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Govindasamy Mugesh - One of the best experts on this subject based on the ideXlab platform.
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Dehalogenation of Halogenated Nucleobases and Nucleosides by Organoselenium Compounds.
Chemistry: A European Journal, 2019Co-Authors: Santanu Mondal, Govindasamy MugeshAbstract:: Halogenated nucleosides, such as 5-iodo-2'-deoxyuridine and 5-iodo-2'-deoxycytidine, are incorporated into the DNA of replicating cells to facilitate DNA single-strand breaks and intra- or interstrand crosslinks upon UV irradiation. In this work, it is shown that the naphthyl-based organoselenium compounds can mediate the dehalogenation of halogenated pyrimidine-based nucleosides, such as 5-X-2'-deoxyuridine and 5-X-2'-deoxycytidine (X=Br or I). The rate of Deiodination was found to be significantly higher than that of the debromination for both nucleosides. Furthermore, the Deiodination of iodo-cytidines was found to be faster than that of iodo-uridines. The initial rates of the Deiodinations of 5-iodocytosine and 5-iodouracil indicated that the nature of the sugar moiety influences the kinetics of the Deiodination. For both the nucleobases and nucleosides, the Deiodination and debromination reactions follow a halogen-bond-mediated and addition/elimination pathway, respectively.
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Regioselective Deiodination of Thyroxine by Iodothyronine Deiodinase Mimics: An Unusual Mechanistic Pathway Involving Cooperative Chalcogen and Halogen Bonding
2016Co-Authors: Debasish Manna, Govindasamy MugeshAbstract:Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that catalyze the conversion of thyroxine (T4) to 3,5,3′-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (rT3) by the outer- and inner-ring Deiodination pathways, respectively. These enzymes also catalyze further Deiodination of T3 and rT3 to produce a variety of di- and monoiodo derivatives. In this paper, the deiodinase activity of a series of peri-substituted naphthalenes having different amino groups is described. These compounds remove iodine selectively from the inner-ring of T4 and T3 to produce rT3 and 3,3′-diiodothyronine (3,3′-T2), respectively. The naphthyl-based compounds having two selenols in the peri-positions exhibit much higher deiodinase activity than those having two thiols or a thiol–selenol pair. Mechanistic investigations reveal that the formation of a halogen bond between the iodine and chalcogen (S or Se) and the peri-interaction between two chalcogen atoms (chalcogen bond) are important for the Deiodination reactions. Although the formation of a halogen bond leads to elongation of the C–I bond, the chalcogen bond facilitates the transfer of more electron density to the C–I σ* orbitals, leading to a complete cleavage of the C–I bond. The higher activity of amino-substituted selenium compounds can be ascribed to the deprotonation of thiol/selenol moiety by the amino group, which not only increases the strength of halogen bond but also facilitates the chalcogen–chalcogen interactions
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selenium mediated dehalogenation of halogenated nucleosides and its relevance to the dna repair pathway
Angewandte Chemie, 2015Co-Authors: Santanu Mondal, Debasish Manna, Govindasamy MugeshAbstract:Halogenated nucleosides can be incorporated into the newly synthesized DNA of replicating cells and therefore are commonly used in the detection of proliferating cells in living tissues. Dehalogenation of these modified nucleosides is one of the key pathways involved in DNA repair mediated by the uracil-DNA glycosylase. Herein, we report the first example of a selenium-mediated dehalogenation of halogenated nucleosides. We also show that the mechanism for the debromination is remarkably different from that of Deiodination and that the presence of a ribose or deoxyribose moiety in the nucleosides facilitates the Deiodination. The results described herein should help in understanding the metabolism of halogenated nucleosides in DNA and RNA.
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Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic for Deiodination of Thyroid Hormones
Angewandte Chemie (International ed. in English), 2015Co-Authors: Karuppusamy Raja, Govindasamy MugeshAbstract:Iodothyronine deiodinases are selenoenzymes which regulate the thyroid hormone homeostasis by catalyzing the regioselective Deiodination of thyroxine (T4). Synthetic deiodinase mimetics are important not only to understand the mechanism of enzyme catalysis, but also to develop therapeutic agents as abnormal thyroid hormone levels have implications in different diseases, such as hypoxia, myocardial infarction, critical illness, neuronal ischemia, tissue injury, and cancer. Described herein is that the replacement of sulfur/selenium atoms in a series of deiodinase mimetics by tellurium remarkably alters the reactivity as well as regioselectivity toward T4. The tellurium compounds reported in this paper represent the first examples of deiodinase mimetics which mediate sequential Deiodination of T4 to produce all the hormone derivatives including T0 under physiologically relevant conditions.
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A chemical model for the inner-ring Deiodination of thyroxine by iodothyronine deiodinase.
Angewandte Chemie (International ed. in English), 2010Co-Authors: Debasish Manna, Govindasamy MugeshAbstract:The I of the beholder: The presented chemical model for the inner-ring Deiodination of thyroxine (T4) and 3,5,3'-triiodothyronine (T3) by iodothyronine deiodinase (see scheme) highlights the importance of an in-built thiol group in proximity to the selenium atom. The effective removal of iodine in the case of T4 indicates that an enol-keto tautomerism is not required for Deiodination.
Debasish Manna - One of the best experts on this subject based on the ideXlab platform.
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Regioselective Deiodination of Thyroxine by Iodothyronine Deiodinase Mimics: An Unusual Mechanistic Pathway Involving Cooperative Chalcogen and Halogen Bonding
2016Co-Authors: Debasish Manna, Govindasamy MugeshAbstract:Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that catalyze the conversion of thyroxine (T4) to 3,5,3′-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (rT3) by the outer- and inner-ring Deiodination pathways, respectively. These enzymes also catalyze further Deiodination of T3 and rT3 to produce a variety of di- and monoiodo derivatives. In this paper, the deiodinase activity of a series of peri-substituted naphthalenes having different amino groups is described. These compounds remove iodine selectively from the inner-ring of T4 and T3 to produce rT3 and 3,3′-diiodothyronine (3,3′-T2), respectively. The naphthyl-based compounds having two selenols in the peri-positions exhibit much higher deiodinase activity than those having two thiols or a thiol–selenol pair. Mechanistic investigations reveal that the formation of a halogen bond between the iodine and chalcogen (S or Se) and the peri-interaction between two chalcogen atoms (chalcogen bond) are important for the Deiodination reactions. Although the formation of a halogen bond leads to elongation of the C–I bond, the chalcogen bond facilitates the transfer of more electron density to the C–I σ* orbitals, leading to a complete cleavage of the C–I bond. The higher activity of amino-substituted selenium compounds can be ascribed to the deprotonation of thiol/selenol moiety by the amino group, which not only increases the strength of halogen bond but also facilitates the chalcogen–chalcogen interactions
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selenium mediated dehalogenation of halogenated nucleosides and its relevance to the dna repair pathway
Angewandte Chemie, 2015Co-Authors: Santanu Mondal, Debasish Manna, Govindasamy MugeshAbstract:Halogenated nucleosides can be incorporated into the newly synthesized DNA of replicating cells and therefore are commonly used in the detection of proliferating cells in living tissues. Dehalogenation of these modified nucleosides is one of the key pathways involved in DNA repair mediated by the uracil-DNA glycosylase. Herein, we report the first example of a selenium-mediated dehalogenation of halogenated nucleosides. We also show that the mechanism for the debromination is remarkably different from that of Deiodination and that the presence of a ribose or deoxyribose moiety in the nucleosides facilitates the Deiodination. The results described herein should help in understanding the metabolism of halogenated nucleosides in DNA and RNA.
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regioselective Deiodination of thyroxine by iodothyronine deiodinase mimics an unusual mechanistic pathway involving cooperative chalcogen and halogen bonding
Journal of the American Chemical Society, 2012Co-Authors: Debasish MannaAbstract:Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that catalyze the conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) by the outer- and inner-ring Deiodination pathways, respectively. These enzymes also catalyze further Deiodination of T3 and rT3 to produce a variety of di- and monoiodo derivatives. In this paper, the deiodinase activity of a series of pen-substituted naphthalenes having different amino groups is described. These compounds remove iodine selectively from the inner-ring of T4 and T3 to produce rT3 and 3,3'-diiodothyronine (3,3'-T2), respectively. The naphthyl-based compounds having two selenols in the pen-positions exhibit much higher deiodinase activity than those having two thiols or a thiol selenol pair. Mechanistic investigations reveal that the formation of a halogen bond between the iodine and chalcogen (S or Se) and the pen-interaction between two chalcogen atoms (chalcogen bond) are important for the Deiodination reactions. Although the formation of a halogen bond leads to elongation of the C-I bond, the chalcogen bond facilitates the transfer of more electron density to the C-I sigma* orbitals, leading to a complete cleavage of the C-I bond. The higher activity of amino-substituted selenium compounds can be ascribed to the deprotonation of thiol/selenol moiety by the amino group, which not only increases the strength of halogen bond but also facilitates the chalcogen chalcogen interactions.
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Deiodination of thyroid hormones by iodothyronine deiodinase mimics does an increase in the reactivity alter the regioselectivity
Journal of the American Chemical Society, 2011Co-Authors: Debasish MannaAbstract:Organoselenium compounds as functional mimics of iodothyronine deiodinase are described. The naphthyl-based compounds having two selenol groups are remarkably efficient in the inner-ring Deiodination of thyroxine. The introduction of a basic amino group in close proximity to one of the selenol moieties enhances the Deiodination. This study suggests that an increase in the nucleophilic reactivity of the conserved Cys residue at the active site of deiodinases is very important for effective Deiodination.
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A chemical model for the inner-ring Deiodination of thyroxine by iodothyronine deiodinase.
Angewandte Chemie (International ed. in English), 2010Co-Authors: Debasish Manna, Govindasamy MugeshAbstract:The I of the beholder: The presented chemical model for the inner-ring Deiodination of thyroxine (T4) and 3,5,3'-triiodothyronine (T3) by iodothyronine deiodinase (see scheme) highlights the importance of an in-built thiol group in proximity to the selenium atom. The effective removal of iodine in the case of T4 indicates that an enol-keto tautomerism is not required for Deiodination.
Theo J. Visser - One of the best experts on this subject based on the ideXlab platform.
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different causes of reduced sensitivity to thyroid hormone diagnosis and clinical management
Clinical Endocrinology, 2013Co-Authors: Edward W Visser, Theo J. Visser, Alies A Van Mullem, Robin P PeetersAbstract:Normal thyroid hormone (TH) metabolism and action require adequate cellular TH signalling. This entails proper function of TH transporters in the plasma membrane, intracellular Deiodination of TH and action of the bioactive hormone T3 at its nuclear receptors (TRs). The present review summarizes the discoveries of different syndromes with reduced sensitivity at the cellular level. Mutations in the TH transporter MCT8 cause psychomotor retardation and abnormal thyroid parameters. Mutations in the SBP2 protein, which is required for normal Deiodination, give rise to a multisystem disorder including abnormal thyroid function tests. Mutations in TRβ1 are a well-known cause of resistance to TH with mostly a mild phenotype, while only recently, patients with mutations in TRα1 were identified. The latter patients have slightly abnormal TH levels, growth retardation and cognitive defects. This review will describe the mechanisms of disease, clinical phenotype, diagnostic testing and suggestions for treatment strategies for each of these syndromes.
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biochemical mechanisms of thyroid hormone Deiodination
Thyroid, 2005Co-Authors: George G J M Kuiper, Monique H A Kester, Robin P Peeters, Theo J. VisserAbstract:Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T4) is activated by outer ring Deiodination (ORD) to 3,3',5-triiodothyronine (T3), whereas both T4 and T3 are inactivated by inner ring Deiodination (IRD) to 3,3',5-triiodothyronine and 3,3'- diiodothyronine, respectively. These reactions are catalyzed by three iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, Deiodination of sulfated iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases.
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characterization of iodothyronine outer ring and inner ring deiodinase activities in the blue tilapia oreochromis aureus
Endocrinology, 1997Co-Authors: K Mol, Theo J. Visser, Serge Van Der Geyten, Veerle Darras, Eduard KuhnAbstract:The presence of iodothyronine deiodinases was investigated in the different tissues of blue tilapia (Oreochromis aureus), and their biochemical properties were compared with those of mammalian deiodinases. High-Km rT3 outer ring Deiodination (ORD) was observed in tilapia kidney, low-Km T4 ORD in liver, and low-Km T3 inner ring Deiodination (IRD) in brain and gill. The rT3 ORD activity in tilapia kidney has a very similar substrate specificity as rat liver type I iodothyronine deiodinase but is much less sensitive to inhibition by propylthiouracil, iodoacetic acid, and aurothioglucose. Tilapia liver T4 ORD activity and tilapia brain and gill T3 IRD activities show very similar substrate specificities as well as similar inhibitor sensitivities as rat type II and type III iodothyronine deiodinase, respectively. The optimal pH of the tilapian enzymes is 6-7, and the optimal incubation temperature is approximately 37 C. All tilapia deiodinases are stimulated by dithiothreitol, but the optimal DTT concentrations are generally lower than those required by the corresponding rat enzymes. The apparent Km values of the various tilapia deiodinases for their preferred substrate are in the same range as for the corresponding rat enzymes. Based on these findings, we conclude that fish deiodinases are more similar to mammalian deiodinases than generally accepted.
Santanu Mondal - One of the best experts on this subject based on the ideXlab platform.
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Dehalogenation of Halogenated Nucleobases and Nucleosides by Organoselenium Compounds.
Chemistry: A European Journal, 2019Co-Authors: Santanu Mondal, Govindasamy MugeshAbstract:: Halogenated nucleosides, such as 5-iodo-2'-deoxyuridine and 5-iodo-2'-deoxycytidine, are incorporated into the DNA of replicating cells to facilitate DNA single-strand breaks and intra- or interstrand crosslinks upon UV irradiation. In this work, it is shown that the naphthyl-based organoselenium compounds can mediate the dehalogenation of halogenated pyrimidine-based nucleosides, such as 5-X-2'-deoxyuridine and 5-X-2'-deoxycytidine (X=Br or I). The rate of Deiodination was found to be significantly higher than that of the debromination for both nucleosides. Furthermore, the Deiodination of iodo-cytidines was found to be faster than that of iodo-uridines. The initial rates of the Deiodinations of 5-iodocytosine and 5-iodouracil indicated that the nature of the sugar moiety influences the kinetics of the Deiodination. For both the nucleobases and nucleosides, the Deiodination and debromination reactions follow a halogen-bond-mediated and addition/elimination pathway, respectively.
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chemistry and biology in the biosynthesis and action of thyroid hormones
Angewandte Chemie, 2016Co-Authors: Santanu Mondal, Karuppusamy Raja, Ulrich SchweizerAbstract:Thyroid hormones (THs) are secreted by the thyroid gland. They control lipid, carbohydrate, and protein metabolism, heart rate, neural development, as well as cardiovascular, renal, and brain functions. The thyroid gland mainly produces l-thyroxine (T4) as a prohormone, and 5'-Deiodination of T4 by iodothyronine deiodinases generates the nuclear receptor binding hormone T3. In this Review, we discuss the basic aspects of the chemistry and biology as well as recent advances in the biosynthesis of THs in the thyroid gland, plasma transport, and internalization of THs in their target organs, in addition to the Deiodination and various other enzyme-mediated metabolic pathways of THs. We also discuss thyroid hormone receptors and their mechanism of action to regulate gene expression, as well as various thyroid-related disorders and the available treatments.
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selenium mediated dehalogenation of halogenated nucleosides and its relevance to the dna repair pathway
Angewandte Chemie, 2015Co-Authors: Santanu Mondal, Debasish Manna, Govindasamy MugeshAbstract:Halogenated nucleosides can be incorporated into the newly synthesized DNA of replicating cells and therefore are commonly used in the detection of proliferating cells in living tissues. Dehalogenation of these modified nucleosides is one of the key pathways involved in DNA repair mediated by the uracil-DNA glycosylase. Herein, we report the first example of a selenium-mediated dehalogenation of halogenated nucleosides. We also show that the mechanism for the debromination is remarkably different from that of Deiodination and that the presence of a ribose or deoxyribose moiety in the nucleosides facilitates the Deiodination. The results described herein should help in understanding the metabolism of halogenated nucleosides in DNA and RNA.
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Regioselective Deiodination of Iodothyronamines, Endogenous Thyroid Hormone Derivatives, by Deiodinase Mimics
Chemistry: A European Journal, 2014Co-Authors: Santanu MondalAbstract:Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation pound of thyroid hormones. It is known that iodothyronamines (TnAMs), produced by the decarboxylation of thyroid hormones, act as substrates for deiodinases. To understand whether decarboxylation alters the rate and/or regioselectivity of Deiodination by using synthetic deiodinase mimics, we studied the Deiodination of different iodothyronamines. The triiodo derivative 3,3',5-triiodothyronamine (T3AM) is deiodinated at the inner ring by naphthyl-based deiodinase mimics, which is similar to the Deiodination of 3,3',5-triiodothyronine (T3). However, T3AM under-goes much slower Deiodination than T3. Detailed experimental and theoretical investigations suggest that T3AM forms a weaker halogen bond with selenium donors than T3. Kinetic studies and single-crystal X-ray structures of T3 and T3AM reveal that intermolecular I center dot center dot center dot I interactions may play an important role in Deiodination. The formation of hydrogen- and halogen-bonding assemblies, which leads to the formation of a dimeric species of T3 in solution, facilitates the interactions between the selenium and iodine atoms. In contrast, T3AM, which does not have I center dot center dot I interactions, undergoes much slower Deiodination.
Eduard Kuhn - One of the best experts on this subject based on the ideXlab platform.
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characterization of iodothyronine outer ring and inner ring deiodinase activities in the blue tilapia oreochromis aureus
Endocrinology, 1997Co-Authors: K Mol, Theo J. Visser, Serge Van Der Geyten, Veerle Darras, Eduard KuhnAbstract:The presence of iodothyronine deiodinases was investigated in the different tissues of blue tilapia (Oreochromis aureus), and their biochemical properties were compared with those of mammalian deiodinases. High-Km rT3 outer ring Deiodination (ORD) was observed in tilapia kidney, low-Km T4 ORD in liver, and low-Km T3 inner ring Deiodination (IRD) in brain and gill. The rT3 ORD activity in tilapia kidney has a very similar substrate specificity as rat liver type I iodothyronine deiodinase but is much less sensitive to inhibition by propylthiouracil, iodoacetic acid, and aurothioglucose. Tilapia liver T4 ORD activity and tilapia brain and gill T3 IRD activities show very similar substrate specificities as well as similar inhibitor sensitivities as rat type II and type III iodothyronine deiodinase, respectively. The optimal pH of the tilapian enzymes is 6-7, and the optimal incubation temperature is approximately 37 C. All tilapia deiodinases are stimulated by dithiothreitol, but the optimal DTT concentrations are generally lower than those required by the corresponding rat enzymes. The apparent Km values of the various tilapia deiodinases for their preferred substrate are in the same range as for the corresponding rat enzymes. Based on these findings, we conclude that fish deiodinases are more similar to mammalian deiodinases than generally accepted.