- Biomimetic deiodination of thyroid hormones and iodothyronamines-a structure-activity relationship study
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Mammalian selenoenzymes, iodothyronine deiodinases (DIOs), catalyze the tyrosyl and phenolic ring deiodination of thyroid hormones (THs) and play an important role in maintaining the TH concentration throughout the body. These enzymes also accept the decarboxylated thyroid hormone metabolites, iodothyronamines (TAMs), as substrates for deiodination. Naphthalene-based selenium and/or sulphur-containing small molecules have been shown to mediate the regioselective tyrosyl ring deiodination of thyroid hormones and their metabolites. Herein, we report on the structure-activity relationship studies of a series of peri-substituted selenium-containing naphthalene derivatives for the deiodination of thyroid hormones and iodothyronamines. Single crystal X-ray crystallographic and 77Se NMR spectroscopic studies indicated that the intramolecular Se?X (X = N, O and S) interactions play an important role in the deiodinase activity of the synthetic mimics. Furthermore, the decarboxylated metabolites, TAMs, have been observed to undergo slower tyrosyl ring deiodination than THs by naphthyl-based selenium and/or sulphur-containing synthetic deiodinase mimics and this has been explained on the basis of the strength of Se?I halogen bonding formed by THs and TAMs.
- Mondal, Santanu,Mugesh, Govindasamy
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supporting information
p. 9490 - 9500
(2016/10/22)
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- Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic for Deiodination of Thyroid Hormones
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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.
- Raja, Karuppusamy,Mugesh, Govindasamy
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supporting information
p. 7674 - 7678
(2015/06/25)
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- Regioselective deiodination of iodothyronamines, endogenous thyroid hormone derivatives, by deiodinase mimics
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Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation￡ 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 (T3 AM) is deiodinated at the inner ring by naphthyl-based deiodinase mimics, which is similar to the deiodination of 3,3,5-triiodothyronine (T3). However, T3 AM undergoes much slower deiodination than T3. Detailed experimental and theoretical investigations suggest that T3 AM forms a weaker halogen bond with selenium donors than T3. Kinetic studies and single-crystal X-ray structures of T3 and T3 AM reveal that intermolecular I...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, T3 AM, which does not have I...I interactions, undergoes much slower deiodination.
- Mondal, Santanu,Mugesh, Govindasamy
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p. 11120 - 11128,9
(2014/11/27)
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- Regioselective deiodination of thyroxine by iodothyronine deiodinase mimics: An unusual mechanistic pathway involving cooperative chalcogen and halogen bonding
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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.
- Manna, Debasish,Mugesh, Govindasamy
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supporting information; experimental part
p. 4269 - 4279
(2012/04/10)
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- Deiodination of thyroid hormones by iodothyronine deiodinase mimics: Does an increase in the reactivity alter the regioselectivity?
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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.
- Manna, Debasish,Mugesh, Govindasamy
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supporting information; experimental part
p. 9980 - 9983
(2011/08/21)
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- A chemical model for the inner-ring deiodination of thyroxine by iodothyronine deiodinase
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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. Copyright
- Manna, Debasish,Mugesh, Govindasamy
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body text
p. 9246 - 9249
(2011/02/22)
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- Structure effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination
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Objectives: Amiodarone (AMI) has proven to be a potent anti-arrhythmic compound. Due to the structural similarity between AMI and thyroid hormone, it is possible that the drug could inhibit the activity of the 5'-thyroxine- deiodinase. Methods: AMI analogues resulting from (1) dealkylation, (2) deiodination and (3) deamination were synthesised and used as inhibitors in an in vitro biotransformation reaction of thyroxine (T4) to 3,3',5'- triiodothyronine (T3). Using high-performance liquid chromatography and ultraviolet detection for quantifying T3, it was found that the 5'-T4 deiodinase type I was involved in the reaction. On separate occasions, AMI or an AMI analogue was added to the reaction as an inhibitor. Results: All studied AMI analogues inhibited 5'-T4 deiodination competitively (K(i) value range 25-360 μM). In the concentration range of 1-1000 μM, AMI and its N- desethylated, deiodinated analogues inhibited 5'-T4 deiodination very weakly. AMI analogues with a hydroxyl group at the 4-position were strong inhibitors. Moreover, diiodo-AMI analogues inhibited 5'-T4 deiodination more strongly than their corresponding monoiodo- or deiodinated derivatives. Conclusion: It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.
- Ha,Stieger,Grassi,Altorfer,Follath
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p. 807 - 814
(2007/10/03)
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- Ratios of Iodination Rates of Tyrosine and Diiodo-Thyronine
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Ratios of the iodination rates of tyrosine and diiodothyronine were determined by measuring the quantity of reacted thyroninine in a mixture of both components.It was found that tyrosine reacts faster, namely, the ratios of rate constants are 4.9 and 2.6 at 20 and 40 deg C, respectively.A comparison between these results and the data for the electron densities, calculated for carbon atom in both compounds, at which the reaction of iodination takes place, indicates a clear correlation.For both compounds, and for the transition state complex heats of formation and bond energies were also calculated.All the calculations were performed by MNDO semiempirical quantum mechanical method.
- Juznic, K.,Hodoscek, M.
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p. 223 - 226
(2007/10/02)
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