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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 73

Module 2: Figure reactive oxygen species (ROS)

O O O 2 Oxygen

e - REACTIVE OXYGEN
SPECIES (ROS)
- .
O O O 2 Superoxide

e -

H O O H H O 2 Hydrogen
2
peroxide

e -
. Hydroxyl
O H OH
radical

Paired electrons
Unpaired electrons

Formation and metabolism of the reactive oxygen species (ROS).
To understand the properties of reactive oxygen species (ROS) and how they are formed, it is best to begin with oxygen. Oxygen is a strong oxidizing
agent in that it has two unpaired electrons (e ; red dots), which have parallel spins (i.e. they spin in the same direction as indicated by the two black
−
arrows) and occupy separate π-antibonding orbitals. Given that they have these unpaired electrons, oxygen qualifies as a free radical. However,
oxygen is relatively inert because, in order to react with another molecule, it has to accept a pair of electrons with antiparallel spins to fit into the empty
−
spaces in the π orbitals. Because of this restriction, oxygen accepts electrons (e ) one at a time and this leads to the formation of the different ROS.

Plasma membrane reactive oxygen species (ROS) to carry out the first step of ROS formation i.e. the re-
formation duction of oxygen to superoxide radical (O 2 −• )(Module
A large number of receptors responding to external sig- 2: Figure plasma membrane ROS formation). In addition
nals stimulate the formation of reactive oxygen species to this activation through Rac, it seems that the enzyme
(ROS), including cytokine receptors (tumour necrosis can also be regulated through diacylglycerol (DAG) and
factor α, interleukin-1 and interferon-γ), growth factor Ca 2 + acting through protein kinase C (PKC), which phos-
receptors [platelet-derived growth factor (PDGF), epi- phorylates p47 phox , one of the cytoplasmic components of
dermal growth factor (EGF) and basic fibroblast growth NADPH oxidase, to bring about the assembly of the mul-
factor (bFGF) receptors] and G protein-coupled receptors ticomponent complex. Non-phagocytic cells that generate
(GPCRs) (5-hydroxytryptamine, bradykinin, angiotensin ROS for signalling use a similar, but genetically distinct,
II, thrombin and endothelin receptors). Just how all these NADPH oxidase called Nox1, which plays a significant
receptors are coupled to the formation of ROS is still role in redox signalling in proliferation and cancer.
somewhat uncertain, but there is increasing evidence that In phagocytes, the O 2 −• is released to the outside of the
the mechanism might resemble that found in phagocytic cell, where it is able to attack invading micro-organisms,
cells. whereas, in non-phagocytic cells, it functions as a mes-
In phagocytes, external signals acting through cell- senger to activate a signalling cascade on the inside of the
surface receptors stimulate the PtdIns 3-kinase signalling cell (Module 2: Figure plasma membrane ROS formation).
−•
pathway to form the lipid messenger PtdIns3,4,5P 3 Superoxide dismutase (SOD) rapidly converts the O 2
(Module 2: Figure PtdIns 3-kinase signalling), which then into hydrogen peroxide (H 2 O 2 ), whichappearstobethe
acts through Rac to stimulate NADPH oxidase. This mul- primary messenger molecule of this redox signalling path-
ticomponent enzyme uses NADPH as an electron donor way.

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