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In humans,
Electron Transport System (ETS) in mitochondria is main mechanism for
Oxidoreductases
(Harper 26th)
1.
Oxidases:
A Containing Cu B As flavoproteins
2.
Dehydrogenases: A. NAD+ or NADP+ as coenzyme B Flavin as coenzyme C Cytochromes (Fe-porphyrin as coenzyme) Hydroperoxidases: A Peroxidase B Catalase Oxygenases: A B
3.
4.
Dioxigenase Monooxigenase
1.
Oxidases: - Remove 2 protons (H+) from substrate and pass to oksigen - Generate H2O or H2O2 Two groups of oxidases: A Containing Cu Example: Cytochrome a3 (cyt a3) also known as cyt aa3 Is a cytochrome oxidase Terminal compound of the respiratory chain in mitochondria
B. Flavoproteins, contain FMN or FAD Ex. : L-aminoacid oxidase Xanthine oxidase Aldehyde dehydrogenase
3.
Hydroperoxidases use H2O2 as substrate A. Peroxidase reduces peroxides using various eacceptors
Peroxidase
H2O2 + AH2
2 H 2O + A
GSSG + H2O
GSH = Reduced gluthatione Glutamyl-cysteinyl-glycine (a tripeptide) -SH = Reducing group of cysteine residue
B.
2 H2O + O2
Found in: Blood, bone marrow, mucous membranes Kidney, liver Catalase destroys peroxides formed by oxidases
Free radicals
- O Transfer of a single e to O2 - (superoxide anion) 2 Can damage membranes, DNA, etc.
Destructive effects Amplified by: Free radical chain reaction Removed by: Superoxide dismutase (SOD) in the reactions
O2 - + O2 2H + SOD
H2 O2 + O2
H2 O2
Catalase
2H2 O2 + O2
Mitochondria
Make > 90% of cellular ATP Powerplant of the cell Four Compartments Matrix has numerous enzymes that reduce NAD+ to NADH during catabolism of foodstuffs Inner Membrane has:
Proteins
(V & V
Fig. 20-3)
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Role of RC of mitochondria in the conversion of food energy to ATP Harper 26 Fig. 12-2
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Harper 26
Fig. 12-4
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Reactive Oxygen Species (ROS) are oxygen radicals that may cause damage to cells and tissues, such as in - Neurodegenerative diseases (Alzheimer, Parkinson) -Cardiovascular diseases
- Rheumatoid Arthritis (RA) (Bone erosion, cartilage loss, loss of joint function)
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In RA :
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Effect of ROS on a. Lipid and Nucleic Acids Double bonds, easy target for oxidative damage (lipid peroxidation) b. Cellular protein and Enzymes Oxidation produces altered proteins
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Altered proteins accumulate with aging. This will interfere with normal homeostasis Can cause age related pathologies, such as - Atherosclerosis - Senile cataract - Diabetes Mellitus - Immune system failure - Neurodegenerative diseases
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Age related changes in enzymes and other proteins: - Alteration in catalytic activities - Altered folding in the 3-D structure The products are altered (abnormal) proteins These have to be eliminated (degradation) With aging: Disturbed balance between accumulation and degradation of modified forms.
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Protein Glycosylation (non enzymatic) Causes aging of long lived proteins Such as: Collagen Crystallin
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Inactivation by glycosylation occurs in proteins with lysine in critical location Superoxidismutase Ribonuclease Na+, K+-ATPase Experimentally inactivated when incubated in glucose
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Final products of glycosylaton called Advanced Glycosylation Endproducts (AGE) Free radicals induce formation and accumulation of AGE ANTIOXIDANTS inhibit protein glycation And accumulation of AGE
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With increasing age and glucose concentration accumulation of AGE in plasma and vessel walls cause many diabetic complications (cataract, atherosclerosis)
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Other type of protein modification due to oxidative stress is formation of protein-protein Cross Links caused mainly by disulfide bonds
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Mitochondrial Dysfunction
ROS generated during aging Chronic oxidative damage to Electron Transport System (ETS)
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Caloric Restriction (CR) Since major endogenous source of ROS is mitochondrial respiration, CR markedly reduces production of Superoxide and H2O2 Effect of CR most striking in brain
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Reference: OXYGEN RADICALS and the DISEASE PROCESS Thomas, C.E., Kalyanaraman, B. eds Harwood academic publishers
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