Iodothyronine Deiodinases

Köhrle, Josef

doi:10.1016/s0076-6879(02)47014-0

Cited by 167 publications

(114 citation statements)

References 212 publications

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“…A few studies exist on the effects of TH on normal prostate, for example, TH modulate the activity of different enzymes involved in glycoprotein metabolism in rat prostate (Maran et al 1998(Maran et al , 2000. In order for TH to exert their effects at the nuclear level, the prohormone thyroxine (T 4 ) must be transformed intracellularly into its most active form (T 3 ) (Bianco et al 2002, Kohrle 2002. There is evidence showing that rat prostate produces T 3 locally; however, the enzymatic mechanisms have not been characterized (Schroder-van der Elst & Van der Heide 1990).…”

Section: Introductionmentioning

confidence: 99%

“…In many different tissues, T 4 is converted into T 3 by a deiodination catalyzed by one or both of two isoenzymes called type 1 (D1) and type 2 (D2) deiodinases. Both enzymes remove one iodine atom from position 5 0 of the T 4 outer ring, giving rise to T 3 (Bianco et al 2002, Kohrle 2002. These enzymes have been cloned and biochemically and molecularly characterized.…”

Section: Introductionmentioning

confidence: 99%

“…D2 activity is resistant to inhibition by PTU and GTG. The regulation of deiodinase activity is a complex process involving neuro-hormonal, environmental, and nutritional factors (Bianco et al 2002, Kohrle 2002. Hepatic D1 activity is higher in male than in female rats (Harris et al 1979); although the mechanisms have not been completely elucidated, the participation of testosterone in this sexual dimorphism has been demonstrated (Miyashita et al 1995).…”

Section: Introductionmentioning

confidence: 99%

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Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones

Anguiano¹,

López²,

Delgado³

et al. 2006

Journal of Endocrinology

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The aim of this study was to characterize the type of 5 0 -deiodinase activity in the prostate of pubescent rats (7-8 weeks), to establish its distribution in the lobes (ventral, dorsolateral, and anterior), and to analyze its modulation by prolactin (PRL), testosterone, dihydrotestosterone (DHT), and 17b-estradiol (E 2 ). Our results showed that the enzymatic activity was highly susceptible to inhibition by 6-n-propyl-2-thiouracil and gold thioglucose, its preferential substrate was reverse tri-iodothyronine (rT 3 ), it exhibited a low dithiothreitol requirement (5 mM), and the apparent K m and V max values for substrate (rT 3 ) were approximately 0$25 mM and 9$0 pmol liberated/mg protein per hour, respectively. All these characteristics indicate the preferential expression of type 1 deiodinase (D1), which was corroborated by demonstrating the presence of D1 mRNA in prostate.D1 activity was detected in all lobes and was most abundant in the dorsolateral. Although we detected type 2 deiodinase (D2) mRNA expression, the D2 activity was almost undetectable. D1 activity was enhanced in animals with hyperthyroidism and hyperprolactinemia, in intact animals treated with finasteride (inhibitor of local DHT production), and in castrated animals with E 2 replacement. In contrast, activity diminished in castrated animals with testosterone replacement. Our results suggest that thyroid hormones, PRL, and E 2 exert a positive modulation on D1 activity, while testosterone and DHT exhibit an inhibitory effect. D1 activity may be associated with prostate maturation and/or function.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones

Anguiano¹,

López²,

Delgado³

et al. 2006

Journal of Endocrinology

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“…The type I iodothyronine deiodinase (D1) selenoprotein is found in mammals predominantly in the microsomal fractions of liver, kidney and thyroid gland (Bianco et al 2002, Köhrle 2002, Kuiper et al 2005). This enzyme is responsible for a large part of the peripheral production of 3,3 ,5-triiodothyronine (T3) from thyroxine (T4) in euthyroid animals (Doorn et al 1983, Nguyen et al 1998, Bianco et al 2002.…”

Section: Introductionmentioning

confidence: 99%

Expression of recombinant membrane-bound type I iodothyronine deiodinase in yeast

Kuiper

Klootwijk²,

Visser³

2005

Journal of Molecular Endocrinology

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The bioactivity of thyroid hormone is determined to a large extent by the monodeiodination of the prohormone thyroxine (T4) by the hepatic selenoenzyme type I iodothyronine deiodinase (D1), i.e. by outer ring deiodination (ORD) to the active hormone triiodothyronine (T3) or by inner ring deiodination (IRD) to the inactive metabolite reverse T3 (rT3). Since D1 is a membrane-bound protein with an N-terminal membrane-spanning domain, the enzyme is very difficult to purify in an active state. This study was undertaken in order to develop a heterologous (over)-expression system that would eventually allow the production of large amounts of purified active D1 protein. We have expressed a mutant rat D1 protein, in which the selenocysteine residue in the core catalytic center was replaced by cysteine (D1 Cys) in yeast cells (Saccharomyces cerevisiae). After yeast cell fractionation, kinetic analysis was performed with dithiothreitol as reducing cofactor. ORD activity was associated with membrane fractions, while no activity could be detected in the cytosolic fraction. The D1 Cys protein displayed a tenfold increase in K m (2 µM) for rT3 as compared with native D1 protein in rat liver microsomes. The D1 protein content is about 65 pmol/mg microsomal protein, as compared with about 3 pmol/mg in rat liver microsomal fraction. SDS-PAGE analysis of N-bromoacetyl-[125 I]T3 affinity-labeled D1 protein showed several labeled protein isoforms with apparent molecular masses between 27 and 32 kDa. Immunoblot analysis with a specific D1 antiserum confirmed the observed D1 protein heterogeneity. Site-directed mutagenesis of several potential N-linked glycosylation sites, phosphorylation sites and a unique myristoylation site established that D1 heterogeneity is not caused by N-linked glycosylation, but probably by a combination of O-linked glycosylation and phosphorylation. Deletion of the endoplasmic reticulum (ER)-signal sequence and the membrane-spanning domain (amino acid residue 2-35), did not result in the production of a soluble D1 enzyme. Although this mutated D1 protein is inactive, the fact that it is still membrane bound indicates the existence of additional membrane attachment site(s) or membrane-spanning domains. Overall, our studies indicate that yeast cells provide a useful system for the expression of relatively high levels of D1 protein which could be used for further structure-function analysis.

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“…Selenenyl iodides (RSeI) have been attracting increasing attention as important intermediates of thyroid hormone deiodination by iodothyronine deiodinases, selenocysteine-dependent enzymes comprising three isoforms (ID-1, ID-2, and ID-3) that catalyze regioselective deiodination of iodothyronines [1,2]. However, model studies on the chemical processes involving the selenenyl iodide intermediates have often been hampered by the notorious instability of the species; selenenyl iodides usually undergo facile disproportionation to the corresponding diselenides and iodine [3,4] (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Stable Primary-Alkyl-Substituted Selenenyl Iodide and Its Hydrolytic Conversion to the Corresponding Selenenic Acid

et al. 2015

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Abstract:A primary-alkyl-substituted selenenyl iodide was successfully synthesized through oxidative iodination of a selenol with N-iodosuccinimide by taking advantage of a cavity-shaped steric protection group. The selenenyl iodide exhibited high thermal stability and remained unchanged upon heating at 100˝C for 3 h in [D 8 ]toluene. The selenenyl iodide was reduced to the corresponding selenol by treatment with dithiothreitol. Hydrolysis of the selenenyl iodide under alkaline conditions afforded the corresponding selenenic acid almost quantitatively, corroborating the chemical validity of the recent proposal that hydrolysis of a selenenyl iodide to a selenenic acid is potentially involved in the catalytic mechanism of an iodothyronine deiodinase.

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Iodothyronine Deiodinases

Cited by 167 publications

References 212 publications

Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones

Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones, prolactin and sex hormones

Expression of recombinant membrane-bound type I iodothyronine deiodinase in yeast

Synthesis of a Stable Primary-Alkyl-Substituted Selenenyl Iodide and Its Hydrolytic Conversion to the Corresponding Selenenic Acid

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