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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 77

Module 2: Figure H 2 O 2 metabolism

Catalase
2 H O 2 H O + O
2 2 2 2

GSH
peroxidase
H O + 2GSH H O
2 2 2 2 + GSSG

Peroxiredoxin
H O + Prx(SH) 2 H O + PrxS 2
2 2 2 2

Hydrogen peroxide (H 2 O 2 ) metabolism by different enzyme systems.
Hydrogen peroxide (H 2 O 2 ) can be metabolized by three main mechanisms. The enzyme catalase, which is restricted to peroxisomes, converts H 2 O 2
into water and oxygen. GSH peroxidase uses the reducing power of glutathione (GSH) to convert H 2 O 2 into water with the formation of GSSG. The
peroxiredoxin (Prx) family is a major player in the metabolism of H 2 O 2 through a series of catalytic cycles (Module 2: Figure peroxiredoxin catalytic
cycles).

6. This hyperperoxidation reaction can be reversed by a 1. The primary action of H 2 O 2 is to oxidize the hyperre-
reaction that requires ATP catalysed by the enzyme active cysteine to form a sulphenic acid group (-SOH),
sulphiredoxin (Srx). which can be metabolized further along a number of
7. The phosphorylated intermediate is reduced back to pathways.
the reduced form of Prx by the Trx system. 2. The sulphenic acid residue can interact with nitrogen on
8. The Prx system is very efficient at limiting the size of a neighbouring serine residue to form an intramolecular
reactive oxygen species (ROS) microdomains.How- cyclic sulphenyl amide as occurs during the oxidation of
ever, cell-surface receptors are capable of enlarging this protein tyrosine phosphatases (Module 2: Figure ROS
microdomain by inducing a local inactivation of Prx. formation and action).
The activated receptor, perhaps acting through the non- 3. The sulphenic acid residue can be converted into an
receptor protein kinase Src, brings about an inactiva- intramolecular disulphide bond with the elimination of
tion of the Prx molecules in the local vicinity by phos- water.
phorylating Prx on Tyr-194 thus enabling the plume of 4. The sulphenic acid residue can interact with glutathione
H 2 O 2 to spread away from the receptor. (GSH) to form an intermolecular disulphide bond.
5. The sulphenic acid residue can undergo hyperperoxid-
The reducing equivalents derived from thioredoxin ation by interacting with another molecule of H 2 O 2 to
(Trx) are used to regenerate Prx-(SH) 2 : form a sulphinic acid intermediate (Cys-SO 2 H).
6. The sulphinic acid intermediate undergoes further hy-
perperoxidation to form the sulphonic acid intermedi-
Prx-S 2 + Trx-(SH) 2 → Prx-(SH) 2 + Trx-S 2
ate (Cys-SO 3 H).
When Prx1 in mice is knocked out, animals develop 7. The sulphinic acid group (Cys-SO 2 H) can be reduced
haemolytic anaemia and malignant cancers. by a reaction that requires ATP and is catalysed by the
enzyme sulphiredoxin (Srx).
Reactive oxygen species (ROS) messenger action
The primary action of hydrogen peroxide (H 2 O 2 )isto The various oxidated intermediates can be converted
reversibly oxidize a variety of target proteins with a high back into the initial reduced state by either the thioredoxin
degree of specificity (Steps 1--7 in Module 2: Figure revers- (Trx) or the glutaredoxin (Grx) system (Module 2: Figure
ible and irreversible ROS oxidations): recovery of protein oxidation).

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