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ROS

a group that includes radicals and also H2O2, which is not a radical, but can lead to hydroxyl radical (worst one) - they are formed during oxidative stress and need to be scavenged in order to prevent cell damage. they are formed on purpose in macrophages as defense mechanism

radical

molecule that has a single unpaired electron in an orbital. oxygen is a bi-radical

free radical

highly reactive radical capable of independent existence and it can initiate chain reactions with other molecules which is why they are dangerous

superoxide

anion radical - O2 + e- leads to O2•-. it is ALWAYS formed in mitochondria during the ETC (CoQ), cytosol by microsomal CYP, and peroxisomes by CYP

cytochrome

can only hold one e- at a time so when they move from one complex to the next, they tend to lose e-

radical scavengers

can be enyzmatic or nonenzymatic

nonenzymatic radical scavengers

vitamin C, vitamin E, and GSH. uric acid represents half of radical scavengers in the blood and lungs. also, melatonin and bilirubin have radical scavenging properties

superoxide anion radical

highly reactive and has limited lipid solubility and cannot diffuse far. superoxide dismutase isozymes are found in the extracellular space (needs Cu), cytosol (needs Zn and Cu), and mitochondria (needs Mn)

superoxide dismutase (SOD)

can use 2 superoxides at the same time as substrates (very efficient and very fast): O2•- + O2•- + 2H+ leads to H2O2 + O2

Amyotrophic Lateral Sclerosis (ALS)

deficiency of superoxide dismutase caused by a genetic defect of the SOD gene. it is a degenerative disease of both upper and lower motor neurons. leads to muscle weakness, fasciculation, atrophy, dysphagia, dysarthria, hyperreflexia

hydrogen peroxide (H2O2)

non-radical ROS formed as a product of SOD. it is also formed in many other reactions and needs to be scavenged. accumulation leads in the Haber-Weiss reaction or in the Fenton reaction to hydroxyl radicals

hydroxyl radical (OH•)

the most detrimental ROS, formed from H2O2 and either superoxide or ferrous iron, as wellas as from H2O during ionizing radiation:
H2O w/ionizing radiation -> OH• + H•

Haber-Weiss reaction

forms OH• from H2O2 with superoxide:
H2O2 + O2•- + H+ -> OH• + H2O + O2

Fenton reaction

forms OH• from H2O2 with ferrous iron:
H2O2 + Fe2+ -> OH• + OH- + Fe3+

catalase

scavenges H2O2 - contains heme and can use 2 hydrogen peroxides as substrates (most efficient, fast). 2 H2O2 lead to 2 H2O and O2

glutathione peroxidase (selenium)

scavenges H2O2 - needs glutathione and acts on hydrogen peroxide or on organic peroxides.
H2O2 + 2 GSH -> GSSG + 2 H2O
ROOH + 2 GSH -> GSSG + ROH

lipid peroxides

results from radical damage of unsaturated fatty acids in the phospholipid membranes. they are also formed in RBC membranes due to high oxygen pressure in the lungs - glutathione can reverse this process, otherwise the fatty acids are broken and shortened and the RBC plasma membranes "leak"

RBCs

contains the triad of G6PD, glutathione reductase, and glutathione peroxidase. they also contain superoxide dismutase and although they do not have peroxisomes, the contain catalase

diseases and damage related to ROS

very common - Alzheimer's disease, reperfusion injury, inflammatory disease, cancer

mitochondrial DNA

are more susceptible to ROS damage than nuclear DNA, as it does not have histones and it is also close to CoQ in mitochondria. severe damage of DNA, proteins and lipids can occur. some of it can be repaired. hydroxyl radicals can lead in proteins to cross-linking and fragmentation or to aggregates that are resistant to proteolysis. unrepaired lipid peroxidation leads to dysfunctional membranes

ROS formation

enhanced at high oxygen tension, like in supplemental oxygen for COPD patients. it is also enhanced by hypoxia, carbon monoxide poisoning, or ischemic reperfusion

free radical theory for aging

relates to the formation of liposuscin (age spots on the skin) due to advanced glycosylation and lipoxidation end products (AGE's)

GSH

needed for glutathione peroxidase and levels decrease w/age

maximum human lifespan

correlates w/low ROS production, high defense mechanisms, and efficient DNA repair

nitric oxide

a radical itself and can also lead to RNOS - it relaxes smooth muscle and prevents platelet aggregation. it also functions as a neurotransmitter in the brain and mediates tumoricidal and bactericidal action of macrophages

nitric oxide synthase

uses arginine as substrate and forms the free radical NO•. it needs as coenzymes heme, FAD, FMN, and tetrahydrobiopterin

isozymes of NO synthase

eNOS (endothelial)
nNOS (neuronal)
iNOS (inducible) - induced when needed

iNO synthase

forms nitric oxide which reacts with superoxide and forms peroxynitrite which is highly destructive and used to destroy bacteria

ROS and RNOS

generated on purpose and used for the defense mechanism against bacteria, viruses, fungi, parasites, and tumor cells

NADPH oxidase

leads to a respiratory burst as it uses molecular oxygen and NADPH. it produces superoxide which leads to hydrogen peroxide (SOD) or RNOS

myeloperoxidase

(heme) - found in phagolysosomes and produces hypochlorous acid (HCOL - bleach) from hydrogen peroxide and chloride ions

chronic granulomatous disease (CGD)

an x-linked deficiency of NADPH oxidase which leads to recurrent bacterial infections, most commonly pneumonia. it is characterized by granulomas in the area of the infected cells (sequestered bacteria)

myeloperoxidase deficiency

a genetic disorder that leads to less hypochlorous acid and presents w/recurrent infections with candida albicans. this fungus leads to oral and genital infections in humans or also to systemic fungal infections

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