Protein-Sulfenic Acids:  Diverse Roles for an Unlikely Player in Enzyme Catalysis and Redox Regulation

Abstract

While it has been known for more than 20 years that unusually stable cysteine-sulfenic acid (Cys-SOH) derivatives can be introduced in selected proteins by mild oxidation, only recently have chemical and crystallographic evidence for functional Cys-SOH been presented with native proteins such as NADH peroxidase and NADH oxidase, nitrile hydratase, and the hORF6 and AhpC peroxiredoxins. In addition, Cys-SOH forms of protein tyrosine phosphatases and glutathione reductase have been suggested to play key roles in the reversible inhibition of these enzymes during tyrosine phosphorylation-dependent signal transduction events and nitrosative stress, respectively. Substantial chemical data have also been presented which implicate Cys-SOH in redox regulation of transcription factors such as Fos and Jun (activator protein-1) and bovine papillomavirus-1 E2 protein. Functionally, the Cys-SOHs in NADH peroxidase, NADH oxidase, and the peroxiredoxins serve as either catalytically essential redox centers or transient intermediates during peroxide reduction. In nitrile hydratase, the active-site Cys-SOH functions in both iron coordination and NO binding but does not play any catalytic redox role. In Fos and Jun and the E2 protein, on the other hand, a key Cys-SH serves as a sensor for intracellular redox status; reversible oxidation to Cys-SOH as proposed inhibits the corresponding DNA binding activity. These functional Cys-SOHs have roles in diverse cellular processes, including signal transduction, oxygen metabolism and the oxidative stress response, and transcriptional regulation, as well as in the industrial production of acrylamide, and their detailed analyses are beginning to provide the chemical foundation necessary for understanding protein-SOH stabilization and function.

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

“…In this regard, both the NO and H 2 O 2 systems rely on the principle of Cys-based posttranslational modifications. It is therefore of some surprise that while many reviews on the topic of redox signaling have been published [1,3,31,50,51] most highlight either H 2 O 2 or NO selectively; co-existence of both oxidants and their respective chemical reactivities within the same cell is rarely considered.…”

The Peroxiredoxin Repair Proteins

“…This hyperoxidized Cys modification can occur under oxidative stress conditions and leads to a loss in peroxidase activity. It has long been thought that this type of modification was irreversible (Claiborne et al, 1999). With the discovery of the sulfinic acid reductases, sulfiredoxin (Srx) and sestrin, not only is this modification reversible, but may play a key role in regulating peroxide-mediated cell signaling by acting as a sulfinic acid switch (Jacob et al, 2004).…”

Fragmentation of protonated ions of peptides containing cysteine, cysteine sulfinic acid, and cysteine sulfonic acid

“…The results are important for the determination of the site of the cysteine oxidation and might be useful for the sequencing of cysteine-containing peptides. C ysteine sulfenic acid (Cys-SOH) is not uncommon [1]; it exists in native proteins, and it can also be introduced via mild oxidation [2,3]. In the latter, active-site cysteine residues of some enzymes can be selectively oxidized at neutral pH [4 -6].…”

“…The thiolate anion can readily be oxidized by H 2 O 2 to give Cys-SOH [4,7]. The Cys-SOH is unstable and it reacts with any accessible thiol to form a disulfide or undergoes further oxidation to give cysteine sulfinic acid (Cys-SO 2 H) and cysteine sulfonic acid (Cys-SO 3 H) [2]. The formation of Cys-SO 2 H and Cys-SO 3 H has been implicated in the activation of matrix metalloproteinase-7 (MMP-7) [8] and nitrile hydratase [9].…”

“…The formation of Cys-SO 2 H and Cys-SO 3 H has been implicated in the activation of matrix metalloproteinase-7 (MMP-7) [8] and nitrile hydratase [9]. The oxidation to Cys-SO 2 H and Cys-SO 3 H is generally thought to be irreversible [2]. However, recent studies show that the oxidation of cysteine to Cys-SO 2 H in human peroxiredoxin is reversible in vivo [6] and a yeast enzyme that catalyzes this reaction has been identified [10].…”