Characterization of Human Iodothyronine Sulfotransferases1

Kester, Maartje I.; Kaptein, Ellen; Roest, Thirza J.; Dijk, Caren H. van; Tibboel, Dick; Meinl, Walter; Glatt, Hansruedi; Coughtrie, Michael W. H.; Visser, Theo J.

doi:10.1210/jcem.84.4.5590

Cited by 27 publications

(11 citation statements)

References 51 publications

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“…Both human SULT1A1 and CAR are expressed in the tissues that show the highest distribution of TH sulfation activity (32). Human SULT1A1 has been shown to sulfate TH in vitro (33), and it shows a higher affinity for iodothyronines compared with the closely related SULT1A3 isozyme (34). In contrast, SULT-N has only recently been described, and its activity as a T 4 sulfotransferase has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Receptor CAR Is a Regulator of Thyroid Hormone Metabolism during Caloric Restriction

Maglich

Watson

McMillen

et al. 2004

Journal of Biological Chemistry

209

192

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The orphan nuclear receptor CAR (NR1I3) has been characterized as a central component in the coordinate response to xenobiotic and endobiotic stress. In this study, we demonstrate that CAR plays a pivotal function in energy homeostasis and establish an unanticipated metabolic role for this nuclear receptor. Wild-type mice treated with the synthetic CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) exhibited decreased serum concentration of the thyroid hormone (TH) thyroxine (T 4 ). However, treatment of Car ؊/؊ mice with TCPOBOP failed to elicit these changes. To examine whether CAR played a role in the regulation of TH levels under physiological conditions, wild-type and Car ؊/؊ mice were fasted for 24 h, a process known to alter TH metabolism in mammals. As expected, the serum triiodothyronine and T 4 concentrations decreased in wild-type mice. However, triiodothyronine and T 4 levels in fasted Car ؊/؊ mice remained significantly higher than those in fasted wild-type animals. Concomitant with the changes in serum TH levels, both CAR agonist treatment and fasting induced the expression of CAR target genes (notably, Cyp2b10, Ugt1a1, Sultn, Sult1a1, and Sult2a1) in a receptor-dependent manner. Importantly, the Ugt1a1, Sultn, Sult1a1, and Sult2a1 genes encode enzymes that are capable of metabolizing TH. An attenuated reduction in TH levels during fasting, as observed in Car ؊/؊ mice, would be predicted to increase weight loss during caloric restriction. Indeed, when Car ؊/؊ animals were placed on a 40% caloric restriction diet for 12 weeks, Car ؊/؊ animals lost over twice as much weight as their wild-type littermates. Thus, CAR participates in the molecular mechanisms contributing to homeostatic resistance to weight loss. These data imply that CAR represents a novel therapeutic target to uncouple metabolic rate from food intake and has implications in obesity and its associated disorders.In Western societies, obesity is reaching potentially epidemic proportions. In the United States, it is estimated that 55% of adults are overweight, and nearly a quarter are obese (1). Associated with the rise in obesity are concomitant rises in the incidence of metabolic syndrome or syndrome X, typified by type 2 diabetes, cardiovascular disease, hypertension, and hyperlipidemia. The epidemic of obesity inflicts significant disadvantages on both the individual and society, i.e. increased risk of death and disease, increased health care costs, and reduced social and educational status.A significant and discouraging factor for obese individuals trying to lose weight is that homeostatic resistance mechanisms operate to resist weight loss (2, 3). A major homeostatic barrier is decreased basal metabolic rate during periods of reduced caloric intake. Thyroid hormones (THs) 1 (thyroxine (T 4 ) and triiodothyronine (T 3 )) are the predominant regulators of basal metabolic rate. Serum levels of TH show a direct correlation with energy expenditure and caloric loss (4), decreasing significantly during fasting. The most potent...

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Section: Discussionmentioning

confidence: 99%

The Nuclear Receptor CAR Is a Regulator of Thyroid Hormone Metabolism during Caloric Restriction

Maglich

Watson

McMillen

et al. 2004

Journal of Biological Chemistry

209

192

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show abstract

Section: Discussionmentioning

confidence: 99%

“…Endogenous substrates such as iodothyronines and 17␤-estradiol (E2) have shown to be catalyzed by SULT1A1 with a clear substrate inhibition (34,35). SULT1A3 also sulfonates the above substrates with a low affinity (34,36), and higher concentrations of these substrates needed to be analyzed to investigate substrate inhibition. In fact, 3,3Ј-diiodothyronine (T2) was recently identified as the endogenous substrate of SULT1A1 (37), and we identified a catalytically feasible binding conformation when T2 modeled into the active site of SULT1A1 (21).…”

Section: Discussionmentioning

confidence: 99%

Active Site Mutations and Substrate Inhibition in Human Sulfotransferase 1A1 and 1A3

Barnett

Tsvetanov

Gamage

et al. 2004

Journal of Biological Chemistry

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Human SULT1A1 is primarily responsible for sulfonation of xenobiotics, including the activation of promutagens, and it has been implicated in several forms of cancer. Human SULT1A3 has been shown to be the major sulfotransferase that sulfonates dopamine. These two enzymes shares 93% amino acid sequence identity and have distinct but overlapping substrate preferences. The resolution of the crystal structures of these two enzymes has enabled us to elucidate the mechanisms controlling their substrate preferences and inhibition. The presence of two p-nitrophenol (pNP) molecules in the crystal structure of SULT1A1 was postulated to explain cooperativity at low and inhibition at high substrate concentrations, respectively. In SULT1A1, substrate inhibition occurs with pNP as the substrate but not with dopamine. For SULT1A3, substrate inhibition is found for dopamine but not with pNP. We investigated how substrate inhibition occurs in these two enzymes using molecular modeling, site-directed mutagenesis, and kinetic analysis. The results show that residue Phe-247 of SULT1A1, which interacts with both p-nitrophenol molecules in the active site, is important for substrate inhibition. Mutation of phenylalanine to leucine at this position in SULT1A1 results in substrate inhibition by dopamine. We also propose, based on modeling and kinetic studies, that substrate inhibition by dopamine in SULT1A3 is caused by binding of two dopamine molecules in the active site.

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“…D3 converts T 4 to rT 3 and T 3 to 3,3 0 diiodothyronine (T 2 ) and it thus the main inactivating enzyme. Besides deiodination, sulfation by sulfotransferases and glucuronidation by UDP-glucuronosyltransferases enhance the metabolism of TH and its excretion via the bile and urine (Visser et al 1990, Kester et al 1999. Upstream of Sults and Ugts is the constitutive androstane receptor (CAR).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of fasting vs food restriction on liver thyroid hormone metabolism in male rats

Vries¹,

Beeren²,

Ackermans³

et al. 2014

Journal of Endocrinology

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A variety of illnesses that leads to profound changes in the hypothalamus-pituitary-thyroid (HPT) are axis collectively known as the nonthyroidal illness syndrome (NTIS). NTIS is characterized by decreased tri-iodothyronine (T 3 ) and thyroxine (T 4 ) and inappropriately low TSH serum concentrations, as well as altered hepatic thyroid hormone (TH) metabolism. Spontaneous caloric restriction often occurs during illness and may contribute to NTIS, but it is currently unknown to what extent. The role of diminished food intake is often studied using experimental fasting models, but partial food restriction might be a more physiologically relevant model. In this comparative study, we characterized hepatic TH metabolism in two models for caloric restriction: 36 h of complete fasting and 21 days of 50% food restriction. Both fasting and food restriction decreased serum T 4 concentration, while after 36-h fasting serum T 3 also decreased. Fasting decreased hepatic T 3 but not T 4 concentrations, while food restriction decreased both hepatic T 3 and T 4 concentrations. Fasting and food restriction both induced an upregulation of liver D3 expression and activity, D1 was not affected. A differential effect was seen in Mct10 mRNA expression, which was upregulated in the fasted rats but not in food-restricted rats. Other metabolic pathways of TH, such as sulfation and UDP-glucuronidation, were also differentially affected. The changes in hepatic TH concentrations were reflected by the expression of T 3 -responsive genes Fas and Spot14 only in the 36-h fasted rats. In conclusion, limited food intake induced marked changes in hepatic TH metabolism, which are likely to contribute to the changes observed during NTIS.

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Characterization of Human Iodothyronine Sulfotransferases1

Cited by 27 publications

References 51 publications

The Nuclear Receptor CAR Is a Regulator of Thyroid Hormone Metabolism during Caloric Restriction

The Nuclear Receptor CAR Is a Regulator of Thyroid Hormone Metabolism during Caloric Restriction

Active Site Mutations and Substrate Inhibition in Human Sulfotransferase 1A1 and 1A3

Differential effects of fasting vs food restriction on liver thyroid hormone metabolism in male rats

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