**1. Introduction**

Selenium has been discovered by the Swedish scientist Jons Jakob Berzelius in 1818. The chemistry of selenium, the next element to sulfur in the chalcogen group, is very less explored as compared to the chemistry of sulfur [1]. The diethyl selenide was synthesized by Lowig in 1836 and it was obtained in pure form in 1869 ass first synthetic selenium compound [2, 3]. Selenium chemistry was initially mainly focused on the synthesis of simple diselenides (RSeSeR), selenols (RSeH) etc. However, due to the unpleasant odor of selenols and aliphatic selenides, and also its toxicity the selenium chemistry faced a serious setback. Furthermore, due to toxicity of selenium was associated with diseases such as liverstock disease [4], intoxication in experimental animals [5–7] etc., therefore, it was considered a toxic element. In 1954 by Pinsent was established with the beneficial effect of selenium for living organisms the discovery that certain bacteria grew faster in selenium fortified medium [8]. However, the exact role of selenium responsible for the growth of bacteria was not clear. Almost after

20 years of this discovery, in 1973, it was found that two bacterial enzymes, formate dehydrogenase and glycine reductase contain selenium in their active sites [9, 10]. Flohe and co-workers was discovered almost at the same time the importance of selenium to mammals [11]. They found that the mammalian enzyme glutathione peroxidase (GPx), contains a selenocysteine residue in its active site. Nowadays the major selenoenzymes discovered to date include formate dehydrogenases [12], hydrogenases [13–16], glycine reductase [17] iodothyronine deiodinases (ID) [18–22], thioredoxin reductases (TrxR) [23–26], selenophosphate synthetase [27], and selenoprotein P [28, 29], glutathione peroxidase (GPx) [30–33].

#### **1.1 Glutathione peroxidase**

Glutathione peroxidase (GPx) an mammalian enzyme, contains selenocysteine residue in its active site, For the last four decades, an extensive research has been carried out on the mammalian antioxidant enzymes GPx [34]. The cGPx utilizes glutathione (GSH) as reducing substrate exclusively for the reduction of H2O2 and organic hydroperoxides such as *tert*-butyl hydroperoxide (t-BuOOH) and cumene hydroperoxide (Cum-OOH). This enzyme exhibits good activity with all phospholipid hydroperoxides, fatty acid hydroperoxides, t-BuOOH, Cum-OOH, cholesterol hydroperoxides, and H2O2. The crystal structure of GPx indicates that the Sec residue (Sec45) forms a 'catalytic triad' with other two amino acids, glutamine (Gln80) and tryptophan (Trp158) (**Figure 1**) [36].

The crystal structure of the seleninic acid form of human pGPx also indicates that Gln79 and Trp153 are located within hydrogen bonding distance of the selenium atom (**Figure 1**). These residues appear to play an important functional role in their catalytic mechanisms.

A catalytic cycle of GPx (**Figure 2**) starts with the oxidation of the selenol (ESeH) moiety of Sec residue by peroxide to generate the selenenic acid (ESeOH) [37, 38], which reacts with cellular thiol (glutathione, GSH) to generate a selenenyl sulfide intermediate (ESeSG).

Another equivalent of GSH cleaves the -Se-S- bond in the selenenyl sulfide intermediate to regenerate the selenol with elimination of glutathione disulfide (GSSG). The cellular level concentration of GSH is maintained by glutathione reductase (GR) [39], which reduces GSSG to GSH by using NADPH as cofactor. The overall catalytic mechanism, two equivalents of NADPH is consumed to reduce one equivalent of peroxide. At very high concentrations of hydroperoxide the selenium centre in GPx may

#### **Figure 1.**

*(a) Catalytic triad at the active site of GPx; (b) active site of glutathione peroxidase (PDB code 1GP1) determined by X-ray crystallography [35].*

*Functional Mimics of Glutathione Peroxidase: Spirochalcogenuranes, Mechanism and Its… DOI: http://dx.doi.org/10.5772/intechopen.102430*

**Figure 2.** *Proposed mechanism for the GPx-catalyzed reduction of H2O2.*

be overoxidized to produce seleninic acid (ESeO2H) and selenonic acid (ESeO3H). Whereas the oxidation of selenenic acid to seleninic acid is reversible in the presence of GSH, the further oxidation to selenonic acid may inactivate the enzyme.
