Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.1.1.3 (HSD)
 3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

20 alpha-Hydroxysteroid dehydrogenase (20 alpha-HSD) in rat luteal tissue catalyzes the conversion of progesterone into a biologically inactive steroid, 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OHP) and depletes the output of progesterone into the circulation. An increase in 20 alpha-HSD activity in luteal tissue is therefore a prerequisite for the regression of functional corpora lutea in rats. We have reported that ovarian 20 alpha-HSD is composed of two isoforms (HSD1 and HSD2). In this study, among batches of ovaries collected randomly during the estrous cycle, we selected two batches (batches A and B): the cytosol preparation from batch A contained both HSD1 and HSD2 activities, whereas that from batch B contained only HSD1 activity. From these 2 batches, we extracted mRNA, and each mRNA preparation was subjected to translation in Xenopus oocytes. The translation products of batch A exhibited both HSD1 and HSD2 activities, and those of batch B only HSD1 activity in accordance with the enzymatic activities observed in the respective cytosolic preparations. The results are compatible with the presence of two distinct mRNAs coding HSD1 and HSD2, and if so their transcription will be regulated separately according to the functional state of the ovary.
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PMID:Translation of rat ovarian mRNA to two 20 alpha-hydroxysteroid dehydrogenase isozymes in Xenopus oocytes. 144 52

To investigate the regulatory mechanism of 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD) (EC 1.1.1.149) activity in ovarian tissue, the enzyme was purified from ovaries of normal mature female rats. Column chromatography of the cytosolic fraction from ovaries on DEAE-Toyopearl 650M revealed two peaks of the 20 alpha-HSD activity at different ionic strengths. These peaks were designated HSD1 and HSD2, respectively. Each of the active fractions was further purified to homogeneity by dye-affinity chromatography using Matrex Green A and AF Red-Toyopearl. Both the fractions appeared as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (at Mr = 33,000 under reducing conditions). Under non-reducing conditions, similar values were obtained on gel-exclusion HPLC, indicating that the enzyme fractions were single-stranded, monomeric polypeptides. Homogeneous HSD1 and HSD2 were purified 361-fold and 509-fold, respectively, and differed in their substrate preference. The two enzyme fractions had Km values of 4.75 microM and 5.16 microM for 20 alpha-dihydroprogesterone, respectively, and showed almost the same RF values on reverse-phase HPLC and free-zone capillary electrophoresis. However, amino acid composition was slightly different, i.e. lysin content was higher in HSD1 than HSD2. Thus, it was clarified that two types of 20 alpha-HSD with very similar molecular structures are present in the rat ovary.
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PMID:Purification and characterization of rat ovarian 20 alpha-hydroxysteroid dehydrogenase. 188 58

A novel variant of 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) mRNA was identified from the ovine liver by reverse transcription-polymerase chain reaction (RT/PCR), and was named 11 beta-HSD1C mRNA. Sequence analysis of the RT-PCR product revealed that 11 beta-HSD1C mRNA was the product of an alternative exon-splicing within the 11 beta-HSD1 gene in which exon 5 was spliced out. Although it caused a deletion of 48 amino acids in the deduced 11 beta-HSD1 protein, this alternative splicing did not result in a shift within the predicted open reading frame of 11 beta-HSD1 cDNA. Thus, 11 beta-HSD1C mRNA was predicted to code for a protein of 244 amino acids. Using RT-PCR, we also examined the expression of 11 beta-HSD1C mRNA in ovine fetal organs and in maternal myometrium, endometrium, chorion, amnion and placenta. The 11 beta-HSD1C mRNA was expressed ubiquitously, similar to 11 beta-HSD1A mRNA, but at a lower abundance. Furthermore, since levels of 11 beta-HSD1C mRNA were directly related to those of 11 beta-HSD1A mRNA, there is no tissue-specificity for this shorter transcript and the only factor regulating its production appears to be 11 beta-HSD1A mRNA itself. To determine whether 11 beta-HSD1C mRNA encoded a functional enzyme, we inserted the cDNA into the expression vector pRc/CMV, and transfected the construct into Chinese hamster ovary cells. The transfected cells expressed a mRNA of expected size but contained no detectable 11 beta-HSD activity. When combined with cellular extracts of 11 beta-HSD1A cDNA transfected cells, they also did not alter either the dehydrogenase or reductase activity. The functional significance of the 11 beta-HSD1 transcript lacking exon 5 (11 beta-HSD1C mRNA) remains to be determined.
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PMID:Identification and tissue distribution of a novel variant of 11 beta-hydroxysteroid dehydrogenase 1 transcript. 749 5

The cellular localization of 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2) gene expression in the ovine adrenal gland was determined by in situ hybridization histochemistry. 11 beta-HSD2 mRNA was localized exclusively to the adrenal cortex of the adult sheep, and within the cortex the mRNA was highly expressed in the zona fasciculata and zona reticularis with relatively low expression in the zona glomerulosa. Radiometric conversion assay using adrenal cortical tissues revealed extremely high levels of 11 beta-HSD activity which was characteristic of 11 beta-HSD2 in that it was NAD-dependent and displayed a Km for cortisol of 41 +/- 4 nM. This indicates that 11 beta-HSD2 mRNA within the ovine adrenal gland is translated and functional with respect to enzymatic activity. In marked contrast, 11 beta-HSD1 mRNA was undetectable in either the cortex or medulla of adult sheep adrenal glands. In conclusion, we have demonstrated, for the first time, the zonal localization of 11 beta-HSD2 mRNA and the presence of 11 beta-HSD2 activity in the adult sheep adrenal cortex. The adrenal 11 beta-HSD2 may function to (1) regulate the rate of cortisol secretion by adrenocortical cells; (2) protect these cells from high levels of locally produced glucocorticoids; and/or (3) provide an important source of circulating cortisone, which can be activated by the action of 11 beta-HSD1 reductase in organs such as the liver.
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PMID:Cellular localization of 11 beta-hydroxysteroid dehydrogenase 2 gene expression in the ovine adrenal gland. 755 71

Two distinct isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) with respect to enzymatic activity were identified in the ovine liver and kidney. 11 beta-HSD1 (the hepatic isoform) was reversible and NADP(H)-dependent. By contrast, 11 beta-HSD2 (the renal isoform) was unidirectional and NAD-dependent. Ovine placenta contained both forms of 11 beta-HSD activities. The cDNA encoding ovine 11 beta-HSD1 was cloned, and used as a probe to study 11 beta-HSD1 gene expression in fetal sheep during development. It was found that fetal and adult liver was the major site of 11 beta-HSD1 biosynthesis, and that 11 beta-HSD1 gene expression was regulated in a tissue-specific and developmentally programmed manner. Two non-functional variants of 11 beta-HSD1 were also identified. In addition, sheep kidney was unique in that both 11 beta-HSD1 mRNA and activity were absent. Although the physiological significance of 11 beta-HSD in individual fetal organs during development remains largely speculative, 11 beta-HSD in the fetal pituitary may contribute, at least in part, to the proposed resetting of cortisol negative feedback on pituitary ACTH during the last few days of gestation. In the fetal liver, the action of 11 beta-HSD may lead to the formation of cortisol which could act locally as well as systematically to modulate developmental processes. Placental 11 beta-HSD may protect fetus from exposure to the growth-inhibiting effects of maternal glucocorticoids.
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PMID:Ovine 11 beta-hydroxysteroid dehydrogenase: from gene to function. 758

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) converts glucocorticoids to receptor inactive metabolites. Two isoforms of the enzyme exist. 11 beta HSD1 is a low affinity NADP dependent enzyme, while 11 beta HSD2 is a high affinity NAD dependent species thought to be responsible for endowing specificity on the mineralocorticoid receptor and for protecting the fetus from high circulating levels of maternal glucocorticoids. We have recently cloned the human renal 11 beta HSD2 enzyme. In this report we show that 11 beta HSD2 potently inactivates the synthetic glucocorticoid dexamethasone, producing a single product thought to be the 11-dehydrodexamethasone metabolite. Sequence analysis shows that the new isoform is a member of the short-chain alcohol dehydrogenase superfamily (SCAD), most closely related to 17 beta HSD2 and distantly related to 11 beta HSD1.
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PMID:Cloning of the 11 beta HSD type II enzyme from human kidney. 758 4

It has been proposed that the inactivation of glucocorticoids by the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) is an obligatory step in the kidney, permitting binding of aldosterone to the mineralocorticoid receptor, and in the placenta, protecting the fetus from high circulating levels of maternal glucocorticoids. Both low and high affinity isoforms of 11 beta HSD are known to exist, with evidence accumulating that the former species (11 beta HSD1) does not fulfill criteria that would allow it to perform these physiological functions. We have recently cloned a high affinity isoform of the enzyme (11 beta HSD2) from a human kidney library and have shown this species to possess all of the characteristics predicted from whole cell studies. In the present study we have raised a polyclonal antibody (HUH23) to a synthetic peptide deduced from the carboxy-terminus of the protein. The immunopurified antibody recognized a single band at 41,000 daltons on Western blots of mammalian cells transfected with an expression plasmid containing 11 beta HSD2, slightly smaller than the predicted 44,140 daltons protein. A single band of identical size was also seen in blots of human kidney and placenta, suggesting post-translational processing of the enzyme. Immunohistochemical studies on frozen sections of human kidney showed strong 11 beta HSD2 immunoreactivity in the cortical distal convoluted tubules and collecting ducts. Strong staining was also observed in medullary tubules, which had the appearance of collecting ducts and the thick ascending limb of Henle's loop. Staining of medium intensity was observed in vascular smooth muscle cells. Epithelial cells of glomeruli showed weak but detectable reactivity with HUH23. In the placenta, HUH23 antibody immunoreactivity was restricted to syncytial trophoblast cells in which strong staining was observed. These results suggest that the 11 beta HSD2 enzyme colocalizes with the mineralocorticoid receptor in the distal nephron where it allows aldosterone to occupy its physiological receptor. Furthermore, 11 beta HSD2 is also ideally situated in the placenta to protect the fetus from high circulating levels of maternal glucocorticoids.
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PMID:Immunohistochemical localization of the 11 beta-hydroxysteroid dehydrogenase type II enzyme in human kidney and placenta. 760 80

11 beta-hydroxysteroid dehydrogenase (11-HSD) activity allows aldosterone occupancy of mineralocorticoid receptors by inactivating endogenous glucocorticoids. The expression of the 11-HSD2 gene, a low Km, NAD+ dependent species of 11-HSD, was found in several discrete areas of the rat brain by in situ hybridization. Cells strongly positive for 11-HSD2 mRNA were found in the commissural portion of the nucleus tractus solitarius, subcommissural organ and ventrolateral ventromedial hypothalamus. Scattered labeled cells were also seen in the medial vestibular nucleus. The expression of 11-HSD2 mRNA in the brain is quite distinct from that of 11-HSD1 mRNA and allows for diverse roles in modulating corticosteroid receptor involvement in control of salt appetite, blood pressure and the hypothalamo-pituitary-adrenal axis.
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PMID:Hybridization histochemical localization of 11 beta-hydroxysteroid dehydrogenase type 2 in rat brain. 766 91

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the metabolism of corticosterone to inert 11-dehydrocorticosterone, thus preventing glucocorticoid access to otherwise non-selective renal mineralocorticoid receptors (MRs), producing aldosterone selectivity in vivo. At least two isoforms of 11 beta-HSD exist. One isoform (11 beta-HSD1) has been purified from rat liver and an encoding cDNA cloned from a rat liver library. Transfection of rat 11 beta-HSD1 cDNA into amphibian cells with a mineralocorticoid phenotype encodes 11 beta-reductase activity (activation of inert 11-dehydrocorticosterone) suggesting that 11 beta-HSD1 does not have the necessary properties to protect renal MRs from exposure to glucocorticoids. This function is likely to reside in a second 11 beta-HSD isoform. 11 beta-HSD1 is co-localized with glucocorticoid receptors (GRs) and may modulate glucocorticoid access to this receptor type. To examine the predominant direction of 11 beta-HSD1 activity in intact mammalian cells, and the possible role of 11 beta-HSD in regulating glucocorticoid access to GRs, we transfected rat 11 beta-HSD1 cDNA into a mammalian kidney-derived cell system (COS-7) which has little endogenous 11 beta-HSD activity or mRNA expression. Homogenates of COS-7 cells transfected with increasing amounts of 11 beta-HSD cDNA exhibited a dose-related increase in 11 beta-dehydrogenase activity. In contrast, intact cells did not convert corticosterone to 11-dehydrocorticosterone over 24 h, but showed a clear dose-related 11 beta-reductase activity, apparent within 4 h of addition of 11-dehydrocorticosterone to the medium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:'Liver-type' 11 beta-hydroxysteroid dehydrogenase cDNA encodes reductase but not dehydrogenase activity in intact mammalian COS-7 cells. 784 28

The NADP dependent enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) metabolizes glucocorticoids to their inactive 11-keto-metabolites in a wide range of tissues. To date very little is known about the regulation of this enzyme at the level of gene transcription. In this study we show significant changes in the uterine, renal, ovarian and hepatic levels of 11 beta HSD1 mRNA over the oestrous cycle. Uterine and renal message levels followed the same pattern, with the highest levels observed at dioestrus and the lowest levels at oestrus, a pattern that correlates with plasma oestrogen levels during the cycle. In both the uterus and kidney 11 beta HSD1 message levels more than halved from dioestrus to oestrus, while renal levels than doubled at metoestrus. In contrast, hepatic 11 beta HSD1 message levels at prooestrus were twice those observed at metoestrus. Ovarian levels remain constant until metoestrus when a marked decrease in message levels was seen. 11 beta HSD1 mRNA levels are thus differentially regulated in a tissue specific manner throughout the oestrous cycle.
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PMID:Changes in the levels of 11 beta-hydroxysteroid dehydrogenase mRNA over the oestrous cycle in the rat. 785 72


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