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What are 5 examples of pathological processes that reactive oxygen species (ROS) are implicated in?

1) Inflammation
2) Carcinogenesis
3) Radiation damage
4) Reperfusion injury
5) Aging


What is reperfusion injury?

1) Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen
2) The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function


What are four examples of reactive oxygen species (ROS)?

1) Molecules like hydrogen peroxide (H2O2; a bleach)
2) Ions like the hypochlorite ion (OCl-; household bleach)
3) Radicals like the hydroxyl radical (OH)
4) The superoxide anion (O2-), which is both an ion and free radical


What is a free radical (radical)?

1) A radical is a cluster of atoms, one of which contains an unpaired electron in its outermost shell of electrons
2) This is an extremely unstable configuration, causing radical to react quickly with other molecules or radicals to achieve the stable configuration of paired electrons in their outermost shell


How are reactive oxygen species formed?

1) Cellular respiration: ROS formed as an unavoidable byproduct of cellular respiration. Some electrons passing "down" the respiratory chain leak away from the main path (especially as they pass through ubiquinone) and go directly to reduce oxygen molecules to the superoxide anion
2) Ionizing radiation: the interaction of ionizing radiation with biological molecules can produce ROS
3) Long Chain Fatty Acid metabolism: In very long chain fatty acid metabolism in peroxisomes, the FADH2 formed is oxidized with the formation of hydrogen peroxide


Where are the dedicated enzymes that synthesize reactive oxygen species (ROS) found?

These enzymes are found in phagocytic cells like neutrophils & macrophages


What are two examples of enzymes found in phagocytes?

1) NADPH oxidase (in both type of phagocytes):
2O2 + NADPH --> 2O2- + NADP+ + H+
2) Myeloperoxidase (in neutrophils only)
H2O2 + Cl- --> OCl- + H2O


What is the function of catalase?

Catalase catalyzes the decomposition of hydrogen peroxide to water and oxygen


What is the function of glutathione peroxidase?

The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water


What is the function of superoxide dismutase?

Superoxide dismutases are enzymes that catalyze the dismutation of superoxide (O2−) into oxygen and hydrogen peroxide


What is are two specific examples that can cause reduction of O2 to form O2-?

1) When ubiquinone in the ETC contains an extra electron, it can donate it to O2 to form O2-. This reaction is dependent on if Complexes 1 and 3 are able to maintain ubiquinone in the reduced state (extra electron)
2) An enzyme called xanthine oxidase (used in purine metabolism, on the way to forming uric acid) can oxidize hypoxanthine to xanthine, resulting in the reduction of O2 to O2-


What does superoxide inactivate?

1) Aconitase is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process
2) The active form of aconitase contains 4 iron atoms and 4 sulfur atoms. The inactive form of aconitase contains 3 iron atoms and 4 sulfur atoms.
3) The iron sulfur cluster in aconitase is highly sensitive to oxidation by superoxide, resulting in the loss of an Fe2+ ion


Describe the steps of the Fenton reaction

1) Fenton's reagent is a solution of hydrogen peroxide and an iron catalyst that is used to oxidize contaminants or waste waters
2) Iron(II) is oxidized by hydrogen peroxide to iron(III), forming a hydroxyl radical and a hydroxide ion in the process
Fe2+ + H2O2 --> Fe3+ + OH + OH-
3) The hydroxyl is a powerful, non-selective oxidant that partakes in secondary reactions
4) Oxidation of an organic compound by Fenton's reagent is rapid and exothermic and results in the oxidation of contaminants to primarily carbon dioxide and water


What is one of the most important and common actions that cause damage to molecules and cell structures?

1) Strong oxidants can damage other molecules and cell structures of which they are a part of
2) Among the most important of these actions are on the fatty acid side chains of lipids in the various membranes of the cell, especially mitochondrial membranes (which are directly exposed to the superoxide anions that are produced in the mitochondria during cellular respiration)


How does a hydroxyl radical damage fatty acid chains?

1) A hydroxyl radical removes a hydrogen atom from one of the carbon atoms in a fatty acid chain forming a molecule of water and leaving the carbon atom with an unpaired electron (a radical)
2) It will then most likely react with a molecule of oxygen forming a peroxyl radical
3) The peroxyl radical may then steal a hydrogen atom from a nearby fatty acid side chain making it a radical
4) This chain reaction will propagate until two radicals meet each other and covalently bond together
5) This process deforms and damages lipid membranes


What is lipofuscin?

1) Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion
2) It is considered to be one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, retina, adrenals, nerve cells, and ganglion cells
3) It appears to be the product of the oxidation of unsaturated fatty acids, and may be symptomatic of membrane damage, or damage to mitochondria and lysosomes


What are bodily defenses against reactive oxygen species (ROS)?

1) Superoxide dismutase (SOD) - converts two superoxide anions into a molecule of hydrogen peroxide and one of oxygen
2) Catalase
3) Antioxidants:
a) Alpha-tocopherol (Vitamin E) - can break the covalent links that ROS have formed between fatty acid side chains in membrane lipids
b) uric acid
c) Vitamin C (in the right concentration) - can be a pro-oxidant in high concentrations
d) beta-carotene
e) bilirubin
f) glutathione


What is an important function of reactive oxygen species (ROS) in the thyroid?

The cells of the thyroid gland must make hydrogen peroxide in order to attach iodine atoms to thyroglobulin in the synthesis of thyroxine


What is an important functions of reactive oxygen species (ROS) in macrophages and neutrophils?

1) Macrophages and neutrophils must generate ROS in order to kill some types of bacteria that they engulf by phagocytosis. 2) Bacteria are engulfed into a phagosome, which fuses with a lysosome
3) Subunits of the enzyme NADPH oxidase assemble in the lysosome membrane forming the active enzyme. It catalyzes the synthesis of the superoxide anion
4) This activity produces a large increase in oxygen consumption called the "respiratory burst"
5) Superoxide dismutase (SOD) converts superoxide into hydrogen peroxide, which kills off the engulfed bacteria (except those that manufacture enough catalase to protect themselves)
6) Neutrophils (but not macrophages) also kill off engulfed pathogens by using the enzyme myeloperoxidase which catalyzes the reaction of hydrogen peroxide (made from superoxide anions) with chloride ions to produce the strongly antiseptic hypochlorite ion (OCl-)


How is nitric oxide (NO) produced?

NO synthase oxidizes NADPH to NADP+ in order to reduce O2 to NO


What is an important function of nitric oxide (NO) in the body relating to ROS?

Mediates tumoricidal and bactericidal actions of macrophages


What causes Chronic Granulomatous Disease (CGD)?

1) It is caused by a defective gene for one of the subunits of NADPH oxidase
2) The gene most frequently mutated in CGD is on the X chromosome, thus principally affecting males
3) Up to 50% of females who are carriers of the mutant allele do not make active NADPH oxidase when they engulf pathogens due to inactivation of the X chromosome with the nonmutant allele


What are problems associated with Chronic Granulomatous Disease (CGD)?

1) People with CGD have a difficult time ridding themselves of bacterial infections - especially those cause by bacteria that produce catalase to protect themselves against the hydrogen peroxide generated by the macrophages and neutrophils that engulf them
2) Often the result is the development of a persisting nest of infected cells called a granuloma


What is Amyotrophic Lateral Sclerosis (ALS)?

1) Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons, leading to progressive and eventually complete paralysis without loss of cognitive function
2) ALS is the most common motor neuron disease in adults
3) ALS is fatal within one to five years after onset
4) Onset usually occurs in mid-life
5) Two forms of ALS with slightly different pathologies exist:
a) Familial - earlier onset
b) Sporadic - constitutes the vast majority of cases


What causes Amyotrophic Lateral Sclerosis (ALS)?

1) ALS is thought to be a protein misfolding disease, a class including Alzheimer's, Parkinson's, & Huntington's diseases, in which protein aggregation is considered the underlying pathology
2) Similarly, proteinaceous intracellular aggregates, or inclusions (inclusion bodies), are a prominent feature in both the sporadic and familial forms of ALS


What mutation occurs to allow protein misfolding in ALS?

1) Mutations in the SOD1 gene, whose product is CuZnSOD, are associated with around 20% of familial ALS cases and comprise the primary known cause of ALS
2) There are two general categories of ALS mutant CuZnSOD proteins: "wild-type-like" mutants, which have similar levels of metal ion levels to wild type CuZnSOD, and "metal-binding-region" mutants, which include mutations in the metal binding ligands themselves or with regions associated with metal binding
3) Evidence supports the claim that SOD1 mutations are inherited in an autosomal dominant manner