Is Halogen Bonding the Basis for Iodothyronine Deiodinase Activity?

Bayse, Craig A.; Rafferty, Erin R.

doi:10.1021/ic100711n

Cited by 80 publications

(137 citation statements)

References 25 publications

(31 reference statements)

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“…The 5-iodine would be w3-4 Å separated from the Sec 170 selenium, consistent with the proposed selenenyliodide formation during catalysis (Bayse & Rafferty 2010;see below). In agreement with this binding mode, activity is dramatically reduced in a mutant mDio3 with Arg 275 replaced by Ala (Schweizer et al 2014a).…”

Section: Dioinsertionsupporting

confidence: 77%

“…Studies with small molecule mimics for deiodination support this notion of a common mechanism for inner and outer ring deiodination (Manna et al 2015). Also, energetic considerations and density functional theory calculations support an in-line attack of the selenolate onto the iodine atom within the aromatic plane (Bayse & Rafferty 2010, Manna et al 2015, reminiscent of the cobalt-dependent mechanism reported recently for a bacterial dehalogenase (Payne et al 2015) (see also above). A model for a thyronine complex of the mDio3 cat domain would indeed position the substrate iodine properly for an in-line attack on the halogen (Manna & Mugesh 2010).…”

Section: A Model Of Deiodinase Catalysissupporting

confidence: 59%

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New insights into the structure and mechanism of iodothyronine deiodinases

Schweizer¹,

Steegborn²

2015

Journal of Molecular Endocrinology

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Iodothyronine deiodinases are a family of enzymes that remove specific iodine atoms from one of the two aromatic rings in thyroid hormones (THs). They thereby fine-tune local TH concentrations and cellular TH signaling. Deiodinases catalyze a remarkable biochemical reaction, i.e., the reductive elimination of a halogenide from an aromatic ring. In metazoans, deiodinases depend on the rare amino acid selenocysteine. The recent solution of the first experimental structure of a deiodinase catalytic domain allowed for a reappraisal of the many mechanistic and mutagenesis data that had been accumulated over more than 30 years. Hence, the structure generates new impetus for research directed at understanding catalytic mechanism, substrate specificity, and regulation of deiodinases. This review will focus on structural and mechanistic aspects of iodothyronine deiodinases and briefly compare these enzymes with dehalogenases, which catalyze related reactions. A general mechanism for the selenium-dependent deiodinase reaction will be described, which integrates the mouse deiodinase 3 crystal structure and biochemical studies. We will summarize further, sometimes isoform-specific molecular features of deiodinase catalysis and regulation, and we will then discuss available compounds for modulating deiodinase activity for therapeutic purposes.

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Section: Dioinsertionsupporting

confidence: 77%

Section: A Model Of Deiodinase Catalysissupporting

confidence: 59%

New insights into the structure and mechanism of iodothyronine deiodinases

Schweizer¹,

Steegborn²

2015

Journal of Molecular Endocrinology

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“…compatible with molecular orbital calculations for 5-deiodination through selenenyl-iodide formation (see below) (10). The carboxyl group of the substrate is positioned close to the guanidinium group of Dio3-Arg 275 situated in the β4/α3-connecting loop (Fig.…”

supporting

confidence: 73%

Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism

Schweizer

Schlicker

Braun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

161

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Local levels of active thyroid hormone (3,3′,5-triiodothyronine) are controlled by the action of activating and inactivating iodothyronine deiodinase enzymes. Deiodinases are selenocysteine-dependent membrane proteins catalyzing the reductive elimination of iodide from iodothyronines through a poorly understood mechanism. We solved the crystal structure of the catalytic domain of mouse deiodinase 3 (Dio3), which reveals a close structural similarity to atypical 2-Cys peroxiredoxin(s) (Prx). The structure suggests a route for proton transfer to the substrate during deiodination and a Prx-related mechanism for subsequent recycling of the transiently oxidized enzyme. The proposed mechanism is supported by biochemical experiments and is consistent with the effects of mutations of conserved amino acids on Dio3 activity. Thioredoxin and glutaredoxin reduce the oxidized Dio3 at physiological concentrations, and dimerization appears to activate the enzyme by displacing an autoinhibitory loop from the iodothyronine binding site. Deiodinases apparently evolved from the ubiquitous Prx scaffold, and their structure and catalytic mechanism reconcile a plethora of partly conflicting data reported for these enzymes.hyroid hormones regulate mammalian development as well as energy expenditure and metabolism in the adult (1). The active, nuclear receptor-binding form of thyroid hormone is 3,3′,5-triiodothyronine (T 3 ). The thyroid gland mainly releases thyroxine [3,3′,5,5′-tetraiodothyronine (T 4 ); Fig. 1A], and T 3 is formed and degraded through elimination of iodine atoms from the 5′-and 5-positions, respectively (2) (Fig. S1). Three types of deiodinase enzymes are involved in activation and inactivation of thyroid hormones (Fig. S1). They form a family of transmembrane enzymes with homologous catalytic domains (2). Type II deiodinase (Dio2) catalyzes the activating (outer ring) 5′-deiodination of the prohormone T 4 to T 3 , whereas type III deiodinase (Dio3) catalyzes inactivating (inner ring) 5-deiodination (2). Type I deiodinase (Dio1) is capable of both types of reactions (3). Cells targeted by the hormone can thereby fine-tune intracellular T 3 levels through deiodinase expression according to their needs during development or upon metabolic challenges. Dio1, Dio2, and Dio3 share a conserved amino acid sequence and a selenocysteine residue essential for efficient deiodination, although nonmammalian cysteine-deiodinases have been found (4, 5). Although most of the characterized selenoproteins act as peroxidases or protein reductases, deiodinases are the only selenoenzymes known to catalyze halogen eliminations from aromatic rings. Despite a large body of experimental data, there is no coherent model for deiodinase catalysis that incorporates the bulk of available data. Results and DiscussionTo explore the unique deiodinase catalytic mechanism, we determined the crystal structure of the cytoplasmic catalytic domain of Mus musculus Dio3 (Dio3 cat ) with Sec 170 replaced by cysteine ( Fig. 1 B and C and Table 1). The structu...

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“…The association of I 2 -I À into I 3 À in fact results in one of the strongest halogen bonds known (180 kJ mol À1 ). [18] The interaction of the most important iodine-containing biomolecule, the thyroid hormone thyroglobulin, with its receptors and the enzyme catalyzing its deiodination are considered to involve C À I···O = C [19] and C À I···Se À C (selenocysteine) [20] halogen bonds, respectively. In the field of supramolecular receptors for the formation of iodide complexes, there are now host-guest systems in which the iodide is bound through halogen bonding to a receptor appended with monoiodoperfluorophenyl groups, [21] in addition to those featuring N À H···I [22] and (triazole) C À H···I hydrogen bonds, and interactions with soft Lewis acids such as Hg in mercuracarborands.…”

Section: Supramolecular Interactions Of Iodine Iodide and Iodocarbonsmentioning

confidence: 99%

Commemorating Two Centuries of Iodine Research: An Interdisciplinary Overview of Current Research

et al. 2011

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Iodine was discovered as a novel element in 1811 during the Napoleonic Wars. To celebrate the bicentennial anniversary of this event we reflect on the history and highlight the many facets of iodine research that have evolved since its discovery. Iodine has an impact on many aspects of life on Earth as well as on human civilization. It is accumulated in high concentrations by marine algae, which are the origin of strong iodine fluxes into the coastal atmosphere which influence climatic processes, and dissolved iodine is considered a biophilic element in marine sediments. Iodine is central to thyroid function in vertebrates, with paramount implications for human health. Iodine can exist in a wide range of oxidation states and it features a diverse supramolecular chemistry. Iodine is amenable to several analytical techniques, and iodine compounds have found widespread use in organic synthesis. Elemental iodine is produced on an industrial scale and has found a wide range of applications in innovative materials, including semiconductors--in particular, in solar cells.

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Is Halogen Bonding the Basis for Iodothyronine Deiodinase Activity?

Cited by 80 publications

References 25 publications

New insights into the structure and mechanism of iodothyronine deiodinases

New insights into the structure and mechanism of iodothyronine deiodinases

Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism

Commemorating Two Centuries of Iodine Research: An Interdisciplinary Overview of Current Research

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