Complex Systems Biology of Networks: The Riddle and the Challenge - Systems Biology of Metabolic and Signaling Networks - page 25

particularly sensitive to oxidation. Thiolate anions (RS - ) are intrinsically better
nucleophiles and show enhanced reactivity with H 2 O 2 , compared to the thiol form
(Winterbourn and Metodiewa 1999 ). Thus, the p K a value of the thiol group can
modulate Cys reactivity. Other determinants of Cys reactivity toward H 2 O 2 include
access of the oxidant to its target and the presence of specific binding sites, e.g., low
pKa catalytic Cys from peroxiredoxins or protein tyrosine phosphatases that react
with H 2 O 2 with different second-order rate constants likely due to the unique
conformation of their active site (Paulsen and Carroll 2010 ).
Thus, the initial reaction of a Cys thiolate with H 2 O 2 yields a SOH, which once
formed can lead to formation of additional posttranslational modifications (PTMs).
The stability of a SOH is influenced, in part, by the presence of nearby Cys residues
and by the accessibility of the modification site to GSH (Paulsen and Carroll 2010 ).
The reaction of SOH with either a neighboring cysteine or GSH will generate a
disulfide bond that, in the case of GSH, corresponds to S -glutathiolation (Mieyal
et al. 2008 ). Both disulfide products can be reduced back to the thiol by the action of
either the GSH/glutathione reductase or the thioredoxin/thioredoxin reductase
systems (Aon et al. 2012a ; Berndt et al. 2007 ; Ghezzi and Di Simplicio 2009 ;
Stanley et al. 2011 ).
SOH can undergo further reaction with H 2 O 2 to generate the SO 2 H (sulfinic) and
SO 3 H (sulfonic) oxoforms, though the rates of these reactions are slower than those
observed for a thiolate (Hugo et al. 2009 ). Both the SO 2 H and SO 3 H modifications
are considered irreversible, and the latter is deemed a hallmark of diseases such as
cancer, diabetes, cardiovascular, and neurodegenerative disorders that are associated
with oxidative stress (Aggarwal and Makielski 2013 ;Andersen 2004 ; Jeong et al.
2012 ; Kembro et al. 2013 ; Klaunig and Kamendulis 2004 ; Leloup et al. 2011 ;
Lowell and Shulman 2005 ). In a subset of eukaryotic peroxiredoxins, the SO 2 H
modification can be reversed by sulfiredoxin (Biteau et al. 2003 ). To prevent over
oxidation of critical Cys residues, SOH may be converted to a disulfide or be
S -glutathiolated or form sulfenamide and hypervalent sulfur species (Paulsen and
Carroll 2010 ).

Fig. 2.3 (continued) family (e.g., PTP1B, PTP ) of phosphatases can be SOH-regulated, which is

facilitated by the low p K a of catalytic Cys that can oxidize to SOH with concomitant inactivation.
Protein kinases also undergo redox control.
Tumor suppressor p53 : its gene is mutated in 30-50 % of human cancers, representing a
checkpoint protein that elicits cell cycle arrest, DNA repair, and apoptosis in response to stressors
(Sun et al. 2003 ). To perform its tumor suppressor activity p53 binds, as a tetramer, to DNA
elements within promoters of its target genes and enhances transcription. P53 is sensitive to redox
signaling: oxidation of Cys residues (some of the ten present in p53), and formation of disulfide
bonds inhibits p53 tetramerization and DNA binding activity (Lago et al. 2011 ; Sun et al. 2003 ).
P53 stimulates mitochondrial respiration and decreases glycolysis by affecting F2,6BP and the
plasma membrane glucose transporters (Lago et al. 2011 ).
Abbreviations: NFκB nuclear factor κ B, MAPK mitogen-activated protein kinase, PKD protein
kinase D, PKC protein kinase C, Src, Abl tyrosine kinases, IKK IkB kinase, JNK c-Jun N-terminal
kinase, MAP kinase mitogen-activated protein kinase, β-MHC b-myosin heavy chain

α