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Daily ingestion of iodide alone is not adequate to sustain production of the thyroid hormones, tri- and tetraiodothyronine. Proper maintenance of iodide in vivo also requires its active transport into the thyroid and its salvage from mono- and diiodotyrosine that are formed in excess during hormone biosynthesis. The enzyme iodotyrosine deiodinase responsible for this salvage is unusual in its ability to catalyze a reductive dehalogenation reaction dependent on a flavin cofactor, FMN. Initial characterization of this enzyme was limited by its membrane association, difficult purification and poor stability. The deiodinase became amenable to detailed analysis only after identification and heterologous expression of its gene. Site-directed mutagenesis recently demonstrated that cysteine residues are not necessary for enzymatic activity in contrast to precedence set by other reductive dehalogenases. Truncation of the N-terminal membrane anchor of the deiodinase has provided a soluble and stable source of enzyme sufficient for crystallographic studies. The structure of an enzyme·substrate co-crystal has become invaluable for understanding the origins of substrate selectivity and the mutations causing thyroid disease in humans. 相似文献
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The thyroid gland synthesizes thyroxine (T4), which passes through the larval tadpole's circulatory system. The enzyme type II iodothyronine deiodinase (D2) converts thyroxine (T4) to the active hormone 3,5,3'-triiodothyronine (T3) in peripheral tissues. An early response to thyroid hormone (TH) in the Xenopus laevis tadpole is the stimulation of cell division in cells that line the brain ventricles, the lumen of the spinal cord, and the limb buds. These cells express constitutively high levels of D2 mRNA. Exogenous T4 induces early DNA synthesis in brain, spinal cord, and limb buds as efficiently as T3. The deiodinase inhibitor iopanoic acid blocks T4- but not T3-induced cell division. At metamorphic climax, both TH-induced cell division and D2 expression decrease in the brain. Then D2 expression appears in late-responding tissues including the anterior pituitary, the intestine, and the tail where cell division is reduced or absent. Therefore, constitutive expression of D2 occurs in the earliest target tissues of TH that will grow and differentiate, while TH-induced expression of D2 takes place in late-responding tissues that will remodel or die. This pattern of constitutive and induced D2 expression contributes to the timing of metamorphic changes in these tissues. 相似文献
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Fasting is characterized by disrupted thyroid feedback, with suppressed levels of thyroid hormones and paraventricular thyrotropin releasing hormone (TRH). We found that third ventricle administration of the deiodinase inhibitor, iopanoic acid, dose-dependently reduced deiodinase type II (DII) activity selectively in the hypothalamus. This suppression of DII by iopanoic acid during fasting prevented elevated DII activity and blunted the decline in hypothalamic TRH mRNA levels. Because fasting-induced elevation in hypothalamic DII activity is paralleled by increased hypothalamic T3 concentration, our study suggests that T3 formation by DII in the hypothalamus is the cause of disrupted thyroid feedback during fasting. 相似文献
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Andreas Baumgartner Luis Hiedra Graziano Pinna Murat Eravci Hans Prengel Harald Meinhold 《Journal of neurochemistry》1998,71(2):817-826
Abstract: The effects of different kinds of acute stressor on thyroid hormone concentrations and deiodinase activities were investigated in four brain regions (frontal cortex, amygdala, hypothalamus, and cerebellum) and in the pituitaries and livers of adult male rats. Five groups of rats were killed after each of the following stressors: (a) an intraperitoneal injection of saline, (b) intragastric intubation, (c) and (d) two different forms of handling, being grasped as for intraperitoneal injection and being moved from one cage to another, and (e) a 2-h period spent in a slowly rotating drum. Two other groups were placed in the rotating drums for 10 and 19 h (sleep deprivation experiment), respectively. All stressors induced significant (in some cases up to 200%) increases in the activity of type II 5′-iodothyronine deiodinase, which catalyzes the deiodination of the prohormone l -thyroxine (T4) to the active metabolite 3,3′,5-triiodo-l -thyronine (T3). As a consequence, the tissue concentrations of T4 fell, and those of T3 rose (sometimes by up to 300%). However, these changes were limited to selected areas of the brain that were specific for each stressor and were not seen in all brain regions investigated in any group. No clear-cut effects of stress were seen on the activities of the type III 5-iodothyronine deiodinase isoenzyme, which catalyzes the inactivation of T3, on liver or serum thyroid hormone concentrations or on liver of brain type I 5′-iodothyronine deiodinase activities. In summary, our results show that even mild and very brief stress can induce marked increases in T3 concentrations specifically in brain but not in liver or blood. Thus, contrary to common opinion, thyroid hormones may play an important physiological role in stress reactions, at least in tissues that contain type II 5′-iodothyronine deiodinase, such as brain and pituitary. 相似文献
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Human lipoprotein lipase last exon is not translated,in contrast to lower vertebrates 总被引:1,自引:0,他引:1
F. Arnault J. Etienne L. Noé A. Raisonnier D. Brault J. W. Harney M. J. Berry C. Tse C. Fromental-Ramain J. Hamelin F. Galibert 《Journal of molecular evolution》1996,43(2):109-115
We have sequenced the first fish (zebrafish,Brachydanio rerio) lipoprotein lipase (LPL) cDNA clone. Similarities were found in mammalian LPL cDNA, but the codon spanning the last two
exons (which is thus split by the last intron) is AGA (Arg) as opposed to TGA in mammals. Exon 10 is thus partially translated.
These results were confirmed with rainbow trout (Oncorhynchus mykiss). We also investigated whether mammal TGA coded for selenocystein (SeCys), the 21st amino acid, but found that this was not
the case: TGA does not encode SeCys but is a stop codon. It thus appears that the sense codon AGA (fish) has been transformed
into a stop codon TGA (human) during the course of evolution. It remains to be determined if the “loss” of the C-terminal
end of mammalian LPL protein has conferred an advantage in terms of LPL activity or, on the contrary, a disadvantage (e.g.,
susceptibility to diabetes or atherosclerosis).
Correspondence to: J. Etienne 相似文献
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The mechanisms by which thyroid hormone accelerates energy expenditure are poorly understood. In the brown adipose tissue
(BAT), activation of thyroid hormone by type 2 iodothyronine deiodinase (D2) has been known to play a role in adaptive energy
expenditure during cold exposure in human newborns and other small mammals. Although BAT is not present in significant amounts
in normal adult humans, recent studies have found substantial amounts of D2 in skeletal muscle, a metabolically relevant tissue
in humans. This article reviews current biological knowledge about D2 and adaptive T3 production and their roles in energy
expenditure. 相似文献
9.
Background
Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified.Scope of review
The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45 years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases.Major conclusions
Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH.General significance
Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling. 相似文献10.
Anna Wojcicka J.H. Duncan Bassett Graham R. Williams 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013