical. A particularly nasty reaction is the insertion of the hydroxy radical into bases in DNA, as shown in the diagram.

09o2chem_hydrox.gif

Dioxygen Reduction Products and Disease

Significant evidence suggests oxygen free radicals are linked to aging and diseases. Mutations caused by hydroxylation reactions (presumably from the generation of hydroxyl free radicals as shown above) can potentially lead to cancer. Recently it has been shown that mitochondrial DNA is more susceptible to oxidation that is nuclear DNA. Human mitochondria has its own small genome (16.5 Kb compared to the nuclear genome of 3 Gb) which code 13 protein subunits involved in respiration, 22 tRNAs and two ribosomal RNAs. (The mitochondria presumably are vestiges of a bacteria which invaded an early cell and established a symbiotic relationship with the cell). A recent study has shown that there is an inverse correlation of oxidized mitochondrial DNA [8-oxoG] with maximal life span of an organism, but this correlation is not seen with nuclear DNA. Presumably the nuclear DNA is somewhat protected from oxidative damage since it is bound to histone proteins (which form nucleosome core particles with DNA) and by DNA repair enzymes, both of which are missing from the mitochondria. Also, examination of human bladder, head and neck and lung primary tumors reveals a high frequency of mitochondrial DNA mutations. In addition most dioxygen use by the cell occurs in the mitochondria. Hence this organelle probably faces the highest concentration of toxic oxygen reduction products. Recently, the crystal structure of an enzyme, adenine DNA glycosylase (MutY), that repairs 8-oxyG modified DNA has been determined in complex with the oxidatively damaged DNA. If not repaired, the 8-oxyG base pairs with adenine instead of cytosine, causing a GC to AT mutation on DNA replication.


Oxidative Modification of Proteins

10protoxidation.gif

Oxidized levels of proteins (as evidenced by increased levels of aldehydes) increase dramatically with age (especially after age 40). The reactions seem to be catalyzed by metals and may proceed by generation of hydroxy free radicals. Diseases associated with premature aging (Werner's Syndrome; another link to Werner's Syndrome; Progeria) show very high levels of oxidized proteins at an early age. Fibroblasts from 10 yr. old children with progeria have levels of oxidized proteins usually not seen until the age of 70. Beta amyloid protein deposits (found in Alzheimer's and Down's Syndrome) cause neurotoxicity and death, partly by increasing superoxide production by endothelial cells, causing vasoconstriction/dilation, and ultimately disease progression. Beta amyloid aggregates appear to increase H2O2 levels, in a process facilitated by Fe2+ and Cu+. Free radical scavengers (antioxidants) help to prevent this damage. Recent studies suggest that vitamin E may delay the symptoms of Alzheimers.

Lou Gehrigs Disease (Amyotrophic Lateral Schlerosis) is a disease of progressive motor neuron degeneration, which affects 1/100,000 people, and is 10-15% familial. Of the familial cases, about 25% have a mutation in superoxide dismutase I, a copper-zinc enzyme. About 2-3% of ALS patients carry 1 of 60 different dominant mutations in this enzyme. Mutations often decrease the stability of the protein which decreases Zn2+ affinity 5-50 fold. The A4V mutation (valine at amino acid 4 substituted for Ala) has the weakest Zn affinity and causes rapid disease progression. In the absence of Zn2+, the apoprotein somehow seems to induce cell death in neurons. This superoxide dismutase also expresses a second activity. It also acts as a peroxidase which takes ROH + H2O2 to form an RHO (an aldehyde) plus water. In some cases, the enzyme retains normal activity against superoxide but altered peroxidase activity.

Is your hair going white?: Wood et al. have shown that millimolar concentrations of hydrogren peroxide build up in hairs that have grayed and whitened. This was associated with a decrease in catalase and in increases in Met oxidation (to Met-sulfoxide) in proteins, also associated with a decrease in the repair enzyme Met-sulfoxide reductase, Met 374 in the active site of tyrosinase, an enzyme required for production of melanin in hair follicles, is also damaged, leading to lack of melanin, a pigment necessary for hair coloration and "senile hair graying".

ROS and Protein Folding

As discussed in Chapter 2D: Protein Folding in Vitro and in Vivo, the cytoplasm has sufficient concentrations of "b-mercaptoethanol"-like molecules (used to reduce disulfide bonds in proteins in vitro) such as glutathione (g-Glu-Cys-Gly) and reduced thioredoxin (with an active site Cys) to prevent disulfide bond formation in cytoplasmic proteins. Disulfide bonds in proteins are typically found in extracellular proteins, where they serve to keep multisubunit proteins together as they become diluted in the extracellular milieu. These proteins destined for secretion are cotranslationally inserted into the endoplasmic reticulum (see below) which presents an oxidizing environment to the folding protein and where sugars are covalently attached to the folding protein and disulfide bonds are formed (see Chapter 3D: Glycoproteins - Biosynthesis and Function). Protein enzymes involved in disulfide bond formation contain free Cys which form mixed disulfides with their target substrate proteins. The enzymes (thiol-disulfide oxidoreductases, protein disulfide isomerases) have a Cys-XY-Cys motif and can promote disulfide bond formation or their reduction to free sulfhydryls. They are especially redox sensitive since their Cys side chains must cycle between and free disulfide forms.

Reactive oxygen species (ROS) can significantly affect redox chemistry, and if present in excess can place the cell in a condition of "oxidative" stress. ROS can indiscriminately oxidize lipids, nucleic acids, and proteins, but more specifically, they may also oxidize proteins involved in creating and maintaining the normal disulfide bond formation in proteins. As the concentration of ROS increase, the concentration of cytoplasmic proteins with incorrect disulfides should increase. Using a two dimension PAGE system (first dimension run under nonreducing and the second reducing conditions) of neural cell proteins derived from cells exposed to normal and differing oxidative conditions (hydrogen peroxide or decreased intracellular glutathione levels), Cumming et al. showed that oxidizing stress increased the levels of disulfide bonds in redox sensitive enzymes and, unexpectedly, among other cytoplasmic proteins involved in many aspects of life, effecting the activity of many cellular processes, suggesting that disulfide bond formation may have not only a structural but regulatory role.

Oxidative Modification of Lipids

05o2chem_pufas.gif

The initial stages of cardiovascular disease appear to involve the development of fatty acid streaks under the artery walls. Macrophages, an immune cell, have receptors which appear to recognize oxidized lipoproteins in the blood, which they take-up. The cells then become fat-containing foam cells which form the streaks. Oxidation of fatty acids in lipoproteins (possibly by ozone) could produce lipid peroxides and lead to protein oxidation in lipoproteins. Cortical neurons from fetal Down's Syndrome patients show 3-4 times levels of intracellular reactive O2 species and increased levels of lipid peroxidation compared to control neurons. This damage is prevented by treatment of the neurons in culture with free radical scavengers or catalase.

 

11jpegLDLoxidFoamcell.jpeg

A recent study of peroxiredoxins by Neumann et al. showed the importance of these gene products in mice. Peroxiredoxins are small proteins with an active site cysteine and are found in most organisms. Transcription of the mammalian peroxiredoxin 1 gene is activated by oxidative stress. They inactivated the gene which produced a mouse that could reproduce and appeared vital, but which had a shortened lifespan. These mice developed severe hemolytic anemia and several types of cancers. High levels of reactive oxygen species and resulting increased levels of oxidized proteins were found in red blood cells of the knockout mice with anemia. High levels of 8-oxoguanine, resulting from oxidative damage to DNA, were found in tumor cells.

Aging

Oxidative damage to biomolecules might not initiate aging and disease processes, but rather might be a secondary effect of other initiating events. Reversing or preventing oxidative damage might slow the progression of aging and disease. Aging is a complex feature of organisms and would be expected to have complex causes and biological effects. At the organismal level, aging has been studied in the round worm C. elegans which lives for only a few weeks. Genetic analyses can be easily used to find gene alterations associated with premature aging. One hormonal system that has recently been associated with aging in eukaryotes (and in C. elegans) involves the signaling pathways for insulin and insulin growth factor I (IGF-1), which regulate carbohydrate, lipid, and reproductive pathways in C. elegans. Mutations that decrease signaling from this pathway increase C. elegans life span. These mutations lead to increased activity of the DAF16 transcription factor, which upregulates the expression of many genes. In contrast, wild type organisms, when exposed to insulin or IGF-1, decrease the activity of DAF16. Using DNA microarrays, investigators determined which DAF16-controlled genes were upregulated in mutant worms in the mid-life point of the organism. These genes included, among others, peroxisomal and cytosolic catalase, Mn-superoxide dismutase, cytochrome P450s, metallothionein-related Cd-binding protein, and heat shock proteins. We will investigate the function of several of these gene products in the next section, but needless to say, they are all involved in cellular responses to stress, often involving dioxygen metabolites. Over expression of mitochondrial catalase in mice increased their lifespan by 20%. It has also been showed that decreased levels of insulin-like growth factor also promote longevity in mice, indicating again that mechanisms in addition to oxidative damage by ROS are involved in aging.

Although oxidative damage in mitochondria clearly can promote premature aging, other independent mechanisms may also. In a recent study, Kujoth et al. developed a mouse model that expressed a mutant form of mitochondrial DNA polymerase that was defective in the proofreading activity of the enzyme. These mice displayed premature aging but showed no increased levels of oxidized mitochondrial lipids or hydroxylated G residues in mitochondrial DNA. They did show significant activation of a cytosolic enzyme called caspase-3, which when active lead to the programmed death of cells (a process called apoptosis). This calcium-activated aspartic acid proteases (with an active site Asp) is activated by binding mitochondrial cytochrome C that has "leaked" into the cytoplasm from its normal location in the intermembrane space in mitochondria. The process is usually associated with DNA damage (mutations, fragmentation) that would arise if the proofreading function of DNA polymerase was defective. This was indeed found in these mice.

 


Antioxidant Protection from Oxidative Modification

If oxidative damage by dioxygen reduction products can cause disease, maybe antioxidant vitamins (E, C, A), which can form reasonably stable free radical, can protect the body from their effects.

Figure: antioxidant vitamins (E, C, A)

16pngantioxidants.png

It has been shown that these vitamins can help protect white blood cells from DNA damage arising from hydroxy free radicals. Vitamin E, a fat-soluble vitamin carried in circulating lipoproteins, can reduce the risk of cardiovascular disease, presumably by preventing oxidation of lipids and proteins in lipoproteins. Vitamin E and C, along with a common food additive, butylated hydroxytoluene (BHT) can form stable free radicals (formed possibly by abstraction of a hydrogen atom by hydroxyl free radicals) since the lone electron is stabilized by resonance and the O-centered resonant form is sterically restricted from intermolecular interactions which could propagate the free radical chain reactions.


How Do Cells Respond to Low O2?

We have spent much time studying how the body deals with and utilizes the toxic byproducts of dioxygen reduction. What happens when the body doesn't get enough dioxygen - a condition call anoxia (no dioxygen) or hypoxia (too little dioxygen)? This might occur in muscles undergoing vigorous exercise, and in the brain and heart when clots occlude blood flow to these organs (as occurs in most strokes and heart attacks). Under low dioxygen concentrations, a family of protein transcription factors called hypoxia-inducible factor (HIF) become activated. The functional proteins appears to be a dimer of HIF-a and HIF-b. In contrast to the concentration of the beta form, the activity of HIF-a is increased under low dioxygen concentrations. HIF-a concentration is regulated not at the transcriptional level, but through proteolysis of the protein. In the presence of abundant dioxygen, HIF-a is hydroxylated at two Pro residues by the enzyme prolyl hydroxlase. This post-translational modification targets the protein for proteolysis (through ubiquitination by the VHL protein and subsequent cleavage by the proteasome). A second independent pathway in rapidly growing tissue leads to increased expression of HIF-a even in the presence of dioxygen. This could be beneficial to cells since rapidly growing tissue, especially tumor cells, might be expected to experience low oxygen conditions.

Figure: Cell response to hypoxia

17hypoxia.gif

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