Current Chemical Biology - Volume 7, Issue 1, 2013

Since the finding that selenium is an essential micronutrient for our life as well as the discovery of selenocysteine (Sec) as the twenty-first proteinogenic amino acid that is expressed by using the information encoded in genes, research fields in chemical biology and biological chemistry have been expanding to a new paradigm where selenium plays important roles. A number of selenoenzymes, which utilize a selenium atom as the active center, have already been characterized, and their biological functions have been identified. However, the chemistry underlying behind their molecular mechanisms is still not fully understood. On the other hand, selenium is a unique element in organic chemistry because it has lower redox potentials than sulfur, rendering organoselenium compounds attractive in applications to redox catalysts and advanced materials. Moreover, selenium atoms in organic compounds have high affinity toward various polar functional groups located in the proximity, forming weak nonbonded interactions between Se and heteroatoms of main-group elements, such as N, O, halogens, etc. Taking advantage of these characteristic features, we recently demonstrated that applications of selenium to the fields of chemical biology and biological chemistry are quite promising for studying various biological problems, such as molecular design of new antioxidants and characterization of oxidative folding pathways of disulfide-containing proteins. In this review, the recent developments in these fields are summarized, along with our own achievements, from a view point of a paradigm shift from sulfur to selenium. This review is divided into four major sections. After brief introduction, physical chemistry aspects of organic selenium compounds, including bond dissociation energies, redox potentials, conformational propensities, and weak nonbonded interactions, are explained in the first section. In the second section, chemical and biological syntheses of selenium compounds, such as Sec and selenomethionine derivatives, selenopeptides, selenoproteins, and other water-soluble selenium compounds, are described. In the third and fourth sections, recent applications of the selenium compounds to the research fields of chemical biology and biological chemistry, respectively, are summarized. The future scopes are given in Conclusions.

Oxidative stress results from the formation of reactive oxygen species (ROS) such as peroxides that cause damage to cell membranes and react with various biomolecules in mammalian cells. The selenoenzyme glutathione peroxidase (GPx) destroys peroxides by catalyzing their reduction to alcohols or water with the stoichiometric reductant glutathione. The effects of oxidative stress have been implicated in a variety of degenerative processes and disease states and for these reasons, there is considerable interest in the discovery of small molecule compounds that could reproduce a GPx-like activity. A review on the most recent acquisition in this area is here reported.

In the last one decade, researchers are exploring the possibility of developing less toxic selenium compounds as alternate class of antioxidants. Since most of the biological effects of selenium are mediated through selenoproteins such as glutathione peroxidase (GPx), new organoselenium compounds are being designed that could mimic the activity of GPx enzyme. One of the essential requirements for an antioxidant is its ability to scavenge reactive oxygen species (ROS), therefore studies are also directed to monitor the reactions of free radical and molecular ROS with important selenium compounds. The redox potentials reported for a few selenium compounds provided useful information on predicting their antioxidant activity. Finally the recent in vitro and in vivo biological studies with certain compounds have indicated that selenium not only exhibits potential antioxidant ability but under some conditions shows pro-oxidant effects. Important highlights on these aspects are summarised in the present article.

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a lipid-soluble organoselenium compound, exhibits numerous biological activities both in vitro and in vivo systems. This compound is undergoing clinical trials for a number of disease states such as stroke and hearing loss. It is known that ebselen exhibits glutathione peroxidase activity (GPx) and is a remarkable scavenger of reactive oxygen species (ROS) such as peroxynitrite (PN). The rate of the reaction between ebselen and PN has been shown to be about three orders of magnitude higher than that of naturally occurring small molecules, such as cysteine, methionine and ascorbate. It is also known that ebselen and related compounds effectively protect against lipid peroxidation induced by transition metal ions. However, the mechanism by which ebselen exerts its antioxidant activity and the importance of the cyclic selenazole moiety are still not well-understood. In this article, the complex chemical mechanisms involved in the antioxidant activity of ebselen and related compounds are discussed.

One potential mechanism for the effectiveness of organoselenium compounds against a number of cancer cell lines is the interaction of selenium with zinc signaling processes. Reducible selenium (rSe) compounds such as diselenides, selenenyl halides and seleninic acids release zinc from zinc fingers and metallothionein. Based upon a review of the literature, two key mechanisms are discussed: the stoichiometric displacement of zinc by selenium and the catalytic oxidation of Cys thiolates by reducible organoselenium compounds produced in situ. Initial DFT calculations of the strengths of interactions between rSe and a Cys2His2-type ZF model are presented to contrast the reactivity of reducible selenium compounds with sulfur and tellurium analogues.

The discovery of selenocysteine as the 21st amino acid has revolutionized the understanding of the significance of the essential micronutrient selenium in human and animal health. About 25 different selenoproteins have been identified that collectively function to detoxify reactive oxygen and nitrogen species (RONS) and thus aid in maintaining an optimal redox tone as a vital component of the antioxidant defense system of cells. Knowledge about the physiological properties of the redox-sensitive transcription factors like nuclear factor-kappa B (NF-κB) has made it clear that oxidative stress is an important factor that triggers and sustains inflammation in various disease states. Moreover, there is emerging epidemiological data suggesting a positive association between selenium deficiency and the prevalence of diseases such as atherosclerosis, rheumatoid arthritis, viral infections including HIV-AIDS, and cancer, where chronic inflammation forms the underlying basis of the disease. Recent studies in our laboratory have shown that selenoproteins modulate many cellular regulatory pathways that influence the expression of pro- and anti-inflammatory genes. Thus, elucidation of the diverse molecular mechanisms involved in the anti-inflammatory properties of selenium is important to appreciate its role in disease prevention and treatment. This article reviews the current status of knowledge on the biology of selenium with an emphasis on inflammation.

Enzymes are catalysts designed to function in the metabolic networks of biological systems. This review shows mechanisms underlying chemical contribution to the biological system performance and adaptations in permanently changing environment. The catalyst is exemplified by the 2-oxoglutarate dehydrogenase complex irreversibly degrading a branch point metabolite 2-oxoglutarate at the crossroad of carbon, nitrogen and fat metabolism. According to the key metabolic position and multienzyme structure, the complex exhibits rich regulation, demonstrating main principles governing the catalysis within metabolic network. First, the catalyst kinetics is changed through the enzyme-ligand interactions affecting the catalyst structure. The ligands include both small molecules and proteins, affecting catalysis by binding either to active (coenzymes, substrates, products or inhibitors) or allosteric sites. Allostery enables enzymatic sensitivity to general cellular signals, transmitted, in particular, by second messengers (Ca2+), adenine nucleotide phosphorylation status or redox potential. Regulation of catalysis by heterologous protein-protein interactions helps organization of metabolic pathways. Secondly, different regulators may interact through the protein structure effecting synergistic or antagonistic relationships through combined conformational stabilization or competitive binding. The latter is supported by common structural elements, e.g. adenine moiety, present in a number of biologically essential molecules. Thirdly, cellular systems may control the enzymatic catalysis by posttranslational modifications which may either effect or disable catalysis. The inactivation may protect catalyst itself and/or surrounding medium under conditions of metabolic impairment. Thus, enzymology enables our predictive capacity regarding both the enzyme impact on general metabolism and response to the metabolic changes within cellular network. This paves the way to the knowledge-based design of pharmacological tools to perform metabolic regulation required for solving medical and bioengineering problems.