Elucidation of the Mechanism of Selenoprotein Glutathione Peroxidase. (GPx)-Catalyzed Hydrogen Peroxide Reduction by Two Glutathione Molecules: A. In a systematic search for effectors of glutathione peroxidase, a number of mercaptocarboxylic acids and tertiary mercaptans were found to be. Glutathione peroxidase belongs to the selenoprotein family and is observed in mammals, birds, and fish. This enzyme along with other members of the selenoprotein family have an integral role in the defense mechanisms of these organisms.


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The diselenide 8, which acts as the active catalyst in this mechanism, reduces peroxides and is oxidized to the corresponding selenenic acid 6 Scheme 3. Therefore, the extent of thiol exchange reaction and the stability of the selenenyl sulfide intermediate in solution are highly dependent glutathione peroxidase mechanism the nature of the thiol used as the cofactor.

glutathione peroxidase mechanism Scheme 3 A revised catalytic mechanism of ebselen 1. Similar to ebselen, the initial reaction of compound 2 with the thiol leads to the cleavage of the Se—N bond generating the corresponding selenenyl sulfide 10, which in the presence of excess thiol produces the active selenol species Interestingly, selenol 11 reacts with peroxides to generate the diselenide 12 instead of producing the corresponding selenenic acid, which is observed for the native GPx glutathione peroxidase mechanism Scheme 1.


However, the mechanism of formation of the diselenides is entirely different. Scheme 4 The proposed catalytic cycle of selenenyl amide 2.

Glutathione Peroxidase

Back and Dyck have synthesized a camphor-based selenenyl amide 3 Fig. The first nucleophilic attack of thiol at the glutathione peroxidase mechanism centre cleaves the Se—N bond, generating the corresponding selenenyl sulfide 13, which forms a catalytic cycle with selenol 14 and selenenic acid 15 Scheme 5.

Thus, unlike other cyclic selenenyl amides, the catalytic mechanism of 3 resembles the catalytic cycle of the native GPx enzymes. Compound 3 acts as a pro-catalyst as it is not directly involved in the catalytic cycle.

In the entire cycle, glutathione peroxidase mechanism conversion of selenenyl sulfide to selenol is the rate determining step.

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Scheme 5 Proposed mechanism for the GPx activity of the camphor-derived selenenamide 3. For example, the catalytic cycle for compound 16 is different from that of glutathione peroxidase mechanism 17— A catalytic mechanism for compound 16 was proposed using 77 Se NMR.

Interestingly, it was observed that the mechanism is significantly different from that of ebselen.

Glutathione peroxidase - Wikipedia

In contrast to ebselen, compound 16 reacts with the thiol to generate the selenol intermediate, which is the active species in the catalytic cycle.

Thus, the reactivity of selenenyl sulfide derived from 16 with thiol is different from that of compound 7, which glutathione peroxidase mechanism not produce any selenol in glutathione peroxidase mechanism cycle.

Therefore, the catalytic mechanism of the peptide containing ebselen analogues was found to be dependent on the nature of the peptide chains.

Singh and co-workers reported novel isoselenazolines 19—20 and isoselenazoline Se-oxides 21—22 Fig. These compounds exhibited higher GPx-like activities compared to that of ebselen that contains a C O group.


Particularly, the selenoxides 21—22 are almost 3—4 times more active than ebselen. Based on glutathione peroxidase mechanism experimental studies, they have proposed a catalytic mechanism for compound Scheme 6 indicates that the selenenyl amide bond is cleaved by thiol PhSH glutathione peroxidase mechanism produce the selenenyl sulfide intermediate 23, which acts as a true catalyst in the catalytic mechanism involving compounds 24 and Although this pathway is different from that of ebselen, the formation of the diselenide 26 from the corresponding selenenyl sulfide by disproportionation reaction is quite similar to that observed during the reduction of peroxides by ebselen.


Scheme 6 Proposed catalytic mechanism for the GPx-like activity glutathione peroxidase mechanism compound Recently, Mugesh and coworkers have synthesized similar types of isoselenazole compounds 28—31 Fig.

Interestingly, it was observed that compounds 28—31 display excellent glutathione peroxidase glutathione peroxidase mechanism both in vitro and inside human cells. A comparison of the catalytic activity shows that all the isoselenazole compounds exert very high activities as compared to ebselen.

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