this chapter looked at the production of different reactive oxygen species, the damage they produce in the body, and the different ways that the body deals with them.
the reactive oxygen species (ROS) produced in the body are dangerous because they have a single electron in the outer orbital of the oxygen atom, which gives them a high capacity for extracting electrons from other molecules in order to complete the orbital. the main ROS are superoxide anion, hydrogen peroxide, and hydroxyl radical. the most potent ROS is hydroxyl radical, which is formed by two different pathways: the haber weiss and the fenton reaction. in the haber weiss reaction, superoxide (O2-) combines with hydrogen peroxide to form O2, H2O, and OH•. in the fenton reaction, hydrogen peroxide is reduced via a transition metal catalyst to a hydroxide ion and hydroxide radical.
in the body, ROS's are particularly attracted to cellular membranes, where they end up oxidizing the double bond of polyunsaturated fatty acids in the membranes. this starts a free radical chain reaction, where one oxidized molecule oxidizes another, etc. etc. in addition, they can cause base pair substitutions in DNA or strand cleavage. finally, they can also cause proteins to either cleave or crosslink excessively.
nitric oxide can also produce reactive oxygen species. normally used in small amounts in neurons and for vasodilation, it can be synthesized in large quantities by cells of the immune system in order to fight pathogens. for example, a macrophage might assemble a nitric oxide synthase complex, which synthesizes nitric oxide, in its phagolysosome, where the pathogen is housed. the nitric oxide can then create reactive oxygen species, such as peroxynitrite or nitric oxide, both of which can be used to destroy microbes.
this synthesis of reactive oxygen species by phagocytic cells in the immune system is called the "respiratory burst", and includes other ROS's as well: superoxide anion is formed by NADPH oxidase, which donates an electron to O2. superoxide can be converted to hydrogen peroxide, which can be converted to the potent hydroxyl radical or hypochlorous acid, both highly damaging to microbes.
the body uses several strategies to deactivate reactive oxygen species. the first is through enzymes such as superoxide dismutase, catalase, and the enzymes that control glutathione activity. superoxide dismutase is one of the body's main defense against antioxidants, since superoxide anion is such a strong initiator of free radical chain reactions- it converts superoxide back to hydrogen peroxide and oxygen. catalase is present in peroxisomes, cellular vesicles that house certain reactions that produce hydrogen peroxide (such as very long chain fatty acid oxidation) and reduces hydrogen peroxide into water. finally, glutathione acts as an antioxidant by reducing peroxides. in this reaction 2 molecules of glutathione combine to form one glutathione disulfide, which can be reduced back into glutathione by glutatione reductase and NADPH (from the pentose phosphate pathway).
some other antioxidants that the body uses: vitamin E, vitamin C (which regenerates vitamin E's antioxidative capacity), carotenoids, and flavonoids.
questions
1. what is a free radical molecule and how does it cause damage?
2. what type of radical is an oxygen atom?
3. oxygen can accept a total of how many electrons? what is it converted to?
4. describe the reduction of oxygen to water.
5. which ROS is the most potent?
6. what is the haber-weiss reaction?
7. what is the fenton reaction?
8. what percentage of consumed oxygen turns into ROS?
9. describe the formation of superoxide from coenzyme Q.
10. how do drugs and alcohol potentially create more ROS?
11. how is fatty acid oxidation related to ROS production?
12. how is eicosanoid synthesis related to ROS production?
13. how does cosmic radiation produce ROS?
14. describe the chain reaction that occurs during lipid membrane damage via ROS.
15. describe the effect of reactive oxygen species on proteins and peptides.
16. describe the potential damage to DNA by ROS.
17. how is nitric oxide synthesized in the body?
18. what are the three isotypes of nitric oxide synthase?
19. how are the activities of the different NOS isotypes regulated?
20. describe how NO can be directly toxic to cells.
21. describe how NO can be indirectly toxic to cells.
22. what does NO form during inflammation?
23. compare the effects of ROS that contain nitrogen vs ROS that do not.
24. what is the respiratory burst?
25. describe the production of superoxide anion during the respiratory burst.
26. describe the production of hypochlorous acid from H2O2.
27. describe how superoxide anion is neutralized and what products are formed.
28. how is hydrogen peroxide neutralized?
29. which cells of the body have the highest peroxisomal content?
30. how does glutathione act as an antioxidant?
31. what role does selenium play in antioxidant activity?
32. what role does NADPH play in antioxidant activity?
33. what is the common structural characteristic of non enzymatic free radical scavengers?
34. how does vitamin E act as an antioxidant?
35. how does vitamin C help in antioxidation?
36. what are the antioxidants contained in red wine, tea, and chocolate?
37. what is the major antioxidant present in extracellular fluid, plasma, mucus membranes, and one of the only antioxidants in the upper airways?
38. what is an antioxidant that is primarily a hormone?
answers
1. a molecule with a single unpaired electron which can extract an electron from another molecule to complete its orbital ring.
2. biradical
3. four electrons, which reduces it to water.
4. oxygen accepts one electron and forms superoxide anion (a thermodynamically unfavorable reaction). superoxide accepts one electron and forms hydrogen peroxide. hydrogen peroxide accepts one electron and forms water and the hydroxyl radical. hydroxyl radial accepts one electron and becomes water.
5. the hydroxyl radical.
6. superoxide and hydrogen peroxide form oxygen, water, and the hydroxyl radical
7. hydrogen peroxide reduced into hydroxyl radical and hydroxyl ion via a transition metal catalyst
8. 3-5%.
9. coenzyme Q in the mitochondrial membrane can accidentally transfer an electron to O2, forming superoxide anion.
10. they induce cytochrome 450 enzymes which are involved in transferring single electrons to O2 and organic substrates, from which accidental leakage of free radical intermediates might occur.
11. oxidation of very long chain fatty acids occurs in the peroxisomes, where the first step oxidation involves formation of H2O2 via oxidase enzymes.
12. some eicosanoid synthesis pathways involve lipid peroxide intermediates, including leukotriene and prostaglandins.
13. it is powerful enough to split H2O into the hydroxide and hydrogen radicals, as well as organic radicals.
14. an initiator such as hydroxyl radical extracts a single electron from the double bond of a polyunsaturated fatty acid, creating a chain reaction that creates lipid peroxides and causing membrane damage.
15. ROS can cause different effects on proteins or peptides; they can cause some proteins to degrade proteolytically and others to undergo more crosslinking and thus be more difficult to degrade.
16. the Fe2+ bound on DNA can catalyze the formation of hydroxyl radical (see question 7) and other reactive oxygen species. these molecules can either cause base substitutions or even strand cleavage.
17. arginine is converted to NO via nitric oxide synthase, via NADPH reduction.
18. neuronal (nNOS), inducible (iNOS), and endothelial (eNOS)
19. neuronal and endothelial and regulated by Ca2+ levels whereas inducible is regulated by gene transcription.
20. they can bind to iron containing compounds such as the complexes in the electron transport chain.
21. NO can be indirectly toxic by catalyzing the formation of other compounds such as peroxynitrite.
22. NO combines with superoxide to form peroxynitrite (ONOO-) or with O2 to form N2O3.
23. N containing ROS can be just as, if not more, damaging to cells, by causing the same sort of oxidative damage to membranes and proteins, and also nitrating and nitrosylating compounds.
24. the production of ROS during inflammation and infection to destroy pathogens.
25. NADPH oxidase is assembled and transported to the phagolysosomes, where it produces superoxide anion, which can be further converted into other ROS to combat the endocytosed pathogens.
26. neutrophils contain myeloperoxidase, which converts H2O2 into hypochlorous acid, which is highly antimicrobial.
27. superoxide anion is converted to hydrogen peroxide and oxygen via superoxide dismutase.
28. hydrogen peroxide is reduced to water by catalase, mainly in the peroxisomes.
29. kidney and liver.
30. two molecules of glutathione reduce one molecle of hydrogen peroxide via glutathione peroxidase, in the process forming glutathione disulfide.
31. selenium is required for the glutathione peroxidases, which are the main enzymes that catalyze antioxidant activity in the mitochondria and cytosol of cells.
32. NADPH is required to reduce glutathione disulfide back into glutathione via glutathione reductase, so that it can perform antioxidative activity again.
33. they a conjugated double bond system that might be in the form of an aromatic ring.
34. it can be oxidized by free radicals, because the high energy intermediates are stabilized by the resonance of the double bonds. it can be oxidized twice and acts as a terminator for the free radical chain reactions.
35. by reducing vitamin E back to its original form.
36. flavonoids.
37. uric acid.
38. melatonin.
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