Biochemistry -I
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- Oxygen is _
- Biradical
- Radical defintion
- Reactive atom or group of atoms that contains one or more unpaired electrons
- ROS definition
- Highly reactive radicals derived from oxygen
- Oxidative stress is _
- When rate of production of ROS exceeds rate of removal by cellular defense mechanisms (enzymes, antioxidants, etc)
- Name ROS
-
Superoxide O2 -
Hydrogen Peroxide H2O2
Hydroxyl radical OH - - How many electrons can O2 accept and describe what happens with each electron
-
Can accept 4 electrons
1 - Superoxide O2 -
2 - Hydrogen Peroxide H2O2
3 - Hydroxyl radical OH -
4 - Water H2O - Describe how hydroxyl radicals can be generated spontaneously
-
Haber Weiss Reaction - Superoxide + Hydrogen peroxide --> Oxygen + Water + Hydroxyl radical
Fenton reaction - Hydrogen peroxide is converted to hydroxyl radical and hydroxyl ion - What is the most potent ROS
- Hydroxyl radical
- Name some of disease states associated with ROS
-
Atherogenesis
Parkinsons
Alcoholic liver disease
Diabetes
Aging
CVA
Ischemia reperfusion - Name 6 sources of ROS
-
1. Ionizing radiation - splitting water in hydroxyl and hydrogen radicals
2. Various drugs and pollutants
3. Intermediates escaping from active site of enzymes (oxygenase, cytochrome P450) and respiratory chain (CoQ)
4. Oxidase reactions producing H2O2
5. Spontaneous oxidation of hemoglobin (superoxide)
6. Respiratory burst during phagocytosis - Respiratory burst results from the activity of _ and produces _
-
NADPH
Superoxide - Formation of hypochlorous acid from hydrogen peroxide is catalyzed by _
- Myeloperoxidase
- Describe cellular damage caused by ROS
-
Peroxidation of lipids - disrupts structural organization of membranes, aldehyde products cross link proteins
Oxidation of amino acids in proteins causes fragmentation, cross linking, aggregation, increased susceptibility to proteolytic digestion
Damage to DNA - strand breaks, base alterations ( guanine to 8 - hydroxyguanine) - Name 4 cellular defenses against oxygen toxicity
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Antioxidant enzymes
Free radical scavengers
Compartmentation
Repair mechanisms - Antioxidant enzymes
-
Superoxide dismutase
Catalase
Glutathione peroxidase (requires Se for full activity)
Glutathione reductase - Free radical scavengers
-
Vitamin E
Vitamin C
Beta carotene (uric acid) - Describe compartmentation
-
Enzymes producing H2O2 sequestered in peroxisomes (with antioxidant enzymes)
Fe tightly bound to ferritin
Superoxygen dismutase is in mitochondria - Describe repair mechanisms
-
DNA repair mechanisms
Removal of oxidized fatty acids from lipids
Oxidized proteins degraded and replaced - _ can terminate free radical chain reactions in membrane lipids
- vitamin E
- What can scavenge free radicals
- Vitamin C
- What inhibits lipid peroxidation
- Beta carotene
- Where are flavonoids present
-
Green tea
Red wine
Chocolate - How ROS involved in atherogenesis
- LDL oxidation plays role in atherogenesis
- How ROS involved in ischemia - reperfusion injury
- Some damage resulting from ischemic conditions may be due to excessive ROS production during reperfusion with oxygen
- How ROS involved in macular degeneration
- Photoreceptor /retinal pigment complex is exposed to sunlight - exposed to high oxygen levels, have high membrane content of unsaturated fatty acids
- Eicosanoid family
-
Modified C20 fatty acids
-produced by almost every cell in the body
-potent regulators of cellular function - Parent eicosanoid is _
- Arachidonic acid
- Name eicosanoids
-
Prostaglandins
Leukotrienes and Lipoxins - produced by leukocytes, contain 3 double bonds in series
Thromboxanes - lead to blood clot formation - General functions of Eicosanoids
-
1. Act as hormones that DO NOT enter blood stream but act locally (autocrine + paracrine)
2. Inflammatory response - pain, swelling, fever, allergic reaction
3.Increase Water and Na excretion by kidneys
4. Regulate smooth muscle contraction - affect BP, bronchoconstriction and dilation, intestinal and uterine contractions - Arachidonic acid can be found in _
-
Dietary plants
Synthesized from essential fatty acids - Two major essential fatty acids from plants are
-
Linoleic from plant oils
Linolenic - Phospholipase A2 releases _
- Arachidonic acid from C2 position of membrane phospholipids --> eicosanoid production
- Phoshpholipase C produces _
-
DAG and IP3
PKC activation - Name 3 pathways of eicosanoid synthesis
-
Cyclooxygenase - prostaglandins + thromboxanes
Lipooxygenase - leukotrienes, HETE, lipoxins
Cytochrome P 450 - epoxides (diHETE, HETE)
These are all derived from arachidonic acid - Capital letters in prostaglandins denote _
- Ring substitutions at positions 9 and 11
- Arabic numbers in prostaglandins denote _
- Series 1, 2, or 3 --> number of double bonds present in linear portion of hydrocarbon chain
- Prostaglandin series 1
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Derived from fish oils
Present is small amounts in human diet - Prostaglandin series 2
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Derived from plant oils
Present in greatest amount in human diet - Prostaglandin series 3
-
Derived from fish oils
Present in small amounts in human diet - PGE2, PGD2, PGI2
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Stimulate - vasodilation, cAMP levels
Inhibit - platelet aggregation, leukocyte aggregation, T cell proliferation - PGF 2alpha stimulates _
-
Vasoconstriction
Bronchoconstriction
Smooth muscle contraction - Cyclooxygenase is inhibited by _
- Aspirin + NSAID
- Thromboxan structure
- 6 membered ring with oxygen atom, otherwise similar to prostaglandins
- Thromboxanes are produced by _
- Platelets
- Thromboxanes cause _
-
Vasoconstriction
Platelet aggregation - Lipooxygenase pathway generates _
-
leukotrienes
lipoxins
HETE