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Steven E Rokita - One of the best experts on this subject based on the ideXlab platform.
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the minimal structure for Iodotyrosine Deiodinase function is defined by an outlier protein from thermophilic bacteria thermotoga neapolitana
Journal of Biological Chemistry, 2021Co-Authors: Zuodong Sun, Jennifer M Kavran, Shaun Spisak, Steven E RokitaAbstract:The nitroreductase superfamily of enzymes encompasses many flavin mononucleotide (FMN)-dependent catalysts promoting a wide range of reactions. All share a common core consisting of a FMN binding domain, and individual subgroups additionally contain one to three sequence extensions radiating from defined positions within this core to support their unique catalytic properties. To identify the minimum structure required for activity in the Iodotyrosine Deiodinase subgroup of this superfamily, attention was directed to a representative from the thermophilic organism Thermotoga neapolitana (TnIYD). This representative was selected based on its status as an outlier of the subgroup arising from its deficiency in certain standard motifs evident in all homologues from mesophiles. We found that TnIYD lacked a typical N-terminal sequence and one of its two characteristic sequence extensions, neither of which was found to be necessary for activity. We also show TnIYD efficiently promotes dehalogenation of iodo-, bromo- and chlorotyrosine, analogous to related Deiodinases (IYDs) from humans and other mesophiles. In addition, 2-iodophenol is a weak substrate for TnIYD as it was for all other IYDs characterized to date. Consistent with enzymes from thermophilic organisms, we observed that TnIYD adopts a compact fold and low surface area compared to IYDs from mesophilic organisms. The insights gained from our investigations on TnIYD demonstrate the advantages of focusing on sequences that diverge from conventional standards to uncover the minimum essentials for activity. We conclude that TnIYD now represents a superior starting structure for future efforts to engineer a stable dehalogenase targeting halophenols of environmental concern.
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redox control of Iodotyrosine Deiodinase
Protein Science, 2019Co-Authors: Jimin Hu, Jamie L. Schlessman, Qi Su, Steven E RokitaAbstract:The redox chemistry of flavoproteins is often gated by substrate and Iodotyrosine Deiodinase (IYD) has the additional ability to switch between reaction modes based on the substrate. Association of fluorotyrosine (F-Tyr), an inert substrate analog, stabilizes single electron transfer reactions of IYD that are not observed in the absence of this ligand. The co-crystal of F-Tyr and a T239A variant of human IYD have now been characterized to provide a structural basis for control of its flavin reactivity. Coordination of F-Tyr in the active site of this IYD closely mimics that of Iodotyrosine and only minor perturbations are observed after replacement of an active site Thr with Ala. However, loss of the side chain hydroxyl group removes a key hydrogen bond from flavin and suppresses the formation of its semiquinone intermediate. Even substitution of Thr with Ser decreases the midpoint potential of human IYD between its oxidized and semiquinone forms of flavin by almost 80 mV. This decrease does not adversely affect the kinetics of reductive dehalogenation although an analogous Ala variant exhibits a 6.7-fold decrease in its kcat /Km . Active site ligands lacking the zwitterion of halotyrosine are not able to induce closure of the active site lid that is necessary for promoting single electron transfer and dehalogenation. Under these conditions, a basal two-electron process dominates catalysis as indicated by preferential reduction of nitrophenol rather than deiodination of iodophenol.
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toward a halophenol dehalogenase from Iodotyrosine Deiodinase via computational design
ACS Catalysis, 2018Co-Authors: Steven E RokitaAbstract:Reductive dehalogenation offers an attractive approach for removing halogenated pollutants from the environment, and Iodotyrosine Deiodinase (IYD) may contribute to this process after it can be engineered to accept a broad range of substrates. The selectivity of IYD is controlled in part by an active site loop of ∼26 amino acids. In the absence of a substrate, the loop is disordered and only folds into a compact helix-turn-helix upon halotyrosine association. The design algorithm of Rosetta was applied to redesign this loop for response to 2-iodophenol rather than Iodotyrosine. One strategy using a restricted number of substitutions for increasing the inherent stability of the helical regions failed to generate variants with the desired properties. A series of point mutations identified strong epistatic interactions that impeded adaptation of IYD. This limitation was overcome by a second strategy that placed no restrictions on side-chain substitution by Rosetta. Nine representative designs containing betw...
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toward a halophenol dehalogenase from Iodotyrosine Deiodinase via computational design
ACS Catalysis, 2018Co-Authors: Zuodong Sun, Steven E RokitaAbstract:Reductive dehalogenation offers an attractive approach for removing halogenated pollutants from the environment, and Iodotyrosine Deiodinase (IYD) may contribute to this process after it can be eng...
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Toward a Halophenol Dehalogenase from Iodotyrosine Deiodinase via Computational Design
2018Co-Authors: Zuodong Sun, Steven E RokitaAbstract:Reductive dehalogenation offers an attractive approach for removing halogenated pollutants from the environment, and Iodotyrosine Deiodinase (IYD) may contribute to this process after it can be engineered to accept a broad range of substrates. The selectivity of IYD is controlled in part by an active site loop of ∼26 amino acids. In the absence of a substrate, the loop is disordered and only folds into a compact helix-turn-helix upon halotyrosine association. The design algorithm of Rosetta was applied to redesign this loop for response to 2-iodophenol rather than Iodotyrosine. One strategy using a restricted number of substitutions for increasing the inherent stability of the helical regions failed to generate variants with the desired properties. A series of point mutations identified strong epistatic interactions that impeded adaptation of IYD. This limitation was overcome by a second strategy that placed no restrictions on side-chain substitution by Rosetta. Nine representative designs containing between 14 and 18 substitutions over 26 contiguous sites were evaluated experimentally. The top performing catalyst (UD08) supported a 4.5-fold increase in turnover of 2-iodophenol and suppressed turnover of Iodotyrosine by 2000-fold relative to the native enzyme. The active site loop of UD08 appeared less disordered than the native sequence in the absence of substrate, as evident from their relative sensitivity to proteolysis. Protection from proteolysis increased 9-fold for UD08 in the presence of 2-iodophenol and nearly rivaled the equivalent response of wild-type IYD to Iodotyrosine. Thus, the Rosetta designs achieved the goal of creating an active site sequence that gained structure in the presence of iodophenol. Although a limited number of point mutations was sufficient to increase the catalytic efficiency for 2-iodophenol dehalogenation, only Rosetta successfully created a loop structure responsive to this substrate
Robert H. Horvitz - One of the best experts on this subject based on the ideXlab platform.
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the caenorhabditis elegans Iodotyrosine Deiodinase ortholog sup 18 functions through a conserved channel sc box to regulate the muscle two pore domain potassium channel sup 9
PLOS Genetics, 2014Co-Authors: Ignacio Perez De La Cruz, Robert H. HorvitzAbstract:Loss-of-function mutations in the Caenorhabditis elegans gene sup-18 suppress the defects in muscle contraction conferred by a gain-of-function mutation in SUP-10, a presumptive regulatory subunit of the SUP-9 two-pore domain K(+) channel associated with muscle membranes. We cloned sup-18 and found that it encodes the C. elegans ortholog of mammalian Iodotyrosine Deiodinase (IYD), an NADH oxidase/flavin reductase that functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The FMN-binding site of mammalian IYD is conserved in SUP-18, which appears to require catalytic activity to function. Genetic analyses suggest that SUP-10 can function with SUP-18 to activate SUP-9 through a pathway that is independent of the presumptive SUP-9 regulatory subunit UNC-93. We identified a novel evolutionarily conserved serine-cysteine-rich region in the C-terminal cytoplasmic domain of SUP-9 required for its specific activation by SUP-10 and SUP-18 but not by UNC-93. Since two-pore domain K(+) channels regulate the resting membrane potentials of numerous cell types, we suggest that the SUP-18 IYD regulates the activity of the SUP-9 channel using NADH as a coenzyme and thus couples the metabolic state of muscle cells to muscle membrane excitability.
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The Caenorhabditis elegans Iodotyrosine Deiodinase Ortholog SUP-18 Functions through a Conserved Channel SC-Box to Regulate the Muscle Two-Pore Domain Potassium Channel SUP-9
2013Co-Authors: Ignacio Perez De La Cruz, Robert H. HorvitzAbstract:Loss-of-function mutations in the Caenorhabditis elegans gene sup-18 suppress the defects in muscle contraction conferred by a gain-of-function mutation in SUP-10, a presumptive regulatory subunit of the SUP-9 two-pore domain K+ channel associated with muscle membranes. We cloned sup-18 and found that it encodes the C. elegans ortholog of mammalian Iodotyrosine Deiodinase (IYD), an NADH oxidase/flavin reductase that functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The FMN-binding site of mammalian IYD is conserved in SUP
Fournier Jean-baptiste - One of the best experts on this subject based on the ideXlab platform.
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Evolution des mécanismes d'accumulation et de transport de l'iode dans les organismes marins (étude de la structure/fonction des protéines du métabolisme iodé chez la bactérie zobellia galactanivorans)
2014Co-Authors: Fournier Jean-baptiste, Leblanc CatherineAbstract:Dans le milieu marin, les émissions biogéniques de composés iodées jouent un rôle essentiel dans le cycle biogéochimique de l iode. Cependant les processus enzymatiques responsables de l'absorption, du stockage ou de la synthèse de métabolites iodés restent mal connus chez les chez les organismes marins, et plus encore chez les bactéries. Plusieurs gènes, potentiellement impliqués dans le métabolisme de l iode, ont été identifiés dans le génome de la bactérie marine, Zobellia galactanivorans, dont celui codant une iodoperoxydase à vanadium (VIPO), enzyme spécifique de l'oxydation des iodures. La partie principale du projet de thèse a consisté à comprendre les mécanismes moléculaires contrôlant la spécificité pour certains halogénures des haloperoxydases à vanadium, en étudiant la VIPO de Z. galactanivorans par des approches de mutagénèse dirigée et de biologie structurale. Les douze enzymes mutantes produites et caractérisées au niveau biochimique montrent soit une perte d activité, soit des modifications de leurs propriétés catalytiques, soit encore une faible activité bromoperoxydase. Les enzymes sauvage et mutantes ont également été étudiées par diffraction et absorption des rayons X, afin de relier les modifications structurales à leurs propriétés catalytiques. Les résultats suggèrent que le principal facteur modulant la spécificité chez ces enzymes est le potentiel d oxydoréduction de l intermédiaire réactionnel, le peroxovanadate. Des analyses biochimiques ont aussi été entreprises pour deux autres protéines identifiées sur le génome de Z. galactanivorans. La première protéine s est révélée être une seconde VIPO. Pour la deuxième protéine, similaire à une Iodotyrosine déiodinase, l activité biochimique reste encore à être caractérisée. Z. galactanivorans posséderait plusieurs enzymes pouvant oxyder l iodure, ainsi qu une permettant de cliver les liaisons C-I. En parallèle à ce travail, la localisation et la spéciation de l iode ont été étudiées par imagerie chimique chez Z. galactanivorans et chez l algue brune, Laminaria digitata, connue pour ses fortes teneurs en iode. Les résultats de ce travail apportent un nouvel éclairage sur les mécanismes contrôlant la spécificité des haloperoxydases à vanadium envers les halogénures, et également sur l origine bactérienne de cette famille d enzymes. Plus globalement, ces études permettent de mieux appréhender le rôle du métabolisme de l iode chez certaines bactéries marines et leurs importances dans le cycle biogéochimique de l iode.In marine environment, biogenic emissions of iodinated compounds play an essential role in biogeochemical cycle of iodine. Nevertheless, enzymatic process involved in absorption and storage of iodine or in the synthesis of iodinated compounds are unknown marine organisms, especially in bacteria. Several genes, potentially involved in iodine metabolism, have been identified in the genome of a marine bacterium, Zobellia galactanivorans. One of these genes codes for a vanadium iodoperoxydase (VIPO), an enzyme specific of iodide oxidation. The main part of the thesis project was to understand molecular mechanisms controlling the specificity vanadium halopéroxydase (VHPO) for some halide, by studying the VIPO from Z. galactanivorans by directed mutagenesis and structural biology. To lead this project, twelve mutated enzymes were produced and characterized at biochemical level. For some of them, mutations lead to a loss of activity or to modification of catalytic properties or to a slight VBPO activity. The wild type enzyme and three mutants were also analyzed by X ray absorption and diffraction spectroscopy in order to link the structural modifications to their catalytic properties. The results of this study suggest that the main factor modulating the specificity in these enzymes is modification of redox potential of the peroxovanadate. Biochemical analyses lead with two other proteins identified in the genome of Z. galactanivorans. The first protein was characterized as a new VIPO. For the second protein, similar to mammal Iodotyrosine Deiodinase, the biochemical activity remains to be characterized. Z. galactanivorans seems to have several enzymes which oxidize iodide or split C-I bond. In parallel at this work, the localization and speciation of iodine were analyzed by chemical imaging in Z. galactanivorans and in the kelp L. digitata, known to concentrate highly iodide. All this information allow to a better understanding of molecular mechanisms involved in the specificity for halide in VHPO and the bacterial origin of these proteins. More generally, these studies assess to understand the role of iodine metabolism in some marine bacteria and there role in biogeochemical cycle of this element.PARIS-JUSSIEU-Bib.électronique (751059901) / SudocSudocFranceF
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Evolution des mécanismes d'accumulation et de transport de l'iode dans les organismes marins : étude de la structure/fonction des protéines du métabolisme iodé chez la bactérie zobellia galactanivorans
HAL CCSD, 2014Co-Authors: Fournier Jean-baptisteAbstract:In marine environment, biogenic emissions of iodinated compounds play an essential role in biogeochemical cycle of iodine. Nevertheless, enzymatic process involved in absorption and storage of iodine or in the synthesis of iodinated compounds are unknown marine organisms, especially in bacteria. Several genes, potentially involved in iodine metabolism, have been identified in the genome of a marine bacterium, Zobellia galactanivorans. One of these genes codes for a vanadium iodoperoxydase (VIPO), an enzyme specific of iodide oxidation. The main part of the thesis project was to understand molecular mechanisms controlling the specificity vanadium halopéroxydase (VHPO) for some halide, by studying the VIPO from Z. galactanivorans by directed mutagenesis and structural biology. To lead this project, twelve mutated enzymes were produced and characterized at biochemical level. For some of them, mutations lead to a loss of activity or to modification of catalytic properties or to a slight VBPO activity. The wild type enzyme and three mutants were also analyzed by X ray absorption and diffraction spectroscopy in order to link the structural modifications to their catalytic properties. The results of this study suggest that the main factor modulating the specificity in these enzymes is modification of redox potential of the peroxovanadate. Biochemical analyses lead with two other proteins identified in the genome of Z. galactanivorans. The first protein was characterized as a new VIPO. For the second protein, similar to mammal Iodotyrosine Deiodinase, the biochemical activity remains to be characterized. Z. galactanivorans seems to have several enzymes which oxidize iodide or split C-I bond. In parallel at this work, the localization and speciation of iodine were analyzed by chemical imaging in Z. galactanivorans and in the kelp L. digitata, known to concentrate highly iodide. All this information allow to a better understanding of molecular mechanisms involved in the specificity for halide in VHPO and the bacterial origin of these proteins. More generally, these studies assess to understand the role of iodine metabolism in some marine bacteria and there role in biogeochemical cycle of this element.Dans le milieu marin, les émissions biogéniques de composés iodées jouent un rôle essentiel dans le cycle biogéochimique de l’iode. Cependant les processus enzymatiques responsables de l'absorption, du stockage ou de la synthèse de métabolites iodés restent mal connus chez les chez les organismes marins, et plus encore chez les bactéries. Plusieurs gènes, potentiellement impliqués dans le métabolisme de l’iode, ont été identifiés dans le génome de la bactérie marine, Zobellia galactanivorans, dont celui codant une iodoperoxydase à vanadium (VIPO), enzyme spécifique de l'oxydation des iodures. La partie principale du projet de thèse a consisté à comprendre les mécanismes moléculaires contrôlant la spécificité pour certains halogénures des haloperoxydases à vanadium, en étudiant la VIPO de Z. galactanivorans par des approches de mutagénèse dirigée et de biologie structurale. Les douze enzymes mutantes produites et caractérisées au niveau biochimique montrent soit une perte d’activité, soit des modifications de leurs propriétés catalytiques, soit encore une faible activité bromoperoxydase. Les enzymes sauvage et mutantes ont également été étudiées par diffraction et absorption des rayons X, afin de relier les modifications structurales à leurs propriétés catalytiques. Les résultats suggèrent que le principal facteur modulant la spécificité chez ces enzymes est le potentiel d’oxydoréduction de l’intermédiaire réactionnel, le peroxovanadate. Des analyses biochimiques ont aussi été entreprises pour deux autres protéines identifiées sur le génome de Z. galactanivorans. La première protéine s’est révélée être une seconde VIPO. Pour la deuxième protéine, similaire à une Iodotyrosine déiodinase, l’activité biochimique reste encore à être caractérisée. Z. galactanivorans posséderait plusieurs enzymes pouvant oxyder l’iodure, ainsi qu’une permettant de cliver les liaisons C-I. En parallèle à ce travail, la localisation et la spéciation de l’iode ont été étudiées par imagerie chimique chez Z. galactanivorans et chez l’algue brune, Laminaria digitata, connue pour ses fortes teneurs en iode. Les résultats de ce travail apportent un nouvel éclairage sur les mécanismes contrôlant la spécificité des haloperoxydases à vanadium envers les halogénures, et également sur l’origine bactérienne de cette famille d’enzymes. Plus globalement, ces études permettent de mieux appréhender le rôle du métabolisme de l’iode chez certaines bactéries marines et leurs importances dans le cycle biogéochimique de l’iode
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Evolution of mecanisms of accumulation and transportation of iodine in marine organisms : structure/function study of proteins of iodine metabolism in the marine bacterium Zobellia galactanivorans
2014Co-Authors: Fournier Jean-baptisteAbstract:Dans le milieu marin, les émissions biogéniques de composés iodées jouent un rôle essentiel dans le cycle biogéochimique de l’iode. Cependant les processus enzymatiques responsables de l'absorption, du stockage ou de la synthèse de métabolites iodés restent mal connus chez les chez les organismes marins, et plus encore chez les bactéries. Plusieurs gènes, potentiellement impliqués dans le métabolisme de l’iode, ont été identifiés dans le génome de la bactérie marine, Zobellia galactanivorans, dont celui codant une iodoperoxydase à vanadium (VIPO), enzyme spécifique de l'oxydation des iodures. La partie principale du projet de thèse a consisté à comprendre les mécanismes moléculaires contrôlant la spécificité pour certains halogénures des haloperoxydases à vanadium, en étudiant la VIPO de Z. galactanivorans par des approches de mutagénèse dirigée et de biologie structurale. Les douze enzymes mutantes produites et caractérisées au niveau biochimique montrent soit une perte d’activité, soit des modifications de leurs propriétés catalytiques, soit encore une faible activité bromoperoxydase. Les enzymes sauvage et mutantes ont également été étudiées par diffraction et absorption des rayons X, afin de relier les modifications structurales à leurs propriétés catalytiques. Les résultats suggèrent que le principal facteur modulant la spécificité chez ces enzymes est le potentiel d’oxydoréduction de l’intermédiaire réactionnel, le peroxovanadate. Des analyses biochimiques ont aussi été entreprises pour deux autres protéines identifiées sur le génome de Z. galactanivorans. La première protéine s’est révélée être une seconde VIPO. Pour la deuxième protéine, similaire à une Iodotyrosine déiodinase, l’activité biochimique reste encore à être caractérisée. Z. galactanivorans posséderait plusieurs enzymes pouvant oxyder l’iodure, ainsi qu’une permettant de cliver les liaisons C-I. En parallèle à ce travail, la localisation et la spéciation de l’iode ont été étudiées par imagerie chimique chez Z. galactanivorans et chez l’algue brune, Laminaria digitata, connue pour ses fortes teneurs en iode. Les résultats de ce travail apportent un nouvel éclairage sur les mécanismes contrôlant la spécificité des haloperoxydases à vanadium envers les halogénures, et également sur l’origine bactérienne de cette famille d’enzymes. Plus globalement, ces études permettent de mieux appréhender le rôle du métabolisme de l’iode chez certaines bactéries marines et leurs importances dans le cycle biogéochimique de l’iode.In marine environment, biogenic emissions of iodinated compounds play an essential role in biogeochemical cycle of iodine. Nevertheless, enzymatic process involved in absorption and storage of iodine or in the synthesis of iodinated compounds are unknown marine organisms, especially in bacteria. Several genes, potentially involved in iodine metabolism, have been identified in the genome of a marine bacterium, Zobellia galactanivorans. One of these genes codes for a vanadium iodoperoxydase (VIPO), an enzyme specific of iodide oxidation. The main part of the thesis project was to understand molecular mechanisms controlling the specificity vanadium halopéroxydase (VHPO) for some halide, by studying the VIPO from Z. galactanivorans by directed mutagenesis and structural biology. To lead this project, twelve mutated enzymes were produced and characterized at biochemical level. For some of them, mutations lead to a loss of activity or to modification of catalytic properties or to a slight VBPO activity. The wild type enzyme and three mutants were also analyzed by X ray absorption and diffraction spectroscopy in order to link the structural modifications to their catalytic properties. The results of this study suggest that the main factor modulating the specificity in these enzymes is modification of redox potential of the peroxovanadate. Biochemical analyses lead with two other proteins identified in the genome of Z. galactanivorans. The first protein was characterized as a new VIPO. For the second protein, similar to mammal Iodotyrosine Deiodinase, the biochemical activity remains to be characterized. Z. galactanivorans seems to have several enzymes which oxidize iodide or split C-I bond. In parallel at this work, the localization and speciation of iodine were analyzed by chemical imaging in Z. galactanivorans and in the kelp L. digitata, known to concentrate highly iodide. All this information allow to a better understanding of molecular mechanisms involved in the specificity for halide in VHPO and the bacterial origin of these proteins. More generally, these studies assess to understand the role of iodine metabolism in some marine bacteria and there role in biogeochemical cycle of this element
Jose C Moreno - One of the best experts on this subject based on the ideXlab platform.
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towards the pre clinical diagnosis of hypothyroidism caused by Iodotyrosine Deiodinase dehal1 defects
Best Practice & Research Clinical Endocrinology & Metabolism, 2014Co-Authors: Ainhoa Iglesias, Laura Garcianimo, Jose Cocho A De Juan, Jose C MorenoAbstract:DEHAL1 (also named IYD) is the thyroidal enzyme that deiodinates mono- and diIodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to the Iodotyrosine Deiodinase deficiency (ITDD), characterized by hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of Iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in Iodotyrosine determinations. A handful of mutations in the DEHAL1 gene have been identified as the molecular basis for the ITDD. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, and psychomotor deficits were present in some affected individuals. This is probably due to the lack of biochemical expression of the disease at the beginning of life, which causes ITDD being undetected in screening programs for congenital hypothyroidism, as currently performed. This worrying feature calls for efforts to improve pre-clinical detection of Iodotyrosine Deiodinase deficiency during the neonatal time. Such a challenge poses questions of patho-physiological (natural history of the disease, environmental factors influencing its expression) epidemiological (prevalence of ITDD) and technical nature (development of optimal methodology for safe detection of pre-clinical ITDD), which will be addressed in this review.
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genetics and phenomics of hypothyroidism and goiter due to Iodotyrosine Deiodinase dehal1 gene mutations
Molecular and Cellular Endocrinology, 2010Co-Authors: Jose C Moreno, Theo J. VisserAbstract:Abstract Iodotyrosine Deiodinase is a thyroidal enzyme that deiodinates mono- and di-Iodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to hypothyroidism, goiter and mental retardation, a clinical phenotype yet described in the 1950s, whose diagnostic hallmark is the elevation of Iodotyrosines in serum and urine. DEHAL1, the gene responsible for this activity, was recently isolated and the molecular basis for the Iodotyrosine Deiodinase deficiency (ITDD) unraveled. The current clinical picture of mutations in DEHAL1 mostly recapitulates the “classical” phenotype of ITDD, including the psychomotor deficits. This is probably due to the lack of expression of the disease at the beginning of life, which causes ITDD being undetected in current screening programs for congenital hypothyroidism. This worrying feature calls for efforts to improve the preclinical detection of Iodotyrosine Deiodinase deficiency in the neonatal time.
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mutations in the Iodotyrosine Deiodinase gene and hypothyroidism
The New England Journal of Medicine, 2008Co-Authors: Jose C Moreno, Mariella Dalessandro, Aubene Leger, Michel Polak, Graziella Pinto, Hans Van Toor, W Klootwijk, David Goudie, Annette Gruters, Theo J. VisserAbstract:DEHAL1 has been identified as the gene encoding Iodotyrosine Deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an Iodotyrosine Deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of Iodotyrosine Deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in Iodotyrosine Deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.
Ignacio Perez De La Cruz - One of the best experts on this subject based on the ideXlab platform.
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the caenorhabditis elegans Iodotyrosine Deiodinase ortholog sup 18 functions through a conserved channel sc box to regulate the muscle two pore domain potassium channel sup 9
PLOS Genetics, 2014Co-Authors: Ignacio Perez De La Cruz, Robert H. HorvitzAbstract:Loss-of-function mutations in the Caenorhabditis elegans gene sup-18 suppress the defects in muscle contraction conferred by a gain-of-function mutation in SUP-10, a presumptive regulatory subunit of the SUP-9 two-pore domain K(+) channel associated with muscle membranes. We cloned sup-18 and found that it encodes the C. elegans ortholog of mammalian Iodotyrosine Deiodinase (IYD), an NADH oxidase/flavin reductase that functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The FMN-binding site of mammalian IYD is conserved in SUP-18, which appears to require catalytic activity to function. Genetic analyses suggest that SUP-10 can function with SUP-18 to activate SUP-9 through a pathway that is independent of the presumptive SUP-9 regulatory subunit UNC-93. We identified a novel evolutionarily conserved serine-cysteine-rich region in the C-terminal cytoplasmic domain of SUP-9 required for its specific activation by SUP-10 and SUP-18 but not by UNC-93. Since two-pore domain K(+) channels regulate the resting membrane potentials of numerous cell types, we suggest that the SUP-18 IYD regulates the activity of the SUP-9 channel using NADH as a coenzyme and thus couples the metabolic state of muscle cells to muscle membrane excitability.
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The Caenorhabditis elegans Iodotyrosine Deiodinase Ortholog SUP-18 Functions through a Conserved Channel SC-Box to Regulate the Muscle Two-Pore Domain Potassium Channel SUP-9
2013Co-Authors: Ignacio Perez De La Cruz, Robert H. HorvitzAbstract:Loss-of-function mutations in the Caenorhabditis elegans gene sup-18 suppress the defects in muscle contraction conferred by a gain-of-function mutation in SUP-10, a presumptive regulatory subunit of the SUP-9 two-pore domain K+ channel associated with muscle membranes. We cloned sup-18 and found that it encodes the C. elegans ortholog of mammalian Iodotyrosine Deiodinase (IYD), an NADH oxidase/flavin reductase that functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The FMN-binding site of mammalian IYD is conserved in SUP
