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Summary case 12
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Case 121. What are free radicals/ROS, how are they formed and what is their effect on the human
body? What is being damaged (not only DNA)?
Definition
(Free) radicals = in chemistry, a radical is an atom, molecule, or ion that has an unpaired valence
(valentie) electron. With some exceptions, these unpaired electrons make radicals highly chemically
reactive. Radicals can have positive, negative or neutral charge.
Oxidant/reactive oxygen species (ROS) = from a chemical point of view, an oxidant takes up
electrons. Biologically, oxidants damage biomolecules. They are reactive species that originate from
various biological processes. Examples of oxidizing reactive species are the superoxide anion radical
(O2•–), the hydroxyl radical (•OH), hydrogen peroxide (H2O2), and hypochlorous acid (HOCl).
Reactive oxygen species are….
- formed as by-products of mitochondrial respiration (metabolism oxygen)
- formed by UV radiation
- generated during inflammation from NADPH oxidase on phagocytes
- Xanthine oxidase, the metabolism of arachidonic acid, cytochrome P450, nitric oxide
synthase, and myeloperoxidase are also possible sources of reactive species.
- The biotransformation of drugs, such as the redox cycling drugs doxorubicin and
nitrofurantoin, leads to the formation of reactive species.
- Formed by mitochondrial electron transport proteins and dysfunctional (uncoupled)
Nitric Oxide Synthases (NOS)
In a biological context, ROS are formed as a natural byproduct of the normal aerobic
metabolism of oxygen and have important roles in cell signaling and homeostasis. Atomic
oxygen has two unpaired electrons in separate orbits in its outer electron shell. This electron
structure makes oxygen susceptible to radical formation. The sequential reduction of oxygen
through the addition of electrons leads to the formation of a number of ROS. ROS are
intrinsic to cellular functioning, and are present at low and stationary levels in normal cells.
However, ROS can cause irreversible damage to DNA as they oxidize and modify some
cellular components and prevent them from performing their original functions. This
suggests that ROS has a dual role, whether they will act as harmful, protective or signaling
factors, depends on the balance between ROS production and disposal at the right time and
place
, Atomic oxygen (two unpaired electrons in outer orbital)
Molecular oxygen (O2) itself contains two unpaired electrons, making it a diradical. However,
it has only weak oxidative potential compared to some of its powerful cell-damaging
metabolites
Oxygen (O2) molecule
What’s the difference between free radicals and ROS?
Reactive oxygen species (ROS) comprise both free radical and non-free radical oxygen
intermediates such as hydrogen peroxide (H 2O2), superoxide (O2•-), singlet oxygen (1O2), and
the hydroxyl radical (•OH). So, ROS is derived from oxygen, while a free radical (can be but)
does not HAVE to be derived from oxygen.
A balance between production and removal of ROS is necessary. An imbalance toward the pro-
oxidative state is often referred to as “Oxidative stress”. What is the cellular defence against ROS?
- Enzymatic
Superoxide dismutase (SOD) catalyzes the conversion of two superoxide anions
into a molecule of hydrogen peroxide (H2O2) and oxygen (O2)
In the peroxisomes of eukaryotic cells, the enzyme catalase converts H2O2 to
water and oxygen, and thus completes the detoxification initiated by SOD.
Glutathione peroxidase is a group of enzymes containing selenium, which also
catalyze the degradation of hydrogen peroxide, as well as organic peroxides to
alcohols
- Non-enzymatic antioxidants
Glutathione may be the most important intra-cellular defense against the
deleterious effects of reactive oxygen species. This tripeptide (glutamyl-cysteinyl-
glycine) provides an exposed sulphhydryl group, which serves as an abundant
target for attack. Reactions with ROS molecules oxidize glutathione, but the
reduced form is regenerated in a redox by an NADPH-dependent reductase.
The ratio of the oxidized form of glutathione (GSSG) and the reduced
form (GSH) is a dynamic indicator of the oxidative stress of an organism.
Vitamin C or ascorbic acid is a water soluble molecule capable of reducing ROS
Vitamin E (α-tocopherol) is a lipid soluble molecule that has been suggested as
playing a similar role in membranes
,Formation of ROS
Electron transport chain (ETC)
NORMAL SITUATION
The electron transport chain is a collection of membrane-embedded proteins and organic molecules,
most of them organized into four large complexes labeled I to IV.
As the electrons travel through the chain, they go from a higher to a lower energy level, moving from
less electron-hungry to more electron-hungry molecules. Energy is released in these “downhill”
electron transfers, and several of the protein complexes use the released energy to pump protons
from the mitochondrial matrix to the intermembrane space, forming a proton gradient.
The electrons that enter the chain come from NADH and FADH, produced in
earlier stages of the cellular respiration.
NADH is a good donor during redox reactions (it’s electrons are at a
higher energy level), so it can transfer its electrons directly to complex 1.
Complex 1 is able to pump protons through the complex thanks to the
energy from the electron movement down the hill of the concentration
gradient.
FADH2 is not as good being a donor as NADH (it’s electrons are at lower
energy levels). Therefore, it cannot transfer electrons to complex 1.
Instead, it feeds them into the transport chain through complex II, which
does not pump protons across the membrane.
Both complex I and complex II pass their electrons to a small, mobile electron
carrier called ubiquinone (Q), which is reduced to form QH2 and travels through
the membrane, delivering the electrons to complex III.
As electrons move through complex III, more H+ ions are pumped across the
membrane, and the electrons are ultimately delivered to another mobile carrier
called cytochrome C (cyt C).
CytC carries the electrons to complex 4 where a final batch of H+ ions is pumped
across the membrane. Complex 5 passes the electrons to O2, which splits into
two oxygen atoms and accepts protons from the matrix to form water. Four
electrons are required to reduce each molecule of O2, and two water molecules
are formed in this process.
, The transport chain builds a proton gradient across the inner mitochondrial
membrane, with a higher concentration of H+ in the intermembrane space and a
lower concentration in the matrix. This gradient represents a stored form of energy,
and, as we’ll see, it can be used to make ATP.
ROS FORMATION SITUATION
Normally, the complexes donate the electrons to each other until it reaches complex 4 and complex
four donates its electron to oxygen to form water. However, we know there are a lot of oxygen
molecules in the mitochondria so every now and then oxygen molecules are pump into complex 1 or
3, the ETC functions imprecisely and leaks, then these oxygen molecules are pre-maturely gaining a
single electron from the electron transport chain.
So, mitochondrial superoxide is a ROS generated on both sides of the inner mitochondrial
membrane. If this happens, a super oxide radical is formed, this is a free radical with an unpaired
electron. These molecules are super reactive and can react with other molecules to form new free
radicals.
- In our body we have the superoxide dismutase enzyme (SOD), this takes the superoxide
radical to form H2O2. H2O2 is still very reactive, to get rid of this, we use catalase
enzyme to form H2O.
- However, this H2O2 can also go into another pathways:
Ionizing radiation *OH
Exposition to ozone *OH
A small amount of the iron in the body is not bound to proteins but occurs as a
chelate complex with adenosine triphosphate, guanosine triphosphate, and
citrate supporting the Fenton reaction as a potential source of free radicals.
H2O2 can for instance react with metals such as iron (Fe+3), this is called the
Fenton reaction. If this happens it forms OH* radical, this is very dangerous and
one of the most reactive radicals. It has an unpaired electron which can react
(stealing electrons) with:
Proteins: such as structure proteins with low turnovers
Lipids: phospholipids form our cellmembrane, if radicals react with this
we can lose the integrity of the barrier from the extracellular space
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