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How do catalase and other antioxidants neutralize free radicals?

How do catalase and other antioxidants neutralize free radicals?


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In learning about how cofactors are essential to proper enzyme function, my textbook mentioned catalase and its relation to the human body. According to my textbook, catalase is similar to hemoglobin in that it has 4 hemes which cradle an Fe (iron) atom; the iron atom is used to neutralize free radicals when it "pulls on the substrate's electrons, which brings on the transition state" after catalase is holding a substrate in its active site. I already know that free radicals have one or more unpaired electrons which make them dangerous as they "seek out" an electron to complete its pair on any molecule, atom, or ion it can find, perhaps causing significant tissue damage in the process. I also know that the transition state is a key point in a reaction in which the activation energy required has been met and the reaction will continue spontaneously until it ends.

My question is, what exactly is happening here that helps to neutralize a free radical, and what is the part after the transition state doing?

If I had to guess, based on that cofactors generally can be affected during a reaction, perhaps Iron somehow binds with the free radical and share its electrons, effectively neutralizing the unpaired electron as well as using up the Iron atom? I imagine the "pulling" in the book could fit a description of a weak chemical bond/attraction, but I'm still unsure.


Catalase (hydrogen peroxide oxidoreductase) does not actually quench free radicals. It catalyzes the conversion of hydrogen peroxide to water; the former is a source of a free radical, not a free radical in itself.

This is the proposed mechanism of action of catalase: First one of the oxygens is deprotonated by at the active site of the enzyme. Then the Iron atom that is bound to heme forms a co-ordination complex with the deprotonated oxygen and pulls it away from the other oxygen. As a result the O-O bond breaks.

Free radical quenchers/antioxidants react with the free radicals and form non-toxic products.


The Role of Oxidative Stress in Endometriosis

Aditi Mulgund MD , . Ashok Agarwal PhD , in Handbook of Fertility , 2015

Antioxidants

Antioxidants are a defense mechanism produced by the body to neutralize the effects of ROS. They can be enzymatic and nonenzymatic. Nonenzymatic sources of antioxidants include vitamin C, vitamin E, selenium, zinc, beta carotene, carotene, taurine, hypotaurine, and glutathione. Enzymatic antioxidants include SOD, catalase, glutaredoxin, and glutathione reductase [64] . However, as the body ages, antioxidant levels decline, resulting in a disruption in the balance between antioxidants and prooxidant molecules. This results in the generation of oxidative stress and in turn, overrides the scavenging capacity by antioxidants either due to the diminished availability of antioxidants or excessive generation of ROS. Therefore, supplementation with oral oxidants may help to alleviate oxidative stress and its contribution to the pathogenesis of obstetrical disease such as endometriosis [65] . Only the most relevant antioxidants beneficial to endometriosis will be discussed.


How do catalase and other antioxidants neutralize free radicals? - Biology

In a previous post, we discussed the concept of oxidative stress and the association that it can have with numerous health concerns. It is also important to understand how the body controls free radicals and prevents oxidative stress from occurring. To review – we know that oxidative stress is the burden on the body as a result of an overproduction of free radicals. This occurs when the control mechanisms of the body that counter free radicals aren’t able to maintain a proper balance. The cause of this imbalance is often attributed to a stressor such as an immune reaction or environmental exposure. It is important to note that free radicals do not always have negative effects on the body a problem only arises when the amount of free radicals is high enough to outweigh the body’s normal antioxidant defenses.

Figure 1: SOD converts free radicals to hydrogen peroxide. Catalase then degrades hydrogen peroxide into water and oxygen with the help of a variety of other enzymes and vitamins.

The body has several ways to deal with an excess of free radicals. The first line of defense includes the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase, and catalase. These enzymes help rid the body of free radicals by converting them into water and oxygen (Figure 1). After oxygen becomes a free radical, SOD converts it into hydrogen peroxide, then catalase and glutathione peroxidase continue the conversion into water and oxygen.

The enzymes discussed above are the first line of defense against free radicals. Their optimal function is dependent on certain antioxidants and mineral cofactors derived from the diet. Polyphenols, vitamins E and C, coenzyme Q10, and glutathione support the antioxidant enzymes. The body makes every effort to minimize the negative effects of free radicals by relying on its own enzymes, as well as antioxidants from the diet. Deficiencies in either of these defense systems can lead to a wide variety of oxidative stress-related clinical symptoms and conditions.

Guest author: Deanna Fall is currently a scientific writer and research analyst for NeuroScience, Inc. and holds a bachelor’s degree in biology from Ferris State University in Big Rapids, Michigan and a master’s degree in health informatics at the University of Minnesota. Deanna joined NeuroScience in 2009 with experience in pharmaceutical research and development in the field of neurotoxicology.


Probing Question: How do antioxidants work?

Blueberries, pomegranates, green tea, and dark chocolate—these are just some of the antioxidant-rich "superfoods" found in almost any supermarket today. As well as improving our general health, there is growing evidence that diets high in antioxidants may confer some protection against a long list of chronic diseases, including Alzheimer's disease, cancer, and even HIV. Given their increasing popularity, the fundamental question bears asking: What exactly are antioxidants, and how do they work in our bodies?

Antioxidants come in several forms, including the vitamins A, C, and E plant-derived polyphenols, found in colorful fruits and vegetables and also the element selenium, found in nuts and broccoli. "What these compounds share," explains K. Sandeep Prabhu, Penn State assistant professor of immunology and molecular toxicology, "is the ability to neutralize harmful molecules in our cells."

These harmful molecules, known as free radicals, contain unpaired electrons—which is unusual because electrons typically come in pairs. "The unpaired electrons make free radicals highly reactive, and in this state, they can cause damage by attacking the components of our cells, and can even cause cancer," Prabhu says.

So where do free radicals come from? Some are created as a natural by-product of reactions in our cells, says Prabhu. Other sources of free radicals include cigarette smoke, air pollution, and exposure to UV light or radiation. And once free radicals are formed, they can make more free radicals by scavenging electrons from other molecules, "creating a domino effect," he adds.

Antioxidants neutralize free radicals either by providing the extra electron needed to make the pair, or by breaking down the free radical molecule to render it harmless. "Antioxidants stop the chain reaction of free radical formation and benefit our health by boosting our immune system ," explains Prabhu. Because antioxidants are used up in the process of free radical neutralization, a diet rich in antioxidants is essential to ensure a constant supply.

Research has shown that antioxidants can have an important impact on serious diseases. In one recent study, the addition of a polyphenol-rich blueberry gel to the diet of oral cancer patients prevented recurrence of the cancer. Another experiment demonstrated that increased levels of selenium in the diets of a group of HIV-positive patients significantly delayed progression of the disease.

In light of these impressive results, should everyone be taking antioxidant diet supplements? Prabhu warns that there can be too much of a good thing: "As with most things, excessive levels of antioxidants can be toxic." Furthermore, he stresses, "We don't yet fully understand the mechanisms by which selenium and other antioxidants work, and so we must be cautious about prescribing diets high in these elements." In the Prabhu Lab, work is currently underway to discover how selenium works, with the goal of introducing selenium as a therapy for HIV.

The take-home message? A diet containing a balance of the various forms of antioxidants will maintain overall good health, and could even impact serious diseases. For instance, the American Cancer Society encourages people to eat five servings of fruits and vegetables per day, and emphasizes the benefits of getting your antioxidants through foods rather than supplements. Prabhu himself makes sure he gets the recommended daily allowance of selenium by eating a few brazil nuts everyday. "The key," says Prabhu, " is to eat a variety of fruits, vegetables, and nuts to ensure that we are taking advantage of all the health benefits that antioxidants can provide."


3. Damaging reactions of free radicals

The general process of lipid peroxidation can be envisaged as depicted bellow (eqn (8)–(11)), where LH is the target PUFA and R˙ is the initializing, oxidizing radical. Oxidation of the PUFA generates a fatty acid radical (L˙) (eqn (8)), which rapidly adds oxygen to form a fatty acid peroxyl radical (LOO˙, eqn (9)). The peroxyl radicals are the carriers of the chain reactions. The peroxyl radicals can further oxidize PUFA molecules and initiate new chain reactions, producing lipid hydroperoxides (LOOH) (eqn (10) and (11)) that can break down to yet more radical species. 17

LH + R˙ → L˙ + RH (8)
L˙ + O2 → LOO˙ (9)
LOO˙ + LH → LOOH + L˙ (10)
LOOH → LO˙ + LOO˙ + aldehydes (11)

Lipid hydroperoxides always break down to aldehydes. Many of these aldehydes are biologically active compounds, which can diffuse from the original site of attack and spread the attack to the other parts of the cell. 18,19 Lipid peroxidation has been widely associated with the tissue injuries and diseases. 20

Oxygen metabolism generates ˙OH, O2˙ , and the non-radical H2O2. The ˙OH is highly reactive and reacts with biological molecules such as DNAs, proteins, and lipids, which results in the chemical modifications of these molecules. There are several research reports on the oxidative damage of DNA due to the ˙OH. 21–23

The ˙OH reacts with the basepairs of DNA, resulting in the oxidative damage of the heterocyclic moiety and the sugar moiety in the oligonucleotides by a variety of mechanisms. This type of oxidative damage to DNA is highly correlated to the physiological conditions such as mutagenesis, carcinogenesis, and aging. 24,25 The addition reactions yield OH-adduct radicals of DNA bases (Scheme 1), whereas the allyl radical of thymine and carbon-centered sugar radicals (Scheme 2) are formed from the abstraction reactions.

As shown in the Scheme 1, the ˙OH reacts with the guanine of the DNA to produce the C-8-hydroxy-adduct radical of guanine, which is converted to the 2,6-diamino-4-hydroxy-5-formamidopyrimidine upon reduction and ring opening reactions. However, the C-8-hydroxy-adduct radical of guanine is converted to the 8-hydroxyguanine upon oxidation reaction. The ˙OH radical reacts with the heterocyclic moiety of the thymine and cytosine at C5- and C6-positions, resulting in the C5–OH and C6–OH adduct radicals, respectively. The oxidation reaction of these adduct radicals with water (followed by deprotonation) results in the formation of the cytosine glycol and thymine glycol, respectively. 26 Overall, the reactions of the ˙OH with the DNA bases result in the impaired dsDNA.

As shown in the Scheme 2, the ˙OH reacts with the sugar moiety of DNA by abstracting an H-atom from rom C5 carbon atom. One unique reaction of the C5′-centered radical of the sugar moiety in DNA is the addition to the C8-position of the purine ring in the same nucleoside ( e.g. guanine). This intramolecular cyclization results in the formation of the 8,5′-cyclopurine-2′-deoxynucleosides. The reactions of carbon-centered sugar radicals result in the DNA strand breaks and base-free sites by a variety of mechanisms.

Proteins are oxidatively damaged by the combined action of activated oxygen species and the trace metal ions such as Fe 2+ and Cu 2+ . The amino acid's lysine, proline, histidine, and arginine have been found to be the most sensitive to oxidative damage. Recent studies indicate that, a wide range of residue modifications can occur including formation of peroxides, 27,28 and carbonyls. 29 Generation of the carbonyl residue is a useful measure of oxidative damage to proteins. Thus, the oxidative damage to tissue results in the increased amount of oxidized protein. A detailed review by Cooke et al. provides important informations on the oxidative DNA damage, mechanisms, mutations, and related diseases. 30

Low levels of antioxidants have been associated with the heart disease and cancer. 31,32 Antioxidants provide protection against a number of disease processes such as aging, allergies, algesia, arthritis, asthma, atherosclerosis, autoimmune diseases, bronchopulmonary dyspepsia, cancer. The other disorders to which antioxidants provide protection are cataract, cerebral ischemia, diabetes mellitus, eczema, gastrointestinal inflammatory diseases, genetic disorders. 33 Following section elaborates the mechanism of action of the radical scavenging activities of various natural antioxidant molecules.


Mechanisms of cell signaling mediated by ROS/RNS

Cells communicate with each other and respond to extracellular stimuli through biological mechanisms called cell signalling or signal transduction. Signal transduction is a process enabling information to be transmitted from the outside of a cell to various functional elements inside the cell [37]. A biochemical basis for transducing extracellular signals into an intracellular event has long been the subject of enormous interest. Being initiators, transmitters, or modifiers of cellular response, free radicals occupy a significant place in the complex system of transmitting information along the cell to the target sensor. The effects of most extracellular signals are promoted via receptor ligation on either cell surface or cytoplasmic receptors. However, some low-molecular-weight signaling molecules, such as ROS/RNS, are able to penetrate the plasma membrane and directly modulate the activity of catalytic domain of transmembrane receptors or cytoplasmic signal transducing enzymes, thus leading to abnormal activation of transcription factors. By the initiation of gene expression and the consequent synthesis of responding functional and structural proteins, ROS/RNS allow for adaptation and survival of the cell or, depending on the intensity and duration of the signal, activate the processes responsible for the cell damage or death [38, 39]. In a given signaling protein, oxidative attack induces either a loss of function or a gain of function or a switch to a different function. The effect of ROS/RNS on the process of cell signaling is promoted through a number of simultaneous mechanisms and, most commonly, by activating an extensive network of various interactive intracellular signal transduction pathways (Fig. 2). The ability of oxidants to act as second messengers is a significant aspect of their physiological activity. The incorporation of free radicals into a complex cascade of transducing the signal to the effectors modifies and alters the order of events: numerous second messengers acquire the properties of third messengers, while intermediaries of free radical activity often function in both initiating and terminating signal transduction. These sequential events ultimately lead to either normal cell proliferation or development of cancer inflammatory conditions, aging, and two common agerelated diseases – diabetes mellitus and atherosclerosis [40–43].

Some cellular signaling pathways in mammals. Under normal conditions (elevated intracellular reduced potential), nuclear factor erythroid 2-related factor 2 (Nrf2) is stabilized through binding to Keap-1 in the cytoplasm. Under oxidative/nitrosative stress, thiol groups in Keap-1 are oxidized (e.g., S-S cross-links) causing the dissociation of Nrf2, translocation to the nucleus, and binding to the antioxidant-responsive elements (ARE). Depending upon the binding site present in the promoter region, different antioxidant genes are induced


Where Do Free Radicals Come From?

It is impossible to completely avoid damage from free radicals. They arise from sources inside (endogenous) and outside (exogenous) your body. Oxidants that develop from processes within your body form as a result of normal breathing, metabolism, and inflammation.

Exogenous free radicals form from environmental factors like pollution, sunlight, strenuous exercise, smoking, and alcohol. Unfortunately, no antioxidant system is perfect. So, cells and DNA damaged by oxidation accumulate as you age. A healthy diet and lifestyle can help minimize this damage.


Antioxidants

I missed answering AskTheScienceBlogger question for a few weeks now, so let me take a quick stab at the latest one:

What's an antioxidant, and why are they healthful? I thought oxygen was supposed to be good for you!

Not that I know too much about this but I should, as the molecule central to my area of research is melatonin which is one of the most powerful antioxidants normally produced in our bodies. I do mention antioxidants when I teach the Intro Bio lab, so I know the very basic, textbook stuff, as I wrote here:

Then I explained in quite a lot of detail what happens in the mitochondria, i.e., starting with food being digested and broken down to glucose, glucose being broken down via glucolysis and Krebs cycle, the electron transfer cascade from one cytochrome to the next with the final recipient being oxygen, and the resulting production of ATP.

As no machine is 100% efficient, there is some wobble in this mechanism as well, resulting in production of free radicals, one of which is hydrogen peroxide. Free radicals are implicated in cell damage and perhaps the process of aging. Catalase is the enzyme [tested in this lab excercise] that neutralizes free radicals and protects the cell from damage.

As every machine that transforms one form of energy into another is less than 100% efficient, some of the energy gets lost, mostly in the form of heat. Heat generated by the mitochondria in this process is what warms up our bodies and keeps our core body temperature more or less constant. Hormones, like thyroxine, can modulate the efficiency of the electron transfer [by opening pores in the mitochondrial membranes], thus modulate the amount of heat produced by the cells in out body, thus controlling thermoregulation.

The main point in answering the question as it is worded is that antioxidants are not anti-oxygen. Instead, they react with and neutralize other molecules (which all contain oxygen atoms) called free radicals.

Oxygen itself is OK, at least in the way our cells transport and sequester it. Without oxygen, there would be no electron transfer and all our cells would stop functioning due to severe lack of ATP - the currency of energy in living systems. Without oxygen our cells (and our whole bodies) suffocate. Alternate methods of ATP synthesis are not sufficient for the long-term needs of the cell.

But the process of glucose breakdown and synthesis of ATP is not 100% efficient. "Mistakes have been made" and instead of water, CO2 and ATP, the free radicals form. Those are highly reactive small molecules that react with anything and everything in sight, including many other important molecules in the cell, rendering them dysfunctional.

To prevent/minimize the constant wear-and-tear of the cells due to the presence of free radicals, organisms have evolved a variety of enzymes and other molecules that scavenge free radicals and neutralize them before they manage to do much damage. Catalase is one such enzyme. Melatonin is one such hormone. It is widely believed - but I do not know how true this is - that ingestion of strong antioxidants (Vitamin E, melatonin pills, etc.) helps the body fight free radicals and lessens the damage, thus slowing down some of the age-related changes in our cells.

The Wikipedia entry on antioxidants appears to be pretty good if you want more detailed information.


Flavay® Improves Endothelial Function and Boosts Nitric Oxide Levels

Nitric oxide is essential for normal blood circulation as it controls the muscular tone of blood vessels and regulates circulation and blood flow. However, nitric oxide is a free radical and excessive amounts of nitric oxide can be deadly to the cardiovascular system and actually contribute to heart disease and strokes, and many other apparently different disorders (such as arthritis, asthma and Alzheimer's disease). So, in order to have good circulatory health, the body must maintain the right balance of nitric oxide—and that's the role of Flavay®. (10,239,265,292,296)

Flavay® aids in production of endothelial nitric oxide which helps to dilate blood vessels and causes blood platelets return to their normal smooth condition. (10,239,265,292,296)

Flavay® is shown to improve vasodilation and mildly inhibit angiotensin-converting enzyme (ACE) by modulating nitric oxide metabolism in endothelial cells. (292,296)


Indoxyl Sulfate Generates Free Radicals, Decreases Antioxidant Defense, and Leads to Damage to Mononuclear Blood Cells

Indoxyl sulfate (IS) is a uremic toxin that has been associated with inflammation and oxidative stress as well as with the progression of chronic kidney disease (CKD). IS is a protein metabolite that is concentrated in the serum of CKD patients. IS is a well-known uremic toxin, but there are very few reports on the effect of IS on cells including mononuclear cells (MNCs). We hypothesized that a high concentration of IS in CKD patients may induce changes in redox balance in the in vitro cells exposed. In the present study, we investigated the effect of IS on free radical production, antioxidant capacity, and protein damage in the mononuclear blood cells. As already determined, the concentrations (0.2 or 1 mM) of IS used in this study do not affect the survival rate of MNCs. For both the concentrations of IS, there was an increase in superoxide and nitric oxide and a release of other reactive oxygen species (ROS) inside the cells, as measured using fluorescent probes. However, an increase in other ROS as indicated by H2DCF-DA was found only for 1 mM of IS. Moreover, a decrease in the non-enzymatic antioxidant capacity and an increase in the superoxide dismutase activity after incubation of the cells with IS were observed. Furthermore, we found an increase in the levels of carbonyl compounds and peroxides in the cells treated with both the concentrations of IS. The obtained results show that IS induces oxidative stress and a decrease in antioxidant defense in cells leading to lipid and protein damage.


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