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Free radicles
1.
2. Definition:
Free radical is a molecule or molecular
fragment that contains one or more
unpaired electrons in its outer orbits.
3.
4. Free radicals conventionally represented by super
script dot R•
Characteristics of free radicals :
1 )Tendency of free radicals to acquire electrons
from other substance makes it more reactive.
2 )Short life span
3 )Generation of new free radicals by chain reaction.
4 )Damage to various tissues.
5. Partial reduction of oxygen leads to
formation of free radicals called as reactive
oxygen species .The following are members
of this group.
Super oxide anion radical (O2 · )
Hydroperoxy radicals ( HOO· )
Hydroxyl radical ( OH· )
Lipid peroxyl radical ( ROO· )
Nitric oxide ( NO· ) , Peroxy nitrite (ONOO · )
H2O2 , singlet oxygen (are not free radicals)
6. Free radicles are generated in oxidative
metabolism due to leak of electrons .
Flavoprotein linked oxidases like xanthine
oxidase , L α amino acid oxidase .
Super oxide is formed by autooxidation of
hemoglobin to methemoglobin
(approximately 3 % of the Hb has been
calculated to autooxidise per day )
7. Cyclooxygenase & lipoxygenase reactions in
metabolism of eicosanoids.
NADPH oxidase system of inflammatory cells
by process of respiratory burst during phase
of phagocytosis.
Free iron causes increased production of free
radicals .
8. Free radicals are formed cytochrome P450
reductase enzyme complex durinrg
metabolism of xenobiotics .
β oxidation of very long chain fatty acids in
peroxisomes produces H2O2 .
9. Transfer of 4 electrons from reduced
cytochrome C to molecular oxygen assisted
by cytochrome oxidase
Transfer of 4 electrons lead to safe product
H2O .
Site of electron escape appears to be
ubiquinone & cytochrome C .
10. Cytochrome C oxidase does not release
partially reduced intermediates , this crucial
criterion meets by holding O2 tightly
between Fe & Cu atoms .
11. Although Cyt C oxidase & other protiens that
reduce O2 are remarkably successful in not
releasing intermediates , small amounts of
super oxide & peroxyl radicals are
unavoidably formed.
About 1-4 % of oxygen taken up in the body is
converted to free radical .
12.
13. Flavoprotien linked oxidases
1 ) Xanthine oxidase ,
2) L α amino acid oxidase ,
3 ) Aldehyde dehydrogenase .
Reduction of isoalloxazine ring of flavin
nucleotides takes place in 2 steps via a
semiquinone ( free radical ) intermediate.
16. NADPH oxidase inflammatory cell produce
supere oxide anion by a process of respiratory
burst during phagocytosis.
This is the deliberate production of free
radicals by the body .
17. activation of inflammatory cell
drastic increase in consumption of oxygen
(respiratory burst )
10% of oxygen uptake by macrophage is used
for free radical generation .
18.
19. In chronic granulomatous disease the NADPH
oxidase is absent in macrophages &
neutrophils .
Streptococci & pneumococci themselves
produce H2O2 therefore they are destroyed
by myeloperoxidase system .
20. Staphylococci being catalase + ve can
detoxify H2O2 in the macrophages & they are
not destroyed .
Hence recurrent pyogenic infections by
staphylococci are common in CGD .
21. Prodstaglandin H synthase & lipooxygenase
enzyme catalysed reactions produce free
radicals , by producing peroxide .
Macrophages produce NO from arginine by
enzyme nitric oxide synthase , this is also an
important anti bacterial mechanism .
23. The capacity to produce tissue damage by
H2O2 is minimal because this is not a free
radical . But in the presence of free iron H2O2
can generate hydroxyl free radical (OH
·)which is highly reactive.
24.
25. Ionising radiation damages tissues by
producing hydroxylradical , H2O2 ,super
oxide anion .
Light of appropriate wave length can cause
photolysis of oxygen to produce singlet
oxygen .
Cigarette smoking contains high
concentrations of free radicals.
Other toxic compounds CCl4 drugs &
inhalation of air pollutants will increase free
radical production .
26. Polyunsaturated fatty acids present in cell
membranes are destroyed by peroxidation.
This occurs by three phases.
1 )intiation phase
2 )prolangation phase
3 )termination phase
27. Production of carbon centered free radical R·
( or ) ROO· (lipid peroxide radical )
1 )RH +OH· R· + H2O
metal ion
2 )ROOH ROO· + H+
R· , ROO· degraded to malon dialdehyde . It is
estimated as an indicator of fatty acid break
down by free radical .
28. Carbon centered radical rapidly reacts with
molecular oxygen forms peroxyl radical
(ROO· ) which can attack another PUFA .
R· + O2 ROO·
ROO· + RH ROOH + R·
One free radical generates another free
radical in the neighbouring molecule a chain
reaction (or) propagation is intiated .
29. The above reactions would proceed
unchecked till a peroxyl radical reacts with
another peroxyl radical to form inactive
products .
ROO· + ROO· RO- -OR+O2
R· + R· R - - R
ROO· + R· RO- -OR
32. Chief amongst the enzymes that defense
against ROS is super oxide dismutase .
Super oxide dismutase is present in all major
aerobic tissues .
Eukaryote contains 2 forms of this enzyme,
1 ) Copper Zinc dependent cytosolic enzyme
2 ) manganese containing mitochondrial
enzyme .
33.
34.
35. The active site of cytosolic enzyme in
eukaryotes contains a copper ion & Zinc ion
coordinated to the side chain of a histidine
residue .
The negatively charged superoxide is guided
electrostatically to a very positively charged
catlytic site at the bottom of the channel .
36.
37. H2O2 formed by SOD & by other processes is
scavenged by catalase ( a ubiquitous heme
protein that catalyze the dismutation of
H2O2 into H2O & O2.)
Catalase is found in blood bone marrow
mucous membranes , liver & kidney .
SOD & catalase are remarkably efficient ,
performing their reactions at or near the
diffusion limited rate.
38. The Kcat / Km ratio of enzyme super oxide
dismutase is 7x 109 enzymes that have high K
cat / K m ratio at the uper limits have attained
kinetic perfection.
Their catalytic velocity restricted only by the
rate at which they encounter the substrate in
the solution .
39. For catalytically perfect enzymes , every
encounter between enzyme & substrate is
productive .
Any rate in catalytic rate can come only by
decreasing the diffusion time.
Circe effect : In this case the electrostatic
attractive forces on the enzyme entice the
substrate to the active site .
40. Catalase decreases the free energy of
activation ∆G 1 of H2O2.
In the absence of catalase ∆G1 free energy of
activation is 18Kcal / mol where as in the
presence of catalase 7 Kcal / mol .
K cat / Km value of catalase is 4 X 107.
41. Catalase is a heme protein containing 4 heme
groups .
In addition to possessing peroxidase activity ,
it is able to use one molecule of H2O2 as a
substrate electron donor & another molecule
of H2O2 as oxidant or electron acceptor .
catalase
2H2O2 2H2O+O2
42.
43. This enzyme is remarkable in containing a
modified aminoacid selenocystein at its
active site in which selenium has replaced the
sulphur .
The enzyme catalyzes the destruction of
H2O2 & lipid hydroperoxides by reduced
glutathione , protecting the membrane lipids
& hemoglobin against oxidation by peroxides
.
44.
45.
46.
47. Vitamin E : lipid soluble , chain breaking
antioxidant.
βcarotene & its anologues (lycopene & retinyl
stearate ): lipid soluble radical scavenger & singlet
oxygen quencher .
Coenzyme Q : may acts as antioxidant in addition to
its major role in energy metabolism .
48. Transferrin : binds ferric ions ( 2 per mole of
protein )
Lactoferrin : binds ferric ions at low pH ( 2 per
mole of protein )
Haptoglobins : binds hemoglobin
Albumin : binds copper , heme , scavenges
OH.
Ceruloplasmin : ferrooxidase activity –
stoichiometricO2 scavenging ,binds copper
ions utilizes H2O2 for reoxidation of copper .
50. Water soluble : urate , ascorbates ,
thiols ,bilirubin,
flavanoids.
Lipid soluble : tocopherol ,
ubiquinol 10 ,
β carotene .
Urate & vitamin E acts in lipid phase to trap
ROO· radicals .
51. Preventive antioxidants reduces the rate of
chain intiation .
Preventive antioxidants include
Catalase , peroxidases ,
Ceruloplasmin , transferrin , albumin.
EDTA , DTPA acts anti xidants by chelating
metal ions .
52. Vitamin E is most important natural
antioxidant .
Vitamin E apear to be the 1st line defense
against peroxidation of PUFA contained in
cellular & subcellular membrane
phospholipids .
The phospholipids of mitochondria,
endoplasmic reticulum & plasma membranes
possess affinities for α tocoferol &
vitamin appears to concentrate at these sites.
53. The tocopherools acts as antioxidants by
breaking free radical chain reactions as a
result of their ability to tranfer a phenolic
hydrogen to peroxyl free radical of a
peroxidized PUFA .
The phenoxy free radical may react with
vitaminC to regenerate tocopherol or it react
with further peroxyl free radicl so that the
chromane ring & the side chain are oxidized
to the non free radical product.
57. The antioxidant action of vitamin E is
effective at high oxygen concentrations , & it
is concentrated in lipid structures exposed to
highO2 partial pressures such as the
erythrocyte membrane , membranes of
respiratory tree & the retina.
58. Glutathione peroxidase contains Selenium,
provides a second line of defense against
hydroperoxides.
Tocopherol & selenium reinforce each other
in their action against lipid peroxides.
Selenium is required for normal pancreatic
function thus promoting absorption of lipids
& vit E.
59. Vitamin E reduces selenium requirement by
preventing loss of selenium from the body or
maintaining it in an active form .
α tocopherol appears to play a role in cellular
respiration either by stabilizing ubiquinone or
by helping transfer of electrons to ubiquinone
.
60. Carotenoids are capble of quenching singlet
molecular oxygen .
Carotenoids like lycopene ,β carotene , are
important biological molecules that can
inactivate electronically excited molecules by
process called quenching.
βcarotene & related compounds can acts as
chain breaking antioxidant
61. Can acts as preventive antioxidant by
decreasing the formation of methyl linoleate
hydroperoxide .
βcarotene & related compounds can acts as
chain breaking antioxidant.
Can acts as preventive antioxidant by
decreasing the formation of methyl linoleate
hydroperoxide .
Singlet oxygen is capable of inducing damage
to the DNA
62. Lycopene shows greater quenching ability
than βcarotene (double ability )
Comparing the structures opening of the β
ionine ring increases the quenching ability.
Quenching ability of cartenoids not only
depends on triplet energy state that is the
length of the conjugated double bond system
but also on the functional groups .
63. VitaminC is aqueous phase antioxidant.
Ascorbic acid is a strong reducing agent with
a hydrogen potential of +0.08 & is capable of
reducing molecular oxygen nitrate Cyt a &
Cyt c.
Has role in converting oxidized tocopherol to
reduced active form .
Due to its role in formation of ferritin this
deceases the free iron in circulation.
64. Reactivespecies antioxidant
singlet oxygen vit A , βcarotene
vit E
Super oxide radical SOD ,vit E
βcarotene
Hydroxyl ,alkoxyl, vit E & vitC
peroxyl radical
H2O2 catalase
G.peroxidase
Lipid peroxides G. peroxidase
