Path 10: Free Radicals

what are free radicals

unstable chemical species with a single unpaired electron in an outer orbital, making it highly reactiive

what do free radicals do?

attack other molecules by stealing an electron (oxidation) or donating an electron (reduction)

endogenous free radicals

from cellular oxidative processes

exogenous free radicals

sunlight, gamma irradiation, pollution, cigarette smoke, drugs, alcohol, heavy metal

reactive oxygen species

-can be radicals or not
-

O2 accepts 4 electrons

-to become H2O

what is the most reactive oxygen species?

Hydroxyl radical (OH)

Haber-Weiss reaction

O2- + H2O2 -----> more reactive OH radical

polyunsaturated fatty acids are most prone to what?

lipid peroxidation
-bc they have unsaturateed double bonds that react with free radical

lipid peroxidation

the destruction of polyunsaturated lipids, leading to membrane damage and increased permeability

oxidative damage of proteins

-affects tertiary, quaternary structure as well as enzymatic function
-can change function, stability, localization; can lead to increased proteasomal degradation

Oxidation of Aldehydes and Ketones

-When aldehydes are further oxidized, they form carboxylic acids (any oxidizing agent stronger than PCC)

-ketones cannot be oxidized further

oxidative damage of DNA

OH free radical can attack DNA, causing strand breaks and mutation, leading to carcinogenesis

formation of 8-oxyguanine

-example of oxidative damage to DNA
-can cause mismatching in base-repair and replication, can cause G--> transversion

beneficial use of free radicals

-neutrophils and macrophages use free radicals to kill bacteria
-however, this can cause extra damage to the infected tissue

-signaling associated with angiogenesis

how do neutrophils/macrophages kill bacteria?

-they use free radicals!
-increased O2 uptake generates O2- by NADPH oxidase into phagosome......

Angiogenesis

formation of new blood vessels

how is free radical production balanced?

antioxidant defense system; imbalance leads to oxidative stress

Antioxidant defense system

includes superoxide dismutase, glutathione peroxidase, glutathione reductase, and physiological compounds that are anti-oxidants

mild oxidative stress leads to

cellular adaptation, excess stress leads to damage to biomolecules

what biomoelcues work to detoxify ROS?

enzymes and anti-oxidants

Vitamin E

can give a hydrogen atom to neutralize a radical
-is fat soluble, thus can protect membranes from lipid peroxidation
-can be regenerated by vitamin C

disorders with pro-oxidative shift

cancer, Diabeetus M, acetaminophen poisoning, retinopathy of prematurity, iron and copper overload, carbon tetrachloride

leading cause of blindness in babies

retinoptathy
-treatment of RDS in newborns destroys retinal cells, leading to blindness

disorders with inflammatory oxidative conditions

atherosclerosis, neurodegenerative disease, rheumatoid arthritis, HIV, ischemia, sleep apnea