Showing papers by "Govindasamy Mugesh published in 2008"
TL;DR: A revised mechanism that accounts for the glutathione peroxidase (GPx)-like catalytic activity of the organoselenium compound ebselen is described and DFT calculations show that the cyclization of selenenic acids to the corresponding selenenyl amides is more favored than that of sulfenic acidsto the corresponding sulfenylAmides.
Abstract: A revised mechanism that accounts for the glutathione peroxidase (GPx)-like catalytic activity of the organoselenium compound ebselen is described. It is shown that the reaction of ebselen with H(2)O(2) yields seleninic acid as the only oxidized product. The X-ray crystal structure of the seleninic acid shows that the selenium atom is involved in a noncovalent interaction with the carbonyl oxygen atom. In the presence of excess thiol, the Se--N bond in ebselen is readily cleaved by the thiol to produce the corresponding selenenyl sulfide. The selenenyl sulfide thus produced undergoes a disproportionation in the presence of H(2)O(2) to produce the diselenide, which upon reaction with H(2)O(2), produces a mixture of selenenic and seleninic acids. The addition of thiol to the mixture containing selenenic and seleninic acids leads to the formation of the selenenyl sulfide. When the concentration of the thiol is relatively low in the reaction mixture, the selenenic acid undergoes a rapid cyclization to produce ebselen. The seleninic acid, on the other hand, reacts with the diselenide to produce ebselen as the final product. DFT calculations show that the cyclization of selenenic acids to the corresponding selenenyl amides is more favored than that of sulfenic acids to the corresponding sulfenyl amides. This indicates that the regeneration of ebselen under a variety of conditions protects the selenium moiety from irreversible inactivation, which may be responsible for the biological activities of ebselen.
181 citations
TL;DR: The aim of this perspective is to present an overview of the thiol cofactor systems used by different selenoenzymes and their mimics.
Abstract: The importance of selenium as an essential trace element is now well recognized. In proteins, the redox-active selenium moiety is incorporated as selenocysteine (Sec), the 21st amino acid. In mammals, selenium exerts its redox activities through several selenocysteine-containing enzymes, which include glutathione peroxidase (GPx), iodothyronine deiodinase (ID), and thioredoxin reductase (TrxR). Although these enzymes have Sec in their active sites, they catalyze completely different reactions and their substrate specificity and cofactor or co-substrate systems are significantly different. The antioxidant enzyme GPx uses the tripeptide glutathione (GSH) for the catalytic reduction of hydrogen peroxide and organic peroxides, whereas the larger and more advanced mammalian TrxRs have cysteine moieties in different subunits and prefer to utilize these internal cysteines as thiol cofactors for their catalytic activity. On the other hand, the nature of in vivo cofactor for the deiodinating enzyme ID is not known, although the use of thiols as reducing agents has been well-documented. Recent studies suggest that molecular recognition and effective binding of the thiol cofactors at the active site of the selenoenzymes and their mimics play crucial roles in the catalytic activity. The aim of this perspective is to present an overview of the thiol cofactor systems used by different selenoenzymes and their mimics.
112 citations
TL;DR: The glutathione peroxidase (GPx) activities of some diaryl diselenides incorporating tertiary amino groups were studied and revealed that the simple 6-OMe groups play multiple roles in each of the catalytically active intermediates by introducing steric and electronic effects that are required for efficient catalysis.
Abstract: The glutathione peroxidase (GPx) activities of some diaryl diselenides incorporating tertiary amino groups were studied with $H_{2}O_{2}$, Cum- OOH, and tBuOOH as substrates and with PhSH as thiol co-substrate. Simple replacement of a hydrogen atom with a methoxy group dramatically enhances the GPx activity. The introduction of methoxy substituents ortho to selenium in N,N-dialkylbenzylamine-based compounds makes the basicity of the amino groups perfect for the catalysis. The presence of 6-OMe groups prevents possible Se···N interactions in the selenols, increasing their zwitterionic characters. The methoxy substituents also protect the selenium in the selenenic acid intermediates from overoxidation to seleninic acids or irreversible inactivation to selenonic acid derivatives. The additional substituents also play a crucial role in the selenenyl sulfide intermediates, by preventing thiol exchange reactions—which would normally lead to an inactivation pathway —at the selenium centers. The strengths of Se···N interactions in the selenenyl sulfide intermediates are dramatically reduced upon introduction of the methoxy substituents, which not only reduce the thiol exchange reactions at selenium but also enhance the nucleophilic attack of the incoming thiols at sulfur. The facile attack of thiols at sulfur in the selenenyl sulfides also prevents the reactions between the selenenyl sulfides and $H_{2}O_{2}$, that can regenerate the selenenic acids (reverse- GPx cycle). These studies reveal that the simple 6-OMe groups play multiple roles in each of the catalytically active intermediates by introducing steric and electronic effects that are required for efficient catalysis.
101 citations
TL;DR: A great deal of effort has been directed to the design and synthesis of biomimetic models for these enzymes, with major emphasis on the role of dinuclear Zn(II) complexes in the hydrolysis of β-lactam antibiotics.
Abstract: Antibiotic resistance to clinically employed beta-lactam antibiotics currently poses a very serious threat to the clinical community. The origin of this resistance is the expression of several beta-lactamases that effectively hydrolyze the amide bond in beta-lactam compounds. These beta-lactamases are classified into two major categories: serine beta-lactamases and metallo-beta-lactamases. The metalloenzymes use one or two zinc ions in their active sites to catalyze the hydrolysis of all classes of beta-lactam antibiotics, including carbapenems. As there is no clinically useful inhibitor for the metallo-beta-lactamases, it is important to understand the mechanism by which these enzymes catalyze the hydrolysis of antibiotics. In this regard, the development of synthetic analogues will be very useful in understanding the mechanism of action of metallo-beta-lactamases. This review highlights some important contributions made by various research groups in the area of synthetic analogues of metallo-beta-lactamases, with major emphasis on the role of dinuclear Zn(II) complexes in the hydrolysis of beta-lactam antibiotics.
49 citations
TL;DR: The keto-enol type tautomerism in anti-thyroid drugs and their selenium analogues are described and the inhibition of lactoperoxidase by the synthetic thiones indicates that the presence of a free N-H moiety is essential for an efficient inhibition.
Abstract: The keto-enol type tautomerism in anti-thyroid drugs and their selenium analogues are described. The commonly used anti-thyroid drug methimazole exists predominantly in its thione form, whereas its selenium analogue exists in a zwitterionic form. To understand the effect of thione/thiol and selone/selenol tautomerism on the inhibition of peroxidase-catalysed reactions, we have synthesized some thiones and selones in which the formation of thiol/selenol forms are blocked by different substituents. These compounds were synthesized by a carbene route utilizing an imidazolium salt. The crystal structures of these compounds reveal that the C=Se bonds in the selones are more polarized than the C=S bonds in the corresponding thiones. The structures of selones were studied in solution by NMR spectroscopy and the 77Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming their zwitterionic structures in solution. The inhibition of lactoperoxidase by the synthetic thiones indicates that the presence of a free N-H moiety is essential for an efficient inhibition. In contrast, such moiety is not required for an inhibition by the selenium compounds.
44 citations
TL;DR: The studies reveal that the degradation of the intracellular H2O2 by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland, as these compounds may act as antioxidants and protect thyroid cells from oxidative damage.
Abstract: Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase $(TPO)/H_2O_2/$iodide system and deiodinated to its active form (T3) by a selenocysteine-containing enzyme, iodothyronine deiodinase (ID). The activation of thyroid - timulating hormone (TSH) receptor by auto-antibodies leads to 'hyperthyroidism', a life-threatening disease which is treated by antithyroid drugs such as 6-propyl-2-thiouracil PTU) and methimazole (MMI). The present review describes the biological activities of a number of S/Se derivatives bearing the methimazole pharmacophore. It is shown that the isosteric substitutions in the existing drugs lead to compounds that can effectively and reversibly inhibit the heme-containing lactoperoxidase (LPO). In contrast to methimazole, the selenium analogue, MSeI, does not interfere with the enzyme directly, but it inhibits LPO by reducing the $H_2O_2$ that is required for the oxidation of the Fe-center in LPO. These studies reveal that the degradation of the intracellular $H2_O_2$ by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland, as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on $H_2O_2$ can reversibly inhibit the thyroid peroxidase, such drugs could be of great importance in the treatment of hyperthyroidism.
42 citations
TL;DR: A structure-activity correlation in a series of CBZ analogues suggests that the presence of a methyl substituent in CBZ and related compounds is important for their antithyroid activity.
Abstract: Synthesis and biological activity of the antithyroid drug carbimazole (CBZ) and its analogues are described. The introduction of an ethoxycarbonyl group in methimazole and its selenium analogue not only prevents the oxidation to the corresponding disulfide and diselenide but also reduces the zwitterionic character. A structure-activity correlation in a series of CBZ analogues suggests that the presence of a methyl substituent in CBZ and related compounds is important for their antithyroid activity.
21 citations
TL;DR: Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as selenolates or zwitterions in which the selenium atom carries a large negative charge.
Abstract: The inhibition of lactoperoxidase (LPO)-catalyzed oxidation of ABTS by anti-thyroid drugs and related derivatives is described. The commonly used anti-thyroid agent methimazole (MMI) inhibits the LPO with an IC 50 value of 7.0 ± 1.1 μ M which is much lower than that of the other two anti-thyroid drugs, PTU and MTU. The selenium analogue of methimazole (MSeI) also inhibits LPO with an IC 50 value of 16.4 ± 1.5 μ M, which is about 4–5 times lower than that of PTU and MTU. In contrast to thiones and selones, the S- and Se-protected compounds do not show any noticeable inhibition under identical experimental conditions. While the inhibition of LPO by MMI cannot be reversed by increasing the hydrogen peroxide concentration, the inhibition by MSeI can be completely reversed by increasing the peroxide concentration. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as selenolates or zwitterions in which the selenium atom carries a large negative ...
13 citations
TL;DR: An overview of the thiol cofactor systems used by different selenoenzymes and their mimics can be found in this paper, where the authors suggest that molecular recognition and effective binding of the cofactors at the active site of the selenocysteine and their corresponding mimics play crucial roles in the catalytic activity.
Abstract: The importance of selenium as an essential trace element is now well recognized. In proteins, the redox-active selenium moiety is incorporated as selenocysteine (Sec), the 21st amino acid. In mammals, selenium exerts its redox activities through several selenocysteine-containing enzymes, which include glutathione peroxidase (GPx), iodothyronine deiodinase (ID), and thioredoxin reductase (TrxR). Although these enzymes have Sec in their active sites, they catalyze completely different reactions and their substrate specificity and cofactor or co-substrate systems are significantly different. The antioxidant enzyme GPx uses the tripeptide glutathione (GSH) for the catalytic reduction of hydrogen peroxide and organic peroxides, whereas the larger and more advanced mammalian TrxRs have cysteine moieties in different subunits and prefer to utilize these internal cysteines as thiol cofactors for their catalytic activity. On the other hand, the nature of in vivo cofactor for the deiodinating enzyme ID is not known, although the use of thiols as reducing agents has been well-documented. Recent studies suggest that molecular recognition and effective binding of the thiol cofactors at the active site of the selenoenzymes and their mimics play crucial roles in the catalytic activity. The aim of this perspective is to present an overview of the thiol cofactor systems used by different selenoenzymes and their mimics.
11 citations
TL;DR: It is observed that lactoperoxidase (LPO) can effectively and selectively iodinate the tyrosyl residues in angiotensin peptides, indicating that iodination is an enzymatic reaction and the mechanism is similar to that of peroxid enzyme-catalyzed iodination of thyroglobulin.
Abstract: The heme peroxidase-catalyzed iodination of human angiotensins I and II is described. It is observed that lactoperoxidase (LPO) can effectively and selectively iodinate the tyrosyl residues in angiotensin peptides. The thiourea/thiouracil-based peroxidase inhibitors effectively inhibit the iodination reactions, indicating that iodination is an enzymatic reaction and the mechanism of iodination is similar to that of peroxidase-catalyzed iodination of thyroglobulin. This study also shows that the monoiodo Ang I is a better substrate for the angiotensin converting enzyme than the native peptide.
4 citations
TL;DR: In this article, a review describes the biological activities of a number of S/Se derivatives bearing the methimazole pharmacophore and shows that the degradation of the intracellular $H2O_2$ by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland.
Abstract: Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase $(TPO)/H_2O_2/$iodide system and deiodinated to its active form (T3) by a selenocysteine-containing enzyme, iodothyronine deiodinase (ID). The activation of thyroid - timulating hormone (TSH) receptor by auto-antibodies leads to 'hyperthyroidism', a life-threatening disease which is treated by antithyroid drugs such as 6-propyl-2-thiouracil PTU) and methimazole (MMI). The present review describes the biological activities of a number of S/Se derivatives bearing the methimazole pharmacophore. It is shown that the isosteric substitutions in the existing drugs lead to compounds that can effectively and reversibly inhibit the heme-containing lactoperoxidase (LPO). In contrast to methimazole, the selenium analogue, MSeI, does not interfere with the enzyme directly, but it inhibits LPO by reducing the $H_2O_2$ that is required for the oxidation of the Fe-center in LPO. These studies reveal that the degradation of the intracellular $H2_O_2$ by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland, as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on $H_2O_2$ can reversibly inhibit the thyroid peroxidase, such drugs could be of great importance in the treatment of hyperthyroidism.