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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 80

Module 2: Figure recovery of protein oxidation

THIOREDOXIN SYSTEM
Glucose
100 M 1 M 1-20 M
NADPH TrxR-(SH) Trx-(SH) 2 S
2
S
Pentose
cycle SH

NADP+ TrxR-S 2 Trx-S 2 SH

GLUTAREDOXIN SYSTEM

100 M 1 M 1-10mM 1- 20 M
NADPH GrxR-(SH) GSH Grx-(SH) S
2 2
S

SH
+
NADP GrxR-S 2 GSSG Grx-S 2 SH

Recovery of protein oxidation by the thioredoxin and glutaredoxin systems.
These two systems operate through protein disulphide oxidoreductases, which function to reduce the disulphide bond on the oxidized protein (red)
back to the reduced thiol groups (blue). Thioredoxin (Trx) system: the active site on Trx is a -Cys-32-Gly-Pro-Cys-35- motif and it is these two cysteine
residues in the reduced Trx-(SH) 2 form that are responsible for reducing disulphide bonds. Upon transferring the two protons to the substrate protein,
the Trx becomes oxidized to Trx-S 2 . Before it can operate again, the Trx-S 2 must be converted back into Trx-(SH) 2 by thioredoxin reductase (TrxR),
which extracts reducing equivalents from the NADPH formed from the pentose cycle. Glutaredoxin (Grx) system: Grx has a -Cys-Pro-Tyr-Cys- motif,
which is the active site for the oxidoreduction reaction. Glutaredoxin can act both as a dithiol--disulphide oxidoreductase and as a GSH--disulphide
oxidoreductase. The latter action enables Grx to reverse mixed protein disulphides (protein-SSG not shown on the figure) formed when proteins
interact with GSH. In order to continue its reducing function, the Grx-S 2 or Grx-SSG must be reduced back to Grx-(SH) 2 by its interaction with GSH,
which is maintained in a reduced form by glutathione reductase.

Recovery of oxidation-sensitive processes Thioredoxin (Trx)
Like other signalling pathways, there are mechanisms in Thioredoxin (Trx) is a redox buffer that operates together
place for the recovery of oxidation-sensitive processes with thioredoxin reductase (TrxR) and NADPH to regu-
basedonthe thioredoxin (Trx) and glutaredoxin (Grx) late the redox state of many different proteins (Module 2:
systems (Module 2: Figure recovery of protein oxidation). Figure recovery of protein oxidation). It is a major dithiol
Although the two systems have much in common, there reductase that functions to re-activate signalling proteins
are some differences, not least of which are their substrate such as tyrosine phosphatases and PTEN (Module 2: Fig-
specificity and the kinds of disulphide bonds that they ure ROS formation and action). One of its other functions
can reduce. For example, Trx is more effective at reducing is to re-juvenate the peroxiredoxins (Prxs), which are a
protein tyrosine phosphatase 1B than is Grx. family of small antioxidant proteins that function to meta-
Trx and Grx exist in a reduced or oxidized state, and bolize hydrogen peroxide (H 2 O 2 ) to water, thus curtail-
it is the former that enables them to reduce their sub- ing its messenger action (Module 2: Figure peroxiredoxin
strates. In doing so, they become oxidized and have to be catalytic cycles). Trx also plays a role in the denitrosylation
converted back into a reduced state by the Trx and Grx reaction (Module 2: Figure NO and cGMP signalling).
systems respectively. In the case of Trx, this is carried out One of the functions of Trx is to regulate apoptosis
by thioredoxin reductase. The Grx system is somewhat signal-regulating kinase 1 (ASK1). Reduced Trx-(SH) 2 is
more complicated in that it depends upon glutathione that known to bind to ASK1, but when it is oxidized to Trx-S 2 ,
is regenerated by a glutathione reductase. the ASK1 is released, and proceeds to induce apoptosis.
The level of Trx is markedly elevated during rheumatoid Thioredoxin-2 (Trx-2) is a mitochondrial-specific mem-
arthritis and this may influence the rate of secretion of ber of the Trx family. It functions together with mito-
matrix metalloproteinases (MMPs). chondrial thioredoxin reductase 2 (TrxR2) to regulate the

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