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Jeanine Pommier - One of the best experts on this subject based on the ideXlab platform.
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the role of iodide and of free Diiodotyrosine in enzymatic and non enzymatic thyroid hormone synthesis
FEBS Journal, 2005Co-Authors: Alain Virion, Danièle Deme, Jeanine PommierAbstract:The respective role of iodide and of free Diiodotyrosine on thyroid hormone synthesis (coupling reaction) has been analyzed under a variety of enzymatic and non-enzymatic conditions. The coupling reaction was studied either during the course of the iodination of poorly-iodinated thyroglobulin or with thyroglobulin containing uncoupled iodotyrosine residues. 1 Free Diiodotyrosine stimulated the coupling reaction not only with thyroid peroxidase but also with lactoperoxidase and horseradish peroxidase. Similar effects of free Diiodotyrosine were obtained under non-enzymatic conditions with iodine + iodide at pH 7.4. In contrast the iodination of the tyrosine residues of poorlyiodinated thyroglobulin was not modified by this orthohalophenol either under enzymatic or non-enzymatic conditions. 2 Preformed iodotyrosine residues were efficiently coupled with thyroid peroxidase only in the presence of either iodide, or free Diiodotyrosine, alone or combined. In the presence of thiocyanate, an anion with the same size and charge as iodide, the coupling of preformed iodotyrosine residues was also observed. However the effect of thiocyanate was not additive with that of free Diiodotyrosine. 3 Hormonogenic but uncoupled iodotyrosine residues present in iodinated thyroglobulin may also couple non-enzymatically, but only in the presence of iodine + iodide, efficient coupling being seen only with iodine concentrations greater than 10 μH. In contrast, in the presence of low concentrations of free Diiodotyrosine (1 μM), significant coupling was obtained with much lower iodine concentrations, but no effect of free Diiodotyrosine was seen in the absence of iodine. These results suggest that the hormonogenic iodotyrosine residues can couple to thyroid hormone only after they are oxidized either by iodine (or another oxidized species of iodine, probably I+) or, more efficiently, by an oxidized derivative of free Diiodotyrosine (itself produced only in the presence of iodine). 4 The iodinating system chloramine-T + iodide was also able to couple preformed iodotyrosine residues of thyroglobulin. Chloramine-T (0.1 mM) alone was inefficient, whereas when used in combination with Diiodotyrosine very efficient coupling was observed. In contrast with high concentrations of both chloramine-T (0.1 mM) and iodide (0.1 mM), free Diiodotyrosine remained without effect. The proposal is made therefore that an oxidized species either of iodine (I+) or of Diiodotyrosine is required to oxidize the hormonogenic residues of thyroolobulin. 5 Maximal stimulation of the coupling reaction catalyzed by thyroid peroxidase was obtained with about 0.5 μM free Diiodotyrosine. The same level of stimulation was obtained under non-enzymatic conditions with the iodine + iodide system only with 2.5 μM free Diiodotyrosine. 6 These data suggest that free Diiodotyrosine or iodide catalyze the coupling reaction after being oxidized either enzymatically or non-enzymatically. The proposal is made that, with thyroid and lactoperoxidase, both iodide and Diiodotyrosine would facilitate the transfer of electrons from the substrate to the heme. Under nonenzymatic conditions of coupling the oxidized species of iodine or of Diiodotyrosine would also catalyze the oxidation of the two hormonogenic iodotyrosine residues present at the surface of the molecule of thyroglobulin.
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the role of lactoperoxidase h2o2 compounds in the catalysis of thyroglobulin iodination and thyroid hormone synthesis
FEBS Journal, 2005Co-Authors: Francoise Courtin, Alain Virion, Jean-luc Michot, Danièle Deme, Jeanine Pommier, Jacques NunezAbstract:Lactoperoxidase catalyzes successively, as thyroid peroxidase, the iodination of several tyrosyl residues of thyroglobulin and the coupling of some of them to thyroid hormones. We show the following results in this paper. 1 The iodination reaction is catalyzed by lactoperoxidase compound I whereas lactoperoxidase ‘compound II’ catalyzes the coupling reaction. Lactoperoxidase compound III catalyzes neither reaction. 2 Titration of lactoperoxidase ‘compound II’ by ferrocyanide showed that this enzyme-H2O2 species is two oxidizing equivalents above the native enzyme, and therefore constitutes a second form of lactoperoxidase ‘compound I’. These two forms of lactoperoxidase ‘compound I’ differ probably from one another in the localization of one of the two oxidizing equivalents either on porphyrin ring: π-compound I (compound I), or on the apoprotein: R°-compound 1 (‘compound II’). The difference in specificity between π-compound I and R°-compound I in catalyzing the iodination and the coupling reaction respectively, might therefore depend differences both in the distribution of the two oxidizing equivalents and in the structure of the substrates. 3 In the presence of free Diiodotyrosine, a halophenol which stimulates at very low concentrations the coupling reaction but has no effect on the iodination reaction, the transfer of electrons between the substrate and lactoperoxidase R°-compound I is nearly stoichiometric: 1 mole of hormone is produced for each mole of lacto-peroxidase R°-compound I. Thus free Diiodotyrosine seems to play the role of a very specific co-factor of the coupling reaction. 4 Iodide and SCN− also stimulate the coupling reaction when the H2O2/enzyme ratio used to prepare lactoperoxidase R°-compound I is higher than one. They do so by preventing the accumulation of the inactive derivative of lactoperoxidase, compound III, which is formed in the presence of excess H2O2. Iodide prevents the formation of compound III whereas SCN− very rapidly decomposes compound III back to the native enzyme.
Alain Virion - One of the best experts on this subject based on the ideXlab platform.
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the role of iodide and of free Diiodotyrosine in enzymatic and non enzymatic thyroid hormone synthesis
FEBS Journal, 2005Co-Authors: Alain Virion, Danièle Deme, Jeanine PommierAbstract:The respective role of iodide and of free Diiodotyrosine on thyroid hormone synthesis (coupling reaction) has been analyzed under a variety of enzymatic and non-enzymatic conditions. The coupling reaction was studied either during the course of the iodination of poorly-iodinated thyroglobulin or with thyroglobulin containing uncoupled iodotyrosine residues. 1 Free Diiodotyrosine stimulated the coupling reaction not only with thyroid peroxidase but also with lactoperoxidase and horseradish peroxidase. Similar effects of free Diiodotyrosine were obtained under non-enzymatic conditions with iodine + iodide at pH 7.4. In contrast the iodination of the tyrosine residues of poorlyiodinated thyroglobulin was not modified by this orthohalophenol either under enzymatic or non-enzymatic conditions. 2 Preformed iodotyrosine residues were efficiently coupled with thyroid peroxidase only in the presence of either iodide, or free Diiodotyrosine, alone or combined. In the presence of thiocyanate, an anion with the same size and charge as iodide, the coupling of preformed iodotyrosine residues was also observed. However the effect of thiocyanate was not additive with that of free Diiodotyrosine. 3 Hormonogenic but uncoupled iodotyrosine residues present in iodinated thyroglobulin may also couple non-enzymatically, but only in the presence of iodine + iodide, efficient coupling being seen only with iodine concentrations greater than 10 μH. In contrast, in the presence of low concentrations of free Diiodotyrosine (1 μM), significant coupling was obtained with much lower iodine concentrations, but no effect of free Diiodotyrosine was seen in the absence of iodine. These results suggest that the hormonogenic iodotyrosine residues can couple to thyroid hormone only after they are oxidized either by iodine (or another oxidized species of iodine, probably I+) or, more efficiently, by an oxidized derivative of free Diiodotyrosine (itself produced only in the presence of iodine). 4 The iodinating system chloramine-T + iodide was also able to couple preformed iodotyrosine residues of thyroglobulin. Chloramine-T (0.1 mM) alone was inefficient, whereas when used in combination with Diiodotyrosine very efficient coupling was observed. In contrast with high concentrations of both chloramine-T (0.1 mM) and iodide (0.1 mM), free Diiodotyrosine remained without effect. The proposal is made therefore that an oxidized species either of iodine (I+) or of Diiodotyrosine is required to oxidize the hormonogenic residues of thyroolobulin. 5 Maximal stimulation of the coupling reaction catalyzed by thyroid peroxidase was obtained with about 0.5 μM free Diiodotyrosine. The same level of stimulation was obtained under non-enzymatic conditions with the iodine + iodide system only with 2.5 μM free Diiodotyrosine. 6 These data suggest that free Diiodotyrosine or iodide catalyze the coupling reaction after being oxidized either enzymatically or non-enzymatically. The proposal is made that, with thyroid and lactoperoxidase, both iodide and Diiodotyrosine would facilitate the transfer of electrons from the substrate to the heme. Under nonenzymatic conditions of coupling the oxidized species of iodine or of Diiodotyrosine would also catalyze the oxidation of the two hormonogenic iodotyrosine residues present at the surface of the molecule of thyroglobulin.
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the role of lactoperoxidase h2o2 compounds in the catalysis of thyroglobulin iodination and thyroid hormone synthesis
FEBS Journal, 2005Co-Authors: Francoise Courtin, Alain Virion, Jean-luc Michot, Danièle Deme, Jeanine Pommier, Jacques NunezAbstract:Lactoperoxidase catalyzes successively, as thyroid peroxidase, the iodination of several tyrosyl residues of thyroglobulin and the coupling of some of them to thyroid hormones. We show the following results in this paper. 1 The iodination reaction is catalyzed by lactoperoxidase compound I whereas lactoperoxidase ‘compound II’ catalyzes the coupling reaction. Lactoperoxidase compound III catalyzes neither reaction. 2 Titration of lactoperoxidase ‘compound II’ by ferrocyanide showed that this enzyme-H2O2 species is two oxidizing equivalents above the native enzyme, and therefore constitutes a second form of lactoperoxidase ‘compound I’. These two forms of lactoperoxidase ‘compound I’ differ probably from one another in the localization of one of the two oxidizing equivalents either on porphyrin ring: π-compound I (compound I), or on the apoprotein: R°-compound 1 (‘compound II’). The difference in specificity between π-compound I and R°-compound I in catalyzing the iodination and the coupling reaction respectively, might therefore depend differences both in the distribution of the two oxidizing equivalents and in the structure of the substrates. 3 In the presence of free Diiodotyrosine, a halophenol which stimulates at very low concentrations the coupling reaction but has no effect on the iodination reaction, the transfer of electrons between the substrate and lactoperoxidase R°-compound I is nearly stoichiometric: 1 mole of hormone is produced for each mole of lacto-peroxidase R°-compound I. Thus free Diiodotyrosine seems to play the role of a very specific co-factor of the coupling reaction. 4 Iodide and SCN− also stimulate the coupling reaction when the H2O2/enzyme ratio used to prepare lactoperoxidase R°-compound I is higher than one. They do so by preventing the accumulation of the inactive derivative of lactoperoxidase, compound III, which is formed in the presence of excess H2O2. Iodide prevents the formation of compound III whereas SCN− very rapidly decomposes compound III back to the native enzyme.
Steven E Rokita - One of the best experts on this subject based on the ideXlab platform.
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iodotyrosine deiodinase a unique flavoprotein present in organisms of diverse phyla
Molecular BioSystems, 2014Co-Authors: Abhishek Phatarphekar, Jennifer M Buss, Steven E RokitaAbstract:Iodide is required for thyroid hormone synthesis in mammals and other vertebrates. The role of both iodide and iodinated tyrosine derivatives is currently unknown in lower organisms, yet the presence of a key enzyme in iodide conservation, iodotyrosine deiodinase (IYD), is suggested by genomic data from a wide range of multicellular organisms as well as some bacteria. A representative set of these genes has now been expressed, and the resulting enzymes all catalyze reductive deiodination of Diiodotyrosine with kcat/Km values within a single order of magnitude. This implies a physiological presence of iodotyrosines (or related halotyrosines) and a physiological role for their turnover. At least for Metazoa, IYD should provide a new marker for tracing the evolutionary development of iodinated amino acids as regulatory signals through the tree of life.
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crystal structure of iodotyrosine deiodinase a novel flavoprotein responsible for iodide salvage in thyroid glands
Journal of Biological Chemistry, 2009Co-Authors: Seth R Thomas, Patrick M Mctamney, Jennifer M Adler, N Larondeleblanc, Steven E RokitaAbstract:The flavoprotein iodotyrosine deiodinase (IYD) salvages iodide from mono- and Diiodotyrosine formed during the biosynthesis of the thyroid hormone thyroxine. Expression of a soluble domain of this membrane-bound enzyme provided sufficient material for crystallization and characterization by x-ray diffraction. The structures of IYD and two co-crystals containing substrates, mono- and Diiodotyrosine, alternatively, were solved at resolutions of 2.0, 2.45, and 2.6 Å, respectively. The structure of IYD is homologous to others in the NADH oxidase/flavin reductase superfamily, but the position of the active site lid in IYD defines a new subfamily within this group that includes BluB, an enzyme associated with vitamin B12 biosynthesis. IYD and BluB also share key interactions involving their bound flavin mononucleotide that suggest a unique catalytic behavior within the superfamily. Substrate coordination to IYD induces formation of an additional helix and coil that act as an active site lid to shield the resulting substrate·flavin complex from solvent. This complex is stabilized by aromatic stacking and extensive hydrogen bonding between the substrate and flavin. The carbon-iodine bond of the substrate is positioned directly over the C-4a/N-5 region of the flavin to promote electron transfer. These structures now also provide a molecular basis for understanding thyroid disease based on mutations of IYD.
Danièle Deme - One of the best experts on this subject based on the ideXlab platform.
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the role of iodide and of free Diiodotyrosine in enzymatic and non enzymatic thyroid hormone synthesis
FEBS Journal, 2005Co-Authors: Alain Virion, Danièle Deme, Jeanine PommierAbstract:The respective role of iodide and of free Diiodotyrosine on thyroid hormone synthesis (coupling reaction) has been analyzed under a variety of enzymatic and non-enzymatic conditions. The coupling reaction was studied either during the course of the iodination of poorly-iodinated thyroglobulin or with thyroglobulin containing uncoupled iodotyrosine residues. 1 Free Diiodotyrosine stimulated the coupling reaction not only with thyroid peroxidase but also with lactoperoxidase and horseradish peroxidase. Similar effects of free Diiodotyrosine were obtained under non-enzymatic conditions with iodine + iodide at pH 7.4. In contrast the iodination of the tyrosine residues of poorlyiodinated thyroglobulin was not modified by this orthohalophenol either under enzymatic or non-enzymatic conditions. 2 Preformed iodotyrosine residues were efficiently coupled with thyroid peroxidase only in the presence of either iodide, or free Diiodotyrosine, alone or combined. In the presence of thiocyanate, an anion with the same size and charge as iodide, the coupling of preformed iodotyrosine residues was also observed. However the effect of thiocyanate was not additive with that of free Diiodotyrosine. 3 Hormonogenic but uncoupled iodotyrosine residues present in iodinated thyroglobulin may also couple non-enzymatically, but only in the presence of iodine + iodide, efficient coupling being seen only with iodine concentrations greater than 10 μH. In contrast, in the presence of low concentrations of free Diiodotyrosine (1 μM), significant coupling was obtained with much lower iodine concentrations, but no effect of free Diiodotyrosine was seen in the absence of iodine. These results suggest that the hormonogenic iodotyrosine residues can couple to thyroid hormone only after they are oxidized either by iodine (or another oxidized species of iodine, probably I+) or, more efficiently, by an oxidized derivative of free Diiodotyrosine (itself produced only in the presence of iodine). 4 The iodinating system chloramine-T + iodide was also able to couple preformed iodotyrosine residues of thyroglobulin. Chloramine-T (0.1 mM) alone was inefficient, whereas when used in combination with Diiodotyrosine very efficient coupling was observed. In contrast with high concentrations of both chloramine-T (0.1 mM) and iodide (0.1 mM), free Diiodotyrosine remained without effect. The proposal is made therefore that an oxidized species either of iodine (I+) or of Diiodotyrosine is required to oxidize the hormonogenic residues of thyroolobulin. 5 Maximal stimulation of the coupling reaction catalyzed by thyroid peroxidase was obtained with about 0.5 μM free Diiodotyrosine. The same level of stimulation was obtained under non-enzymatic conditions with the iodine + iodide system only with 2.5 μM free Diiodotyrosine. 6 These data suggest that free Diiodotyrosine or iodide catalyze the coupling reaction after being oxidized either enzymatically or non-enzymatically. The proposal is made that, with thyroid and lactoperoxidase, both iodide and Diiodotyrosine would facilitate the transfer of electrons from the substrate to the heme. Under nonenzymatic conditions of coupling the oxidized species of iodine or of Diiodotyrosine would also catalyze the oxidation of the two hormonogenic iodotyrosine residues present at the surface of the molecule of thyroglobulin.
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the role of lactoperoxidase h2o2 compounds in the catalysis of thyroglobulin iodination and thyroid hormone synthesis
FEBS Journal, 2005Co-Authors: Francoise Courtin, Alain Virion, Jean-luc Michot, Danièle Deme, Jeanine Pommier, Jacques NunezAbstract:Lactoperoxidase catalyzes successively, as thyroid peroxidase, the iodination of several tyrosyl residues of thyroglobulin and the coupling of some of them to thyroid hormones. We show the following results in this paper. 1 The iodination reaction is catalyzed by lactoperoxidase compound I whereas lactoperoxidase ‘compound II’ catalyzes the coupling reaction. Lactoperoxidase compound III catalyzes neither reaction. 2 Titration of lactoperoxidase ‘compound II’ by ferrocyanide showed that this enzyme-H2O2 species is two oxidizing equivalents above the native enzyme, and therefore constitutes a second form of lactoperoxidase ‘compound I’. These two forms of lactoperoxidase ‘compound I’ differ probably from one another in the localization of one of the two oxidizing equivalents either on porphyrin ring: π-compound I (compound I), or on the apoprotein: R°-compound 1 (‘compound II’). The difference in specificity between π-compound I and R°-compound I in catalyzing the iodination and the coupling reaction respectively, might therefore depend differences both in the distribution of the two oxidizing equivalents and in the structure of the substrates. 3 In the presence of free Diiodotyrosine, a halophenol which stimulates at very low concentrations the coupling reaction but has no effect on the iodination reaction, the transfer of electrons between the substrate and lactoperoxidase R°-compound I is nearly stoichiometric: 1 mole of hormone is produced for each mole of lacto-peroxidase R°-compound I. Thus free Diiodotyrosine seems to play the role of a very specific co-factor of the coupling reaction. 4 Iodide and SCN− also stimulate the coupling reaction when the H2O2/enzyme ratio used to prepare lactoperoxidase R°-compound I is higher than one. They do so by preventing the accumulation of the inactive derivative of lactoperoxidase, compound III, which is formed in the presence of excess H2O2. Iodide prevents the formation of compound III whereas SCN− very rapidly decomposes compound III back to the native enzyme.
Suzie H. Pun - One of the best experts on this subject based on the ideXlab platform.
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reversibly switchable ph dependent peptide ligand binding via 3 5 Diiodotyrosine substitutions
ACS Chemical Biology, 2018Co-Authors: Chayanon Ngambenjawong, Meilyn Sylvestre, Heather H. Gustafson, Julio Marco B. Pineda, Suzie H. PunAbstract:Cell type-specific targeting ligands utilized in drug delivery applications typically recognize receptors that are overexpressed on the cells of interest. Nonetheless, these receptors may also be expressed, to varying extents, on off-target cells, contributing to unintended side effects. For the selectivity profile of targeting ligands in cancer therapy to be improved, stimuli-responsive masking of these ligands with acid-, redox-, or enzyme-cleavable molecules has been reported, whereby the targeting ligands are exposed in specific environments, e.g., acidic tumor hypoxia. One possible drawback of these systems lies in their one-time, permanent trigger, which enables the “demasked” ligands to bind off-target cells if released back into the systemic circulation. A promising strategy to address the aforementioned problem is to design ligands that show selective binding based on ionization state, which may be microenvironment-dependent. In this study, we report a systematic strategy to engineer low pH-selec...
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Reversibly Switchable, pH-Dependent Peptide Ligand Binding via 3,5-Diiodotyrosine Substitutions
2018Co-Authors: Chayanon Ngambenjawong, Meilyn Sylvestre, Heather H. Gustafson, Julio Marco B. Pineda, Suzie H. PunAbstract:Cell type-specific targeting ligands utilized in drug delivery applications typically recognize receptors that are overexpressed on the cells of interest. Nonetheless, these receptors may also be expressed, to varying extents, on off-target cells, contributing to unintended side effects. For the selectivity profile of targeting ligands in cancer therapy to be improved, stimuli-responsive masking of these ligands with acid-, redox-, or enzyme-cleavable molecules has been reported, whereby the targeting ligands are exposed in specific environments, e.g., acidic tumor hypoxia. One possible drawback of these systems lies in their one-time, permanent trigger, which enables the “demasked” ligands to bind off-target cells if released back into the systemic circulation. A promising strategy to address the aforementioned problem is to design ligands that show selective binding based on ionization state, which may be microenvironment-dependent. In this study, we report a systematic strategy to engineer low pH-selective targeting peptides using an M2 macrophage-targeting peptide (M2pep) as an example. 3,5-Diiodotyrosine mutagenesis into native tyrosine residues of M2pep confers pH-dependent binding behavior specific to acidic environment (pH 6) when the amino acid is protonated into the native tyrosine-like state. At physiological pH of 7.4, the hydroxyl group of 3,5-Diiodotyrosine on the peptide is deprotonated leading to interruption of the peptide native binding property. Our engineered pH-responsive M2pep (Ac-Y-Î-Î) binds target M2 macrophages more selectively at pH 6 than at pH 7.4. In addition, 3,5-Diiodotyrosine substitutions also improve serum stability of the peptide. Finally, we demonstrate pH-dependent reversibility in target binding via a postbinding peptide elution study. The strategy presented here should be applicable for engineering pH-dependent functionality of other targeting peptides with potential applications in physiology-dependent in vivo targeting applications (e.g., targeting hypoxic tumor/inflammation) or in in vitro receptor identification