The INDIVIDUALIST

A Wiki about biochemical individuality

Biochemistry

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Description

An organism is said to experience oxidative stress when the effects of prooxidants (e.g. free radicals, reactive oxygen and reactive nitrogen species) exceed the ability of antioxidant systems to neutralize them.

Discussion

Oxidative stress is a medical term for damage to animal or plant cells (and thereby the organs and tissues composed of those cells) caused by reactive oxygen species, which include (but are not limited to) superoxide, singlet oxygen, peroxynitrite or hydrogen peroxide. It is defined as an imbalance between pro-oxidants and anti-oxidants, with the former prevailing. Superoxide, is produced deleteriously by 1-electron transfers in the mitochondrial electron transfer chain. Other enzymes capable of producing superoxide are xanthine oxidase, NADPH oxidases and cytochrome P450(s). Hydrogen peroxide is produced by a wide variety of enzymes including monoxygenases and oxidases.

Reactive oxygen species may also play a role in cell signalling. Oxidative stress is known to contribute to tissue injury following irradiation and hyperoxia and is thought to be a cause of neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease, Alzheimer's disease and Huntington's disease. Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the endothelium is a precursor to plaque formation. However treatment in this area of medicine is sometimes controversial, as clinical trials with the antioxidant vitamin E have failed to demonstrate a clear beneficial effect. It did shown that vegetable rich in vitamin E is beneficial to neurodegenerative disease. However, epidemiological evidence suggests that vitamin E supplementation decreases the incidence of ALS and Alzheimer's.

Oxidative stress (as formulated in Harman's free radical theory of aging) is also thought to contribute to the aging process. While there is rather strong evidence to support this idea in the model organism Drosophila melanogaster, the evidence in mammals is contradictory.

Metal catalysts

Metals such as iron, copper, chromium, vanadium and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes reactions that produce reactive radicals and can produce reactive oxygen species such as hydroxyl radical in reactions like Fenton's reaction. The hydroxyl radical then can lead to modifications of amino acids (e.g. meta-tyrosine and ortho-tyrosine formation from phenylalanine), carbohydrates, initiate lipid peroxidation. Most enzymes that produce reactive oxygen species contain one of these metals. The presence of such metals in biological systems in an unsequestered form (not in an enzyme or other protein) can significantly increase the level of oxidative stress.

Free Radicals

In chemistry, Radicals (often referred to as free radicals) are atomic or molecular species with unpaired electrons on an otherwise open shell configuration. These unpaired electrons are usually highly reactive, so radicals are likely to take part in chemical reactions. Radicals play an important role in combustion, atmospheric chemistry, polymerization, plasma chemistry, biochemistry, and many other chemical processes, including human physiology.

A free radical is a molecule inside a cell that has an unpaired electron. It steals an electron from a neighboring molecule, and while the free radical become more stable, it creates a reactive oxygen species (ROS) from the molecule it stole the electron from. ROS are species such as superoxide, hydrogen peroxide, and hydroxyl radical.

This new ROS steals an electron from a neighboring molecule, thus starting an ionic chain reaction, eventually causing molecular rearrangement and damage to the cell as a whole. Free radicals are also produced inside organelles, such as the mitochondria. The mitochondria create energy for the cell by producing adenosine triphosphate (ATP). In the cycle of production of the ATP, the third step of reattaching a phosphate group to the adenosine diphosphate to create adenosine triphosphate, is called the electron transport chain. In the electron transport chain, electrons are passed down a series of proteins which lower the energy of an electron so it can be safely harnessed by the mitochondria. The third protein in the electron transport chain is called Coenzyme Q. This “protein” is in fact not a protein at all, but a lipid. One out of every twenty times an electron passes through this lipid in the electron transport chain, the electron is accidentally released and it becomes attached to an oxygen molecule, giving this electron an extra unpaired electron. This oxygen molecule, O2- is known as superoxide. Superoxide needs an additional electron to make it more stable, so it steals an electron from the nearest source, either the [mitochondrial DNA]? or the mitochondrial membrane. If too much damage is caused to the mitochondrion, it goes through apoptosis, or programmed cell death.

Free radicals in biology

Free radicals play an important role in a number of biological processes, some of which are necessary for life, such as the intracellular killing of bacteria by neutrophil granulocytes. Free radicals have also been implicated in certain cell signalling processes. The two most important oxygen-centered free radicals are superoxide and hydroxyl radical. They are derived from molecular oxygen under reducing conditions. However, because of their reactivity, these same free radicals can participate in unwanted side reactions resulting in cell damage. Many forms of cancer are thought to be the result of reactions between free radicals and DNA, resulting in mutations that can adversely affect the cell cycle and potentially lead to malignancy. Some of the symptoms of aging such as atherosclerosis are also attributed to free-radical induced oxidation of many of the chemicals making up the body. In addition free radicals contribute to alcohol-induced liver damage, perhaps more than alcohol itself. Radicals in cigarette smoke have been implicated in inactivation of alpha 1-antitrypsin in the lung. This process promotes the development of emphysema.

Free radicals may also be involved in Parkinson's disease, senile and drug-induced deafness, schizophrenia, and Alzheimer's. The classic free-radical syndrome, the iron-storage disease hemochromatosis, is typically-associated with a constellation of free-radical-related symptoms including movement disorder, psychosis, skin pigmentary melanin abnormalities, deafness, arthritis, and diabetes. The free radical theory of aging proposes that free radicals underly the aging process itself.

Mechanisms of free radical damage

Because free radicals are necessary for life, the body has a number of mechanisms to minimize free radical induced damage and to repair damage which does occur, such as the enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. In addition, antioxidants play a key role in these defense mechanisms. These are often the three vitamins, vitamin A, vitamin C and vitamin E and polyphenol antioxidants. Further, there is good evidence bilirubin and uric acid can act as antioxidants to help neutralize certain free radicals. Bilirubin comes from the breakdown of red blood cells' contents, while uric acid is a breakdown product of purines. Too much bilirubin, though, can lead to jaundice, which could eventually damage the central nervous system, while too much uric acid causes gout.

Bcl-2 proteins are layered on the surface of the mitochondria, detect damage, and activate a class of proteins called Bax, which punch holes in the mitochondrial membrane, causing cytochrome C to leak out. This cytochrome C binds to Apaf-1, or apoptotic protease activating factor-1, which is free-floating in the cell’s cytoplasm. Using energy from the ATPs in the mitochondrion, the Apaf-1 and cytochrome C bind together to form apoptosomes. The apoptosomes binds to and activates caspase-9, another free-floating protein. The caspase-9 then cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and eventually phagocytosis of the cell.

Free radicals and aging

According to the Free Radical theory of aging, aging occurs in a cell when mitochondria begin to die out because of free radical damage. The focus of the project is to neutralize the effect of these free radicals with antioxidants. Antioxidants neutralize free radicals by donating one of their own electrons, ending the ionic reaction. The antioxidant nutrients themselves don’t become free radicals by donating an electron because they are stable in either form.

Superoxide dismutase (SOD) is formed in two places naturally in the cell. SOD that is formed in the mitochondria contains manganese (MnSOD). This SOD is formed in the matrix of the mitochondria. SOD that is formed in the cytoplasm of the cell contains copper and zinc (CuZnSOD). The genes that control the formation of SOD are located on chromosomes 21, 6, and 4. When superoxide dismutase comes in contact with a superoxide ROS, it reacts with the superoxide and forms hydrogen peroxide. This hydrogen peroxide is dangerous in the cell because it can easily transform into a hydroxyl radical, one of the most destructive free radicals. Catalase, which is concentrated in peroxisomes located next to mitochondria but formed in the rough endoplasmic reticulum and located everywhere in the cell, reacts with the hydrogen peroxide and forms H20 and 02. Glutathione peroxidase reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a very small sulfur containing protein called glutathione. The selenium contained in the enzymes acts as the reactive centre, carrying reactive electrons from the peroxide to the glutathione.

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