Hydrogen Peroxide: A Key Messenger That Modulates Protein Phosphorylation Through Cysteine Oxidation

Abstract

Ligand-receptor interactions can generate the production of hydrogen peroxide (H(2)O(2)) in cells, the implications of which are becoming appreciated. Fluctuations in H(2)O(2) levels can affect the intracellular activity of key signaling components including protein kinases and protein phosphatases. Rhee et al. discuss recent findings on the role of H(2)O(2) in signal transduction. Specifically, H(2)O(2) appears to oxidize active site cysteines in phosphatases, thereby inactivating them. H(2)O(2) also can activate protein kinases; however, although the mechanism of activation for some kinases appears to be similar to that of phosphatase inactivation (cysteine oxidation), it is unclear how H(2)O(2) promotes increased activation of other kinases. Thus, the higher levels of intracellular phosphoproteins observed in cells most likely occur because of the concomitant inhibition of protein phosphatases and activation of protein kinases.

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…Amino acids that are targets for reversible oxidation include cysteines with a low pKa sulhydryl group (4)(5), which causes unique susceptibility to oxidation compared to the typical pKa of non-reactive cysteines (8.5) [29]. In addition, methionine, tryptophan, and tyrosine residues are also prone to oxidative modification, although the functional impact of those events in physiological signal transduction remains to be established.…”

“…Compelling data also indicates that oxidants are produced and employed in physiological settings as signaling molecules in control of cell and tissue homeostasis, cell division, migration, contraction, and mediator production [1][2][3][4]. Collectively, these signaling oxidants--which include nitric oxide (NO), S-nitrosothiols (SNO, in particular Snitrosoglutathione; GSNO) and hydrogen peroxide (H 2 O 2 )--are produced mainly by NADPHdependent enzymes (NO synthases and NADPH oxidases) whose expression is tightly controlled, compartmentalized and tissue-specific.…”

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

“…Currently, the focus is largely on how cysteine residues on particular proteins work in the cells as redox sensors. The oxidative reaction of cysteine with H 2 O 2 may change structure and function of protein mediating response to changes of redox state in the cell (61,62). An important protein effector by which H 2 O 2 signaling occurs is the family of PTPs (34,(36)(37)(38)63,64).…”

Oxidation of proteins: Basic principles and perspectives for blood proteomics

“…Moreover, as cysteines play a pivotal role in protein structure through the formation of disulphide bonds, their oxidation status is of primary importance for protein function. In the recent years, cysteine oxidation has been more and more recognised as a basal regulation mechanism [57]. Free sulphydryl groups can undergo direct, reversible oxidation to sulphenic acid, and most often further irreversible oxidation to sulphinic and sulphonic acid, as shown in Fig.…”