Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
...
PMID:The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. 1041 17

11beta-Hydroxysteroid dehydrogenase enzymes (11beta- HSD) regulate the ratio of active endogenous glucocorticoids to their inactive keto-metabolites, thereby controlling the access of glucocorticoids to their cognate receptors. In this study, the topology and intracellular localization of 11beta-HSD1 and 11beta-HSD2 have been analyzed by immunohistochemistry and protease protection assays of in vitro transcription/translation products. 11beta-HSD constructs, tagged with the FLAG epitope, were transiently expressed in HEK-293 cells. The enzymatic characteristics of tagged and native enzymes were indistinguishable. Fluorescence microscopy demonstrated the localization of both 11beta-HSD1 and 11beta-HSD2 exclusively to the endoplasmic reticulum (ER) membrane. To examine the orientation of tagged 11beta-HSD enzymes within the ER membrane, we stained selectively permeabilized HEK-293 cells with anti-FLAG antibody. Immunohistochemistry revealed that the N terminus of 11beta-HSD1 is cytoplasmic, and the catalytic domain containing the C terminus is protruding into the ER lumen. In contrast, the N terminus of 11beta-HSD2 is lumenal, and the catalytic domain is facing the cytoplasm. Chimeric proteins where the N-terminal anchor sequences of 11beta-HSD1 and 11beta-HSD2 were exchanged adopted inverted orientation in the ER membrane. However, both chimeric proteins were not catalytically active. Furthermore, mutation of a tyrosine motif to alanine in the transmembrane segment of 11beta-HSD1 significantly reduced V(max). The subcellular localization of 11beta-HSD1 was not affected by mutations of the tyrosine motif or of a di-lysine motif in the N terminus. However, residue Lys(5), but not Lys(6), turned out to be critical for the topology of 11beta-HSD1. Mutation of Lys(5) to Ser inverted the orientation of 11beta-HSD1 in the ER membrane without loss of catalytic activity. Our results emphasize the importance of the N-terminal transmembrane segments of 11beta-HSD enzymes for their proper function and demonstrate that they are sufficient to determine their orientation in the ER membrane.
...
PMID:The N-terminal anchor sequences of 11beta-hydroxysteroid dehydrogenases determine their orientation in the endoplasmic reticulum membrane. 1049 48

Glucocorticoid access to renal corticosteroid receptors is regulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), converting 11beta-hydroxyglucocorticoids into inactive 11-ketones. This mechanism plays a key role in maintaining normal salt-water homeostasis and blood pressure. To study whether renal cortical proximal and distal tubular 11beta-HSDs are modulated, upon shifting the electrolyte status (and may thereby contribute to adjusting the salt-water homeostasis), rats were treated for 14 days with diets with low (0.058 w/w%), normal (0.58%, which is the KCl content of standard European laboratory rat food) or high (5.8%) potassium chloride content. In proximal tubules, dietary KCl had no effect regarding corticosterone 11beta-oxidation in intact cells as well as 11beta-HSD1 and 11beta-HSD2 protein (Western blotting) and mRNA levels (semi-quantitative RT-PCR). In distal tubules, the low KCl diet also had no effect. However, distal tubules of rats fed the high KCl diet showed increased corticosterone 11beta-oxidation rates (1.6-fold, P<0.01) and 11beta-HSD2 protein (4-fold, P<0.01), whereas 11beta-HSD1 protein was decreased (no longer detected, P<0.05). Distal tubular 11beta-HSD mRNA levels were not changed upon dietary treatment. Our results suggest that upon dietary KCl loading distal tubular mineralocorticoid receptor selectivity for aldosterone is increased because of enhanced corticosterone 11beta-oxidation. This may contribute to the fine-tuning of salt-water homeostasis by the kidney.
...
PMID:High dietary potassium chloride intake augments rat renal mineralocorticoid receptor selectivity via 11beta-hydroxysteroid dehydrogenase. 1056 68

Adrenocorticosteroid activity in Lyon hypertensive (LH) and low blood pressure (LL) rat strains differ in several respects. Abnormal activity of 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSD1 and 11beta-HSD2), which interconvert corticosterone and inactive 11-dehydrocorticosterone, might contribute to the LH phenotype by regulating corticosteroid hormone access to receptors. 11beta-HSD2 (expressed in kidney but not liver) prevents endogenous glucocorticoids from binding to mineralocorticoid receptors. 11beta-HSD1 (expressed in liver and kidney) favors active glucocorticoid formation from 11-dehydrocorticosterone. 11beta-HSD properties in LH and LL have been compared by several approaches: (1) 11betaHSD activities have been measured in vitro as corticosterone dehydrogenation and in vivo as interconversion of injected cortisol and cortisone; (2) the effects of cortisol and cortisone on urine electrolytes and volume have been measured; and (3) 11beta-HSD mRNA expression has been measured by in situ hybridization. 11beta-HSD2 enzyme activities in LH and LL rats were similar and urinary cortisone:cortisol ratios were not different after cortisol injection. Cortisol caused a natriuresis and kaliuresis in both strains, with a slightly reduced response in LH rats. Renal 11beta-HSD2 mRNA expression was slightly lower in LH rats. 11beta-HSD1 was less active in LH than LL rats: enzyme activities were lower in tissue extracts; urinary cortisone:cortisol was lower in LL rats after cortisone injections; cortisone increased urine volume in LL but not LH rats; and mRNA levels tended to be lower in LH tissues. We conclude that 11beta-HSD1 is impaired in LH rats. The LH phenotype of heavier adrenals, raised corticosterone, and reduced thymus weight is similar to that described for 11beta-HSD1 knockout mice.
...
PMID:11beta-hydroxysteroid dehydrogenase and corticosteroid action in lyon hypertensive rats. 1056 93

Placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) converts glucocorticoids to 11-keto-products and is believed to play an important role in protecting fetuses from higher maternal glucocorticoid levels. Recent reports have speculated that prenatal glucocorticoid exposure leads to fetal growth retardation and adult offspring hypertension and hyperglycemia. To investigate the effects of placental 11beta-HSD2 inhibition on glucose metabolism and the 11beta-HSD system in adult offspring, pregnant rats were treated with daily injections of carbenoxolone (CBX), an inhibitor of 11beta-HSD. The offspring of the maternal CBX treatment group showed reduced birth weight (treated v control, 5.6 +/- 0.5 v 6.4 +/- 0.4 g, P < .0001). In adult offspring of the maternal CBX treatment group, plasma hemoglobin A1c was significantly increased (7.3% +/- 1.8% v 4.8% +/- 0.3%, P < .01) and glucose intolerance was shown on the oral glucose tolerance test. The gene expression of hepatic 11beta-HSD1 and renal 11beta-HSD2 was decreased 87.6% (P < .05) and 52.3% (P < .01) in adult offspring of the maternal CBX treatment group, whereas renal 11beta-HSD1 was not significantly altered. The change in 11beta-HSD activity corresponded to the change in the gene expression. These results suggest that inhibition of placental 11beta-HSD2 causes growth retardation, glucose intolerance, and partial suppression of the 11beta-HSD system in the offspring.
...
PMID:Influence of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) inhibition on glucose metabolism and 11beta-HSD regulation in adult offspring of rats. 1059 92

The biological actions of glucocorticoids in target organs are determined at least in part by the local expression of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which is responsible for the inactivation of glucocorticoids. The human endometrium is a glucocorticoid target tissue, and is known to express 11beta-HSD2. However, little is known about the function and regulation of 11beta-HSD2 in the endometrium, probably owing to the lack of in vitro model systems (i.e., cell lines) that express 11beta-HSD2. Here, we describe the characterization of 11beta-HSD expression in Ishikawa cells, a well-differentiated human endometrial adenocarcinoma cell line. The 11beta-HSD activity in intact Ishikawa cells was characteristic of 11beta-HSD2 in that it only possessed dehydrogenase activity (cortisol to cortisone) and had a high affinity for cortisol (apparent Km of 34 nM). The exclusive expression of 11beta-HSD2 in Ishikawa cells was confirmed by RT-PCR which demonstrated the presence of the mRNA for 11beta-HSD2 but not that for 11beta-HSD1. To investigate the regulation of 11beta-HSD2 in Ishikawa cells, we treated these cells with sex steroid hormones, glucocorticoids and epidermal growth factor (EGF), and determined the effects of these treatments on 11beta-HSD2 activity by an established intact cell radiometric conversion assay. Treatment with estradiol-17beta (E2, 10 nM) and medroxyprogesterone acetate (MPA, 100 nM) produced a classic sex steroid effect; the greatest increase (330% of the control) in the level of 11beta-HSD2 activity was caused by the combined treatment, followed by MPA (240% of the control) with E2 being the least effective (156% of the control). The stimulatory effect of E2 was blocked by the pure antiestrogen ICI 182,780. The synthetic glucocorticoid dexamethasone (Dex) increased 11beta-HSD2 activity in a time- and dose-dependent manner (200% of the control; 100 nM for 48 h), and the endogenous glucocorticoid cortisol was equally effective in this regard. The antiprogesterone-antiglucocorticoid RU486 did not counteract with MPA or Dex but rather acted as an agonist; increased 11beta-HSD2 activity (160% of the control; 100 nM for 72 h). By contrast, treatment with EGF caused a dose- and time-dependent decrease in 11beta-HSD2 activity (60% of the control; 10 ng/ml for 72 h). In addition, semi-quantitative RT-PCR analysis revealed that there were corresponding changes in the level of 11beta-HSD2 mRNA following the treatment of Ishikawa cells with these steroid hormones and EGF, indicating that the effects of these hormones and EGF are mediated, at least in part, at the level of 11beta-HSD2 gene transcription. In conclusion, we have demonstrated for the first time that the human Ishikawa endometrial cell line expresses exclusively the 11beta-HSD2 isozyme. Moreover, we have presented the first direct evidence that sex steroid hormones and glucocorticoids stimulate while EGF inhibit the expression of 11beta-HSD2 in Ishikawa cells, suggesting that endometrial 11beta-HSD2 is under the control of steroid hormones and EGF. Thus, the Ishikawa cell line represents an excellent model in which the function and regulation of endometrial 11beta-HSD2 may be studied.
...
PMID:Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by steroid hormones and epidermal growth factor in the Ishikawa human endometrial cell line. 1062 9

In the endometrium two enzymes are known to convert estradiol to its inactive metabolite estrone: microsomal 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) and peroxisomal 17beta-HSD4. In order to elucidate the particular function of each of these two different enzymes, the human endometrial epithelial cell lines HEC-1-A and RL95-2 were examined with respect to the expression of 17betaHSD isozymes. They were compared with human endometrium in vivo. Non-radioactive in situ hybridization revealed both enzymes in glandular epithelial cells of human endometrium. The two cell lines were screened for mRNA expression of 17beta-HSD 1-4 by RT-PCR and Northern blot. 17beta-HSD2 and 4 could be detected by either method, 17beta-HSD1 only by RT-PCR, 17beta-HSD3 not at all. Both cell lines were proven to have no receptor for progesterone which is known as a physiological inducer of several 17beta-HSD isozymes. To study the regulation of 17beta-HSD2 and 17betaHSD4, the concentration of fetal calf serum in the cell culture media was reduced stepwise to 0.3% by dilution with a defined serum replacement. This treatment led to an inhibition of 17beta-HSD2 mRNA expression and an increase in the mRNA expression of 17beta-HSD4. Concomitantly, distinct morphological changes were observed, such as a decrease in the number and length of microvilli and a decrease in the formation of domes on top of the monolayers. The endometrial epithelial cell lines HEC-1-A and RL95-2 represent a suitable in vitro model for further studies of the differential expression of the major endometrial HSD isozymes, independent of the effect of progesterone.
...
PMID:Differential expression of 17beta-hydroxysteroid dehydrogenases types 2 and 4 in human endometrial epithelial cell lines. 1065 5

17 beta-Estradiol (E2) is a potent stimulator of certain forms of breast cancer. The final step of E2 biosynthesis is catalyzed by the estrogenic 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD1), which is an important target for anti-cancer drugs. X-ray crystallography indicated that the binding site for the steroids has a tunnel-like shape. We have used a Monte Carlo-Minimization (MCM) protocol to explore possibilities of interactions of E2 with the binding site tunnel of 17 beta-HSD1. The enzyme was represented by flexible residues having at least one atom within 6 A from either E2 or NADP (as seen in a crystal ternary complex) and by rigid residues having at least one atom within 10 A from E2 or NADP. Special constraints were used to pull the substrate 10 A along the tunnel with 1 A step; the complex was MCM-optimized at each position of the steroid. The optimal binding mode of E2 in 17 beta-HSD agrees with the crystallographic data; however, wide and flat minima of the MCM profile suggest alternative modes of the steroid binding. The advance of the steroid along the tunnel is accompanied by essential conformational rearrangements of the enzyme side chains, noticeable rotation of the substrate along its longitudinal axis, and certain conformational deformations of the substrate. The contributions of the enzyme residues and of the steroid atoms to the intermolecular energy were estimated.
...
PMID:Monte Carlo-minimized energy profile of estradiol in the ligand-binding tunnel of 17 beta-hydroxysteroid dehydrogenase: atomic mechanisms of steroid recognition. 1070 28

11Beta-hydroxysterold dehydrogenase enzymes (11beta-HSD1, 11beta-HSD2) regulate access of adrenocorticosteroids to receptors. 11Beta-HSD2 is a dehydrogenase that protects mineralocorticoid receptors from circulating glucocorticoid hormones, 11beta-HSD1 is a reductase that promotes formation of active hormone in glucocorticoid-sensitive tissues. Here we investigate whether low or high sodium diets affect 11beta-HSD enzyme activities and mRNA expression in liver and kidney tissues. 11Beta-HSD activity was measured as dehydrogenation of 3H-corticosterone by microsomes in the presence of NAD or NADP. In situ hybridisation techniques were used to assess expression of 11beta-HSD1 mRNA (liver and kidney) and 11beta-HSD2 mRNA (kidney). Dietary sodium did not affect 11beta-HSD2 mRNA expression in collecting tubules of the medulla: 11beta-HSD1 mRNA in proximal tubules of the inner cortex/outer medulla was lower after a high sodium diet. 11Beta-HSD1 mRNA in liver was unaffected by treatment. Renal enzyme activity with NAD (11beta-HSD2 cofactor) was lower following a high sodium diet (P < 0.05). In the presence of NADP (11beta-HSD1 co-factor), neither renal nor hepatic activities were affected. Dietary sodium restriction appears to increase 11beta-HSD activity by a non-genomic mechanism; this should enhance aldosterone specificity for mineralocorticoid receptors. 11Beta-HSD1 mRNA expression varies independent of enzyme activity and is not clearly related to altered glucocorticoid activity.
...
PMID:Regulation of 11beta-hydroxysteroid dehydrogenase enzymes by dietary sodium in the rat. 1071 25

The serum concentration of active glucocorticosteroids depends not only on adrenal synthesis but also on enzymatic activation of 11-dehydro-glucocorticoids in the liver by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In order to define the respective involvement of other regulative enzymes in the metabolism of 11-dehydro-glucocorticoids in the liver, the objective of this study was to evaluate the kinetic behavior of NADPH:delta 4-3-ketosteroid-5alpha-reductase (5alpha-reductase, EC 1.3.99.5). The interrelations to liver 11beta-HSD1 will be discussed. The kinetic properties of 5alpha-reductase of the rabbit liver were measured by a radioenzymatic assay and characterized with respect to protein-, substrate-, cosubstrate-, and pH-dependence. Michaelis-Menten enzyme kinetic parameters (Km and Vmax) were obtained for the formation of 5alpha-reduced 11-dehydrocorticosterone and corticosterone metabolites. We found that both 11-dehydrocorticosterone (Km 4.2 x 10(-6) mol/l, Vmax 2,600 pmol x min(-1) x mg(-1)) and corticosterone (Km 0.5 x 10(-6) mol/l, Vmax 38 pmol x min(-1) x mg(-1)) exhibit a high affinity to 5alpha-reductase. With respect to cosubstrate-, pH-dependence and finasteride inhibition, it is likely that 11-dehydrocorticosterone metabolism is primarily controlled by isoenzyme 5alpha-reductase type 1. This study shows that the deactivation of GCS especially of 11-dehydro-glucocorticoids via 5alpha-reductase is an important metabolic pathway in the liver. The metabolic activation of GCS by 11beta-HSD could possibly lead to an excess of GCS in the hepatocytes. Due to 5alpha-reductase activity this excess can be limited - on the level of CORT as well as of 11-DHC.
...
PMID:Kinetic studies on rabbit liver glucocorticoid 5alpha-reductase. 1072 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---