NUTR 3210 Lecture Notes - Lecture 10: Superoxide Dismutase, Glutathione Peroxidase, Reactive Oxygen Species

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27 Jul 2016
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Unit 10: Macronutrients II
Introduction to Oxidant Defense:
What is Oxidant Defence?:
The process of defending oneself against damage done by oxidants.
One major group of damaging oxidants are called Reactive Oxygen Species (ROS), since they contain
oxygen and readily undergo chemical reactions with other molecules. Oxidants are molecules that act as
oxidizing agents in redox (oxidation/reduction) reaction to accept electrons, thereby becoming reduced.
Damage results when oxidants pull electrons from molecules like proteins, lipids and DNA
Oxidant molecules can be formed endogenously through reactions that occur in the body, or exposure can
be exogenous from the diet or environment
Antioxidant molecules are those that oppose the oxidizing action of oxidants by acting as reducing agents.
Antioxidants donate electrons to oxidants, allowing them to become reduced without doing damage.
Antioxidants can be exogenous, such as from diet (vitamin E), or endogenous, such as enzymes (like
catalase and superoxide dismutase)
It is critical to defend against oxidative damage, since it can impair the function of important proteins and
cause DNA mutations and cell death
What are Redox Reactions?:
Redox reactions form the basis of cellular respiration/energy metabolism
Oxidation = Loss of Electrons
Reduction = Gain of Electrons
Oxidizing Agent: causes another molecule to become oxidized, and is therefore reduced
Reducing Agent: causes another molecule to become reduced, and is therefore oxidized
Aerobic metabolism is baed on the removal of electrons from nutrient substrates, captured in the form of
electron acceptors like NAD+ and FAD. (e.g in glycolysis, the reaction in which glyceraldehyde-3-
phosphate gets converted to 1:3-bisphophoglycerate involves transfer of two electrons to NAD+ to form
NADH. Several additional steps in the TCA Cycle form NADH and FADH2)
The electrons from NADH and FADH2 are passed to the electron transport chain, where they move down
a electrochemical gradient, pumping protons through the mitochondrial membrane. The proton gradient is
then used to form ATP. The electrons ultimately get transferred to oxygen to form water (along with H+
from solution). If oxygen is not present, the whole system becomes highly reduced and stops functioning.
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NAD is derived from the B vitamin niacin, while FAD
is derived from the B vitamin riboflavin. Additionally,
iron and copper ions are responsible for passing the
electrons down the ETC. This system does not work
with 100% efficiency. Instead of accepting 4 electrons
to form water, some oxygen accepts 1 or 2 electrons
to form reactive oxygen species (ROS), which
contribute to cell death, and aging and disease
conditions. Various nutrients are involved in defence
against these ROS
How are Reactive Oxygen Species Formed?:
Reactive Oxygen Species (ROS) are formed in reactions of oxygen containing molecules with electrons.
1.Most of the reactions of carb and lipid metabolism takes place in
the mitochondria, including the ETC. On an average basis, around
1% of the electron flow “leaks”, leading to the formation of
potentially harmful ROS. ROS formation can also be induced by
inflammation and drug and toxin metabolism. Oxygen accepting
electrons is exactly what is supposed to happen in the ETC: ideally,
we see that oxygen accepts 4 electrons at the bottom of the chain
and reacts with H+ from solution to form H2O. However, when
oxygen reacts with only one electron, it form the superoxide anion
radical O2*. This molecule is a radical because it has an unpaired
electron in an orbital. Radicals can have variable reactivity, with
some vein more reactive than others. Superoxide is considered to
be ‘modestly’ reactive
2.If the superoxide radical accepts another electron, it forms
hydrogen peroxide H2O2. This reaction is catalyzed by the enzyme
superoxide dismutase, or it can happen spontaneously. SOD is part
of the body’s enzymatic antioxidant system. In eukaryotes, the
cytosolic enzyme uses copper and zinc as metal cofactors, while prokaryotes (and mitochondrial SOD) use
manganese. The physiological importance of SOD is illustrated by the pathologies in mice genetically
engineered to lack these enzymes. In humans, a genetic mutation of one of the SOD genes is associated with a
familial form of amyotrophic lateral sclerosis (ALS). Even though SOD adds to the H2O2 pool without really
resolving the oxidant problem, it appears to be critical to maintain low levels of superoxide (likely due to ability to
redox cycle free iron)
3. H2O2 is still reactive, and if it accepts another unpaired electron, forms the very problematic hydroxyl radical
OH*. The electron donor in this case are “free” reduced iron or copper. These metals are usually controlled in
metabolism by their binding in protein and cytochrome structures, but during oxidant stress, the proteins can be
damaged releasing dangerous iron and copper. Once iron and copper participate in hydroxyl radical formation,
they become oxidized and unreactive, but they can continuously be reduced by superoxide, explaining the
importance of SOD activity. Unlike superoxide radical, which can be metabolized by various SOD proteins, there
is no enzymatic system that can intercept OH*. It can damage virtually any type of macromolecule. The hydroxyl
radical is so reactive that its targets are “diffusion limited”, i.e the first susceptible molecule that it contacts, it will
abstract an electron from and become water. The best strategy to deal with it is to stop before it is formed, by
adding 2 electrons to H2O2 to water. The conversion of H2O2 to water is accomplished by the enzyme
glutathione peroxidase, which requires selenium
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It is important to remember that ROS can play important biological roles.
-H2O2 is needed to attach iodine atoms to thyroglobulin in the synthesis of T3/T4, and also to convert
arachidonic acid to eicosanoids
-ROS formation is also critical in immune function: macrophages and neutrophils must generate ROS
in order to kill some types of bacterias that they engulf by phagocytosis. Problems arise when there is
imbalance between production of ROS and consumption of antioxidants from food, whereby we
produce more ROS and consume less antioxidants
Where do Micronutrients Fit In?
Two types of oxidant defense systems:
1. Non-enzymatic defense: These are defense molecules that come from outside of the body, in this
case, from the diet, and that work independently of one of the endogenous enzymatic defense
systems. Examples are vitamin E, a lipid soluble antioxidant, and vitamin C, a water soluble
antioxidant
2. Enzymatic defense: These are defense molecules that work as part of endogenous enzymatic
defense systems; note that their origin may still be exogenous. Examples are copper, zinc, and
manganese, that work as part of superoxide dismutase enzymes, and selenium which works as
part of fatty acid and glutathione peroxidase enzymes
Further in the unit you will learn:
-Vitamin E protects against lipid damage done by the hydroxyl radical (OH*)
-Vitamin C (may) help to regenerate vitamin E and improve the GSH:GSSG ratio
- Copper/zinc/manganese are required for superoxide dismutases, which convert superoxide anion
radical (O2*-) to hydrogen peroxide (H2O2)
-Selenium is required for glutathione peroxidase, which converts H2O2 to water and fatty acid
peroxidase that helps mitigate damage done by OH*
-The pentose phosphate pathway (thiamine) produces reducing equivalents in the form of NADPH
(niacin) which move through FAD (riboflavin) in glutathione reductase
-Sulphur amino acids are required to provide cysteine for the
formation of glutathione (GSH) the major reducing agent in cells
We will consider activities of vitamins E and C in the process of oxidant
defense as well as the mineral selenium. It is important to note that
other vitamins, like niacin (as NADPH) and riboflavin (as cofactor for
glutathione reductase) and minerals such as copper, zinc and
manganese (as cofactors for superoxide dismutase enzymes) relate to
oxidant defence
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