Publications

• Characteristics of inner ring (3 or 5) monodeiodination of 3,5-diiodothyronine in rat liver: evidence suggesting marked similarities of inner and outer ring deiodinases for iodothyronines.

  Chopra I.J., Chua Teco G.N.

  Endocrinology 110:89-97(1982) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Biochemical mechanisms of thyroid hormone deiodination.

  Kuiper G.G., Kester M.H., Peeters R.P., Visser T.J.

  Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T(4)) is activated by outer ring deiodination (ORD) to 3,3',5-triiodothyronine (T(3)), whereas both T(4) and T(3) are inactivated by inner ring deiodination (IRD) to 3,3',5 ... >> More

  Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T(4)) is activated by outer ring deiodination (ORD) to 3,3',5-triiodothyronine (T(3)), whereas both T(4) and T(3) 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. << Less

  Thyroid 15:787-798(2005) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• Iodothyronine deiodinase structure and function: from ascidians to humans.

  Darras V.M., Van Herck S.L.

  Iodothyronine deiodinases are important mediators of thyroid hormone (TH) action. They are present in tissues throughout the body where they catalyse 3,5,3'-triiodothyronine (T(3)) production and degradation via, respectively, outer and inner ring deiodination. Three different types of iodothyroni ... >> More

  Iodothyronine deiodinases are important mediators of thyroid hormone (TH) action. They are present in tissues throughout the body where they catalyse 3,5,3'-triiodothyronine (T(3)) production and degradation via, respectively, outer and inner ring deiodination. Three different types of iodothyronine deiodinases (D1, D2 and D3) have been identified in vertebrates from fish to mammals. They share several common characteristics, including a selenocysteine residue in their catalytic centre, but show also some type-specific differences. These specific characteristics seem very well conserved for D2 and D3, while D1 shows more evolutionary diversity related to its Km, 6-n-propyl-2-thiouracil sensitivity and dependence on dithiothreitol as a cofactor in vitro. The three deiodinase types have an impact on systemic T(3) levels and they all contribute directly or indirectly to intracellular T(3) availability in different tissues. The relative contribution of each of them, however, varies amongst species, developmental stages and tissues. This is especially true for amphibians, where the impact of D1 may be minimal. D2 and D3 expression and activity respond to thyroid status in an opposite and conserved way, while the response of D1 is variable, especially in fish. Recently, a number of deiodinases have been cloned from lower chordates. Both urochordates and cephalochordates possess selenodeiodinases, although they cannot be classified in one of the three vertebrate types. In addition, the cephalochordate amphioxus also expresses a non-selenodeiodinase. Finally, deiodinase-like sequences have been identified in the genome of non-deuterostome organisms, suggesting that deiodination of externally derived THs may even be functionally relevant in a wide variety of invertebrates. << Less

  J Endocrinol 215:189-206(2012) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Iodothyronine deiodinases.

  Kohrle J.

  Methods Enzymol 347:125-167(2002) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Sequential deiodination of thyroxine to 3,3'-diiodothyronine via 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in rat liver homogenate. The effects of fasting versus glucose feeding.

  Gavin L.A., Bui F., McMahon F., Cavalieri R.R.

  The characteristics of thyroxine (T4) deiodination to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) and of each of the latter to 3,3'-diiodothyronine (3,3'T2) were examined in rat liver homogenate. Each of the four reactions was enzymatic in nature, demonstrating pH and temperatu ... >> More

  The characteristics of thyroxine (T4) deiodination to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) and of each of the latter to 3,3'-diiodothyronine (3,3'T2) were examined in rat liver homogenate. Each of the four reactions was enzymatic in nature, demonstrating pH and temperature optima, and tissue and time dependence. All reactions were considerably augmented (greater than 10-fold) by the presence of a thiol agent. At pH 7.2 with 2 muM T4 as substrate, rT3 generation was 3.3 +/- 0.44 (S.E.) and T3 formation was 4.8 +/-0.57 pmol/min/100 mg of homogenate protein. Fasting for 72 h resulted in a significant inhibition of T4 deiodination, compared to that in the glucose-fed animals, in a 2% homogenate preparation. Enzyme activity for T4 to T3 was reduced by 54% (p less than 0.05) in the homogenate from the fasted rats. Fasting lowered the enzyme activity of T4 to rT3 by 56% (p less than 0.05). Although the monodeiodination of T3 to 3,3'-T2 was also significantly depressed (p less than 0.01) by fasting, rT3 deiodination to 3,3'-T2 was not. The in vitro additon of 5 mM dithioerythritol did not reverse the effect of fasting on any reaction. These results demonstrate that a 72-h fast significantly impairs the sequential deiodination of T4 in liver homogenate. The effect of fasting appears to be mediated mainly through a reduction in enzyme concentration rather than co-factor availability. << Less

  J Biol Chem 255:49-54(1980) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Development of a validated liquid chromatography/tandem mass spectrometry method for the distinction of thyronine and thyronamine constitutional isomers and for the identification of new deiodinase substrates.

  Piehl S., Heberer T., Balizs G., Scanlan T.S., Koehrle J.

  Thyronines (THs) and thyronamines (TAMs) are two groups of endogenous iodine-containing signaling molecules whose representatives differ from each other only regarding the number and/or the position of the iodine atoms. Both groups of compounds are substrates of three deiodinase isozymes, which ca ... >> More

  Thyronines (THs) and thyronamines (TAMs) are two groups of endogenous iodine-containing signaling molecules whose representatives differ from each other only regarding the number and/or the position of the iodine atoms. Both groups of compounds are substrates of three deiodinase isozymes, which catalyze the sequential reductive removal of iodine from the respective precursor molecule. In this study, a novel analytical method applying liquid chromatography/tandem mass spectrometry (LC-MS/MS) was developed. This method permitted the unequivocal, simultaneous identification and quantification of all THs and TAMs in the same biological sample. Furthermore, a liquid-liquid extraction procedure permitting the concurrent isolation of all THs and TAMs from biological matrices, namely deiodinase (Dio) reaction mixtures, was established. Method validation experiments with extracted TH and TAM analytes demonstrated that the method was selective, devoid of matrix effects, sensitive, linear over a wide range of analyte concentrations and robust in terms of reproducible recoveries, process efficiencies as well as intra-assay and inter-assay stability parameters. The method was applied to study the deiodination reactions of iodinated THs catalyzed by the three deiodinase isozymes. With the HPLC protocol developed herein, sufficient chromatographic separation of all constitutional TH and TAM isomers was achieved. Accordingly, the position of each iodine atom removed from a TH substrate in a Dio-catalyzed reaction was backtracked unequivocally. While several established deiodination reactions were verified, two as yet unknown reactions, namely the phenolic ring deiodination of 3',5'-diiodothyronine (3',5'-T2) by Dio2 and the tyrosyl ring deiodination of 3-monoiodothyronine (3-T1) by Dio3, were newly identified. << Less

  Rapid Commun. Mass Spectrom. 22:3286-3296(2008) [PubMed] [EuropePMC]

  This publication is cited by 7 other entries.

• Substitution of cysteine for selenocysteine in the catalytic center of type III iodothyronine deiodinase reduces catalytic efficiency and alters substrate preference.

  Kuiper G.G., Klootwijk W., Visser T.J.

  Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amin ... >> More

  Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. To evaluate the contribution of SeC144 to the catalytic properties of D3 enzyme, we generated mutants in which cysteine (D3Cys) or alanine (D3Ala) replaces SeC144 (D3wt). COS cells were transfected with expression vectors encoding D3wt, D3Cys, or D3Ala protein. Kinetic analysis was performed on homogenates with dithiothreitol as reducing cofactor. The Michaelis constant of T(3) was 5-fold higher for D3Cys than for D3wt protein. In contrast, the Michaelis constant of T(4) increased 100-fold. The D3Ala protein was enzymatically inactive. Semiquantitative immunoblotting of homogenates with a D3 antiserum revealed that about 50-fold higher amounts of D3Cys and D3Ala protein are expressed relative to D3wt protein. The relative substrate turnover number of D3Cys is 2-fold reduced for T(3) and 6-fold reduced for T(4) deiodination, compared with D3wt enzyme. Studies in intact COS cells expressing D3wt or D3Cys showed that the D3Cys enzyme is also active under in situ conditions. In conclusion, the SeC residue in the catalytic center of D3 is essential for efficient inner-ring deiodination of T(3) and in particular T(4) at physiological substrate concentrations. << Less

  Endocrinology 144:2505-2513(2003) [PubMed] [EuropePMC]