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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 78

Module 2: Figure peroxiredoxin catalytic cycles

Growth
Cytokines factors Hormones

PI 3-K PIP
P 3 NOX/DUOX
Prx -SH Src 1
-SH
-SH
-SH
8
P H
2 O 2
O
PTP H O H O
Prx -SH 2 2 O S Prx -SH 6 ATP
-SH
-SH -SH S O
-SH
S O Srx
Trx 2
S 5
4 -SOH Prx -SH O
P S -SH
-SOH Prx
-SH 3 -SH -SH -SH S P
S Prx S Trx -SH O
Trx -SH
S S
7
H O
2
S -SH
Trx -SH Prx
S -SH -SH
Metabolism of H 2 O 2 by peroxiredoxin.
Peroxiredoxin (Prx) plays a major role in restricting the microdomain of hydrogen peroxide (H 2 O 2 ) that forms beneath the plasma membrane by rapidly
removing this messenger through a series of catalytic reactions as described in the text. Information adapted from Curr. Opin. Cell Biol., Vol. 17, Rhee,
S.G., Kang, S.W., Jeong, W., Chang, T.-S., Yang, K.-S. and Woo, H.A., Intracellular messenger function of hydrogen peroxide and its regulation by
peroxyredoxins, pp. 183--189. Copyright (2005), with permission from Elsevier; see Rhee et al. 2005.
These oxidation processes can occur through a num- reversible change may accumulate with time and the pro-
ber of mechanisms. What is remarkable about this process gressive damage may result in ageing.
is its specificity. Only a subset of proteins are modified, There is a suggestion that the hyperperoxidation reac-
and within these there is a high degree of specificity in tions that lead to the irreversible oxidation may be avoided
that only certain thiols are modified. How is it that an by an internal reaction whereby the sulphenic acid is rap-
oxidizing agent such as H 2 O 2 is able to seek out and se- idly converted into a sulphenylamide species by interacting
lectively modify specific target proteins?The answer lies with the main-chain nitrogen atom of an adjacent serine
in the fact that proteins vary considerably in their sens- residue (Step 2 in Module 2: Figure reversible and irrevers-
itivity to mild oxidizing agents, such as H 2 O 2 . Most of ible ROS oxidations). The formation of this sulphenyl-
the cysteine residues in proteins have a high acidic con- amide intermediate protects against further oxidation, and
stant (i.e. pK a values of approximately 8.5), which means the enzyme can be reactivated by converting the intermedi-
that they are resistant to attack by H 2 O 2 . However, some ate back into a thiol group via a mixed disulphide reaction
of the cysteine residues, particularly those located next to involving GSH.
positively charged amino acids, have pK a values between Two of the main signalling molecules whose activities
4 and 5 and thus exist as a thiolate anion (Cys-S ), which are reduced by oxidation are the protein tyrosine phos-
−
is very vulnerable to oxidation, and these have been re- phatases and phosphatase and tensin homologue deleted
ferred to as hyperreactive cysteine residues (the S − group on chromosome 10 (PTEN) (Module 2: Figure ROS form-
marked with an asterisk in Module 2: Figure reversible and ation and action). An analysis of tyrosine phosphatase
irreversible ROS oxidations). structure and function reveals the presence of a hyperre-
The sulphenic acid intermediate is somewhat unstable active cysteine residue in the catalytic domain that is sens-
and can be converted into a number of intermediates by itive to oxidants resulting in inactivation of the enzyme.
either eliminating water or causing it to interact with GSH Other examples of proteins that have such hypersensitive
(Reactions 2, 3 and 4 in Module 2: Figure reversible and ir- residues include the cell cycle regulatory enzyme Cdc25C,
reversible ROS oxidations). In addition, sulphenic acid can the Ca 2 + -release channels ryanodine receptors (RYRs)
be oxidized further by H 2 O 2 to sulphinic acid and sulph- and inositol 1,4,5-trisphosphate receptors (InsP 3 Rs). The
onic acid. The formation of sulphinic acid is reversible specificity with which this redox signalling system exerts
through a reaction that requires ATP and sulphiredoxin its effects therefore depends on the fact that H 2 O 2 will
(Srx). However, the final step to form sulphonic acid is only modify hyperreactive cysteine residues that exist in
irreversible and can result in serious damage and has been these target proteins of the different oxidation-sensitive
implicated in the ageing process. One idea is that this ir- processes.

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