Selenocysteine in Thiol/Disulfide-Like Exchange Reactions

Abstract

Significance: Among trace elements used as cofactors in enzymes, selenium is unique in that it is incorporated into proteins co-translationally in the form of an amino acid, selenocysteine (Sec). Sec differs from cysteine (Cys) by only one atom (selenium versus sulfur), yet this switch dramatically influences important aspects of enzyme reactivity. Recent Advances: The main focus of this review is an updated and critical discussion on how Sec might be used to accelerate thiol/disulfide-like exchange reactions in natural selenoenzymes, compared with their Cys-containing homologs. Critical Issues: We discuss in detail three major aspects associated with thiol/ disulfide exchange reactions: (i) nucleophilicity of the attacking thiolate (or selenolate); (ii) electrophilicity of the center sulfur (or selenium) atom; and (iii) stability of the leaving group (sulfur or selenium). In all these cases, we analyze the benefits that selenium might provide in these types of reactions. Future Directions: It is the biological thiol oxidoreductase-like function that benefits from the use of Sec, since Sec functions to chemically accelerate the rate of these reactions. We review various hypotheses that could help explain why Sec is used in enzymes, particularly with regard to competitive chemical advantages provided by the presence of the selenium atom in enzymes. Ultimately, these chemical advantages must be connected to biological functions of Sec.

Oxidant Sensing by Reversible Disulfide Bond Formation

“…This single atom change increases the reactivity of selenocysteine compared with cysteines (26). Selenocysteines are almost exclusively found in the catalytic sites of enzymes, either performing thiol-selenodisulfide exchange reactions or scavenging oxidants (27).…”

Redox active motifs in selenoproteins

“…Selenium is incorporated into proteins via the amino acid selenocysteine (Sec or U), which is structurally similar to cysteine yet more reactive (2). Selenoproteins exploit Sec to catalyze a wide range of electron-transfer reactions (3). Although selenoproteins are rare, they are essential for mammals and have important roles in antioxidant defense and redox regulation (4).…”

“…The majority of selenoproteins either directly scavenge oxidants (such as the reactive oxygen and nitrogen species that lead to deleterious covalent modification of cellular components), or they may signal the cellular level of these reactive species, thereby activating defense pathways. Selenoproteins are particularly well-suited for the task of combating oxidative stress because they are both sensitive to low levels of oxidants and yet resilient to inactivation by these reactive species (3). Because of their role in longevity and human diseases, there has been sustained interest in deciphering the unique role of Sec in selenoproteins (5).…”

Carbon disulfide. Just toxic or also bioregulatory and/or therapeutic?

“…In general, selenols are stronger nucleophiles than are thiols under conditions of equal ionization and even more so under physiological conditions where a higher percentage of the selenide anion would be present compared to thiolate. 181 Of course, selenoproteins are far less prevalent compared to thiol proteins. To date, only about 25 human selenoproteins have been identified with functions ranging from thyroid hormone regulation to antioxidant function.…”