1. Biokim Prof Rondang - Oxygen Radicals & Aging

8/12/2019 1. Biokim Prof Rondang - Oxygen Radicals & Aging

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OXYGEN RADICALSand AGING

Rondang R. Soegianto

2009


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Oxidative Damage and Aging are

two processes commonly found

in eukaryotic organisms


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ENERGY, essential for life processes

In humans,

Electron Transport System (ETS) in

mitochondria is main mechanism for

aerobic energy supply


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ATP = Energy currency of the cell

Produced in mitochondria via

Oxidative Phosphorylation (OXPHOS)

Oxidation processes in living systems are

catalyzed by class I enzymes:

OXIDOREDUCTASES


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Oxidoreductases (Harper 26th)

1. Oxidases: A Containing Cu

B As flavoproteins

2. Dehydrogenases:

A. NAD+ or NADP+ as coenzymeB Flavin as coenzyme

C Cytochromes (Fe-porphyrin as coenzyme)

3. Hydroperoxidases:

A PeroxidaseB Catalase

4. Oxygenases:

A Dioxigenase

B Monooxigenase


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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 inmitochondria

B. Flavoproteins, contain FMN or FAD

Ex. : L-aminoacid oxidase

Xanthine oxidaseAldehyde dehydrogenase


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3. Hydroperoxidases use H2O2as substrate

A. Peroxidase reduces peroxides using various e-acceptors

H2O2 + AH2 2 H2O + A

In erythrocytes and other tissues:

H2O2 + 2 GSH GSSG + H2O

GSH = Reduced gluthatione

Glutamyl-cysteinyl-glycine (a tripeptide)-SH = Reducing group of cysteine residue

Peroxidase

Gluthatione peroxidase


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B. Catalase

Hemoprotein with 4 heme groups

2 H2O2 2 H2O + O2

Found in: Blood, bone marrow, mucous

membranes

Kidney, liver

Catalase destroys peroxides formed by oxidases

Catalase


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Free radicals

Transfer of a single e to O O (superoxide anion)Can damage membranes, DNA, etc.

Destructive effects

Amplified by: Free radical chain reaction

Removed by: Superoxide dismutase (SOD) in the reactions

O + O 2H H O + O

H O 2H O + OCatalase22 2

-2

-2 + 2 2SOD

2 2

2

- 2 2 -


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Mitochondria

Make > 90% of cellular ATP

Powerplant of the cell

Four Compartments

Matrix has numerous enzymes that reduceNAD+to NADH during catabolism of foodstuffs

Inner Membrane has:

Proteins that transfer electrons (the ETS)

ATP synthase

Intermembrane Space

Outer Membrane


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Faces of mitochondrial membrane (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 :

ROS does not destroy collagen directly

ROS induces synthesis ofMatrix Metalloproteinase (MMP)

that attacks connective tissues

Therapy targeted at possible MMP inhibitors


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Effect of ROS ona. 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 betweenaccumulation and degradation of

modified forms.


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Other type of age associated modification:

Protein Glycosylation

(non enzymatic)

Causes aging of long lived proteins

Such as: Collagen

Crystallin


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Glycosylation = Maillard reaction

Addition of carbohydrate to protein

Normally for protein secreted by cellor protein bound to cell surface

Hb can be glycosylated in blood glucose


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Final products of glycosylaton called

Advanced Glycosylation Endproducts (AGE)

Free radicals induce formation andaccumulation of AGE

ANTIOXIDANTS inhibit protein glycation

And accumulation of AGE


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With increasing age and glucoseconcentration

accumulation of AGE in plasmaand 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)

Resulting decrease in functional capacity

of cells and tissues during aging


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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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Kristal and Yu (1992)

Age related deterioration is produced

by the sum of the damage induced by

free radicals, by glycation (Maillard reaction)

and by their interactions.


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Reference:

OXYGEN RADICALS and the

DISEASE PROCESS

Thomas, C.E., Kalyanaraman, B. eds

Harwood academic publishers

Documents

1. Biokim Prof Rondang - Oxygen Radicals & Aging