Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q7LGC8 (HSD)
 3,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyzes the conversion of cortisol to cortisone. This activity may be deficient in the syndrome of apparent mineralocorticoid excess (AME). 11 beta-HSD L (Type I), isolated from liver, is widely expressed and utilizes NADP+ as a cofactor. The gene for 11 beta-HSD L was found to be normal in patients of AME. A second isoform, 11 beta-HSD K (Type II), isolated from kidney, is more tissue specific in expression and utilizes NAD+ as a cofactor. The cDNA clone encoding 11 beta-HSD K was isolated from sheep kidney. The cDNA is 1.8 kb in length and encodes a protein of 404 amino acid residues with a predicted M(r) 43,953. The recombinant enzyme functions as an NAD(+)-dependent 11 beta-dehydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD(+)-dependent isozyme of 17 beta-hydroxysteroid dehydrogenase. It is expressed at high levels in the kidney, placenta, adrenal and at lower levels in colon, stomach, heart and skin. The human 11 beta-HSD K gene consists of five exons spread over 6 kb. The nucleotide binding domain lies in the first and the second exon, and the catalytic domain in the fourth exon. The promoter for 11 beta-HSD K gene lacks a TATA box and has a high GC base content, suggesting that the gene may be transcriptionally regulated by factors that recognize GC-rich sequences. Fluorescent in situ hybridization of metaphase chromosomes with a positive bacteriophage P1 genomic 11 beta-HSD K clone localized the gene to chromosome 16q22. In contrast, the 11 beta-HSD L gene is located on chromosome 1 and contains 6 exons; the coding sequences of these genes are only 21% identical. Different transcriptional start sites are utilized in kidney and placenta.
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PMID:Analysis of the human gene encoding the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. 854 72

An overview of the application of kinetic methods to the delineation of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) heterogeneity in mammalian tissues is presented. Early studies of 17 beta-HSD activity in animal liver and kidney subcellular fractions were suggestive of multiple forms of the enzyme. Subsequently, detailed characterization of activity in cytosol and subcellular membrane fractions of human placenta, with particular emphasis on inhibition kinetics, yielded evidence of two kinetically-differing forms of 17 beta-HSD in that organ. Gene cloning and transfection experiments have confirmed the identity of these two proteins as products of separate genes. 17 beta-HSD type 1 is a cytosolic enzyme highly specific for C18 steroids such as 17 beta-estradiol (E2) and estrone (E1). 17 beta-HSD type 2 is a membrane bound enzyme reactive with testosterone (T) and androstenedione (A), as well as E2 and E1. Useful parameters for the detection of multiple forms of 17 beta-HSD appear to be the E2/T activity ratio, NAD/NADP activity ratios, steroid inhibitor specificity and inhibition patterns over a wide range of putative inhibitor concentrations. Evaluation of these parameters for microsomes from samples of human breast tissue suggests the presence of 17 beta-HSD type 2. The 17 beta-HSD enzymology of human testis microsomes appears to differ from placenta. Analysis of human ovary indicates granulosa cells are particularly enriched in the type 1 enzyme with type 2-like activity in stroma/theca. Mouse ovary appears to contain forms of 17 beta-HSD which differ from 17 beta-HSD type 1 and type 2 in their kinetic properties.
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PMID:Kinetic analysis of enzymic activities: prediction of multiple forms of 17 beta-hydroxysteroid dehydrogenase. 854 76

17 beta-Hydroxysteroid dehydrogenase (17 beta-HSD) type 2 catalyzes the NAD(+)-dependent oxidation of androgens, estrogens and progestins, predominantly in the secretory endometrium, placenta, liver and small intestine. 17 beta-HSD type 3 catalyzes the NADPH-dependent conversion of androstenedione to testosterone in the testis, and the genetic disease 17 beta-HSD deficiency is caused by mutations in the 17 beta-HSD3 gene.
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PMID:Molecular genetics of androgenic 17 beta-hydroxysteroid dehydrogenases. 854 78

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) modulates the access of corticosteroids to their receptors and is important in blood pressure control. The excretion of renal 11 beta-HSD (ie, NAD(+)-dependent isoform) is thought to protect renal mineralocorticoid receptors from cortisol. To examine whether endogenous renal 11 beta-HSD inhibitory factor(s) may be involved in the pathophysiology of hypertension, we studied the urinary excretion of such inhibitors in 30 patients with low-renin essential hypertension and 20 normotensive control subjects. The effect of sodium restriction on the urinary excretion of the inhibitors wa also evaluated in six normotensive control subjects. Urine was extracted with Sep-Pak cartridges and high-performance liquid chromatography. Endogenous renal 11 beta-HSD inhibitors were measured by the inhibition of 11 beta-HSD bioactivity in microsomes from the human kidney. The urinary excretion of the inhibitors was significantly increased in patients with low-renin essential hypertension (1280 +/- 88 nmol/d, mean +/- SEM) compared with normotensive control subjects (704 +/- 56 nmol/d) (P < .05). Ratios of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone did not differ significantly. Sodium restriction reduced the urinary excretion of the endogenous renal 11 beta-HSD inhibitors but did not affect the ratio of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone. Endogenous renal 11 beta-HSD inhibitory factors may contribute to the pathogenesis of low-renin essential hypertension by modulating the activity of 11 beta-HSD. Sodium intake may directly or indirectly regulate the inhibitory factors.
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PMID:Endogenous renal 11 beta-hydroxysteroid dehydrogenase inhibitory factors in patients with low-renin essential hypertension. 856 41

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) modulates glucocorticoid interactions with mineralocorticoid and glucocorticoid receptors in vivo, by converting 11 beta-hydroxyglucocorticoids to their inactive 11-ketone derivatives. Defective 11 beta-oxidation of glucocorticoids has been associated with hypertension. The objective of this study was to investigate whether 11 beta-HSD contributes to the occurrence of hypertension in spontaneously hypertensive rats (SHRs). The liver and kidney microsomal oxidations of corticosterone (the physiological glucocorticoid in rats) in organs from juvenile (3 weeks old) and adult (3 months old) SHR and Wistar-Kyoto (WKY) rats, with NAD and NADP, show no differences between rat strains. For cortisol, with NADP, adult SHRs show (1.3-3 times; P < 0.05) lower kidney microsomal oxidation rates. The liver microsomal reduction of cortisone shows remarkable interstrain differences; with NADH, reduction is conducted only by adult WKY rats, whereas with NADPH, juvenile animals show similar reduction rates, but at adulthood, only WKYs reduce cortisone. Using Western blot analysis with antibodies against 11 beta-HSD1, positive signals are obtained only for liver microsomes, appearing somewhat lower in SHRs for juvenile but not adult animals. Urinary corticosterone/11-dehydrocorticosterone ratios (measured in adult animals) are not different between rat strains, but are elevated after administration of corticosterone in both strains (although significant only in SHRs). The data provide no indications for exaggerated stimulation of renal corticosteroid receptors, due to modified 11 beta-HSD, in SHRs. However, the experiments suggest the existence of multiple 11 beta-HSDs, in addition to 11 beta-HSD1 and 11 beta-HSD2, some of which may be modified in SHR, but the nature and physiological role of these 11 beta-HSDs is unclear.
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PMID:Comparison of 11 beta-hydroxysteroid dehydrogenase in spontaneously hypertensive and Wistar-Kyoto rats. 858 2

This study evaluated the expression of the corticosteroid-metabolizing enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) during in vitro decidualization of human endometrial stromal cells. The cultured stromal cells displayed both NADP(+)-dependent (type 1) and NAD(+)-dependent (type 2) 11 beta HSD activities under basal conditions. Although the cells did not respond to estradiol (E2) added alone, catalytic levels of both isoforms were enhanced by medroxyprogesterone acetate (MPA) and further enhanced by E2 plus MPA. Type I messenger RNA (mRNA) was undetected by Northern analysis of total RNA, but was evident as a 1.5-kilobase band in polyadenylated selected RNA from E2- plus MPA-treated cultures. Use of RT-PCR to augment the sensitivity of mRNA detection revealed the presence of type I mRNA as a faint band in the MPA-treated cultures and as an intense band in the E2- plus MPA-treated cultures. Thus, type I mRNA is present as a low abundance message in the cultured stromal cells whose steady state levels parallel progestin-enhanced enzyme activity. As the expression of several progestin-regulated decidualization markers is also augmented by E2, the results of the present study reveal a correlation between enhanced 11 beta HSD expression and the decidualization reaction. Time-course measurements indicated that elevated 11 beta HSD expression is an early event in the decidualization response, which precedes E2- plus MPA-enhanced PRL production by several days. Clear dose-response effects on both type 1 and type 2 11 beta HSD activities were obtained in cells incubated with 10(-8) mol/liter E2 added together with MPA at concentrations that approximated circulating progesterone levels from the luteal phase (10(-9) mol/liter) through pregnancy (10(-7) mol/liter). Corticosteroids are thought to exert toxic and teratogenic effects on the implanting embryo and could influence trophoblast invasion by regulating extracellular matrix turnover. Therefore, the novel finding that decidualization involves marked enhancement of the corticosteroid-metabolizing capacity of stromal cells suggests a mechanism by which decidual cells could affect the health and invasiveness of implanting trophoblastic cells.
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PMID:Expression of 11 beta-hydroxysteroid dehydrogenase during decidualization of human endometrial stromal cells. 859 7

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyzes the conversion of the glucocorticoid corticosterone (cortisol in humans) to inert 11-dehydrocorticosterone (cortisone). 11 beta-HSD activity is present in the hippocampus, where it is induced by glucocorticoids and stress in vivo, prompting suggestions that the enzyme may attenuate the deleterious effects of chronic glucocorticoid excess on neuronal function and survival. Two isoforms exist: 11 beta-HSD1, a bidirectional NADPH-dependent enzyme, and 11 beta-HSD2, an NAD(+)-dependent exclusive 11 beta-dehydrogenase (corticosterone-inactivating enzyme). In this study, 11 beta-HSD1 activity and mRNA synthesis were demonstrated in primary fetal hippocampal cell cultures. Unexpectedly, the reaction direction in intact hippocampal cells was 11 beta-reduction (reactivation of inert 11-dehydrocorticosterone), although homogenization revealed that the enzyme was capable of 11 beta-dehydrogenation when removed from its normal cellular context. Dexamethasone (10(-7) M) increased 11 beta-HSD activity in homogenates of hippocampal cultures (102% increase). In intact hippocampal cells, dexamethasone induced 11 beta reductase, not dehydrogenase. To determine the functional relevance of hippocampal 11 beta-reductase, glucocorticoid potentiation of kainic acid neurotoxicity was examined. Pretreatment of hippocampal cells with corticosterone reduced survival on kainate exposure. Hippocampal cell 11 beta-HSD activity was potently inhibited by carbenoxolone. Carbenoxolone had no effect on cell survival after kainate alone and did not alter the effect of corticosterone. 11-Dehydrocorticosterone also potentiated kainate neurotoxicity; this effect was lost, however, if 11 beta-HSD was inhibited with carbenoxolone. Thus, hippocampal 11 beta-HSD seems to be a functional 11 beta-reductase in intact cells. Measures to attenuate hippocampal 11 beta-reductase may reduce neuronal vulnerability to glucocorticoid toxicity.
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PMID:11 beta-Hydroxysteroid dehydrogenase in cultured hippocampal cells reactivates inert 11-dehydrocorticosterone, potentiating neurotoxicity. 861 10

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) is thought to confer aldosterone specificity to mineralocorticoid target cells by protecting the inherently non-selective mineralocorticoid receptor (MR) from occupancy by endogenous glucocorticoids. Recently, we characterized a novel isoform of 11beta-HSD in aldosterone target cells, which has high affinity for its substrate, is unidirectional, and prefers NAD as cofactor. In this study we utilized a green fluorescent protein (GFP) technique to determine the subcellular localization of this isoform, 11beta-HSD2. We generated a chimeric gene encoding the full-length rabbit 11beta-HSD2 and, fused to its C terminus, the coding sequence of GFP. This construct was stably transfected into CHO cells. The enzymatic characteristics of the expressed 11beta-HSD2/GFP fusion protein were undistinguishable from those of the native enzyme: high affinity for corticosterone (KM 8-10 nM), NAD dependence, and lack of reductase activity. The intracellular location of the recombinant protein was determined by fluorescence microscopy. 11beta-HSD2-associated fluorescence was observed as a reticular network over the cytoplasm and nuclear envelope, whereas the plasma membrane and the nucleus were negative, suggesting endoplasmic reticulum (ER) localization. Staining of CHO cells expressing 11beta-HSD2/GFP with established subcellular organelle markers revealed a colocalization of 11beta-HSD2/GFP only with ER markers and tubulin. To examine the orientation of 11beta-HSD2 within the ER, we selectively permeabilized CHO cells and stained them with an anti-GFP antibody. Fluorescence microscopy indicated that the C-terminal region of 11beta-HSD2 is on the cytoplasmic surface of the ER membrane, since it was accessible to the GFP antibody. This conclusion was confirmed by trypsin treatment of permeabilized cells followed by Western blotting. The C-terminal region of 11beta-HSD2 was accessible to trypsin, indicating that it is on the cytoplasmic side of the ER membrane. These results indicate that 11beta-HSD2 is localized exclusively to the ER. Since 11beta-HSD2 does not contain any known ER retrieval signal, experiments are currently under way to determine what structural motifs are responsible for its ER localization.
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PMID:Subcellular localization of the type 2 11beta-hydroxysteroid dehydrogenase. A green fluorescent protein study. 866 22

Receptor-ligand binding is an essential component of mineralocorticoid (MC) activity in target tissues. Detection of type 1 mineralocorticoid receptors (MR) in cardiac tissue is therefore suggestive that, like kidney, the heart is MC responsive. The presence of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) within MC responsive tissue is essential to prevent saturation of MR by glucocorticoids. Using both high-performance liquid chromatography (HPLC) and thin layer chromatography (TLC), we have found that a high-affinity species of 11 beta-HSD predominates within human heart. Although two 11 beta-HSD isoforms were detected in human cardiac tissues, the activity of high-affinity (type 2) 11 beta-HSD was found to be at least twice that of low affinity (type 1) 11 beta-HSD. Human cardiac type 2 11 beta-HSD possesses characteristics identical to the high-affinity enzyme of distal renal tubules; 11 beta-dehydrogenation of corticosterone or cortisol to their 11-keto metabolites is NAD(+)-dependent and, with corticosterone as substrate, the enzyme has a nanomolar Km (15.1 nM as determined by Lineweaver-Burke analysis). Furthermore, its activity is unidirectional; corticosterone and cortisol are 11 beta-dehydrogenated to inactive 11-keto metabolites, whereas 11-oxoreductase activity (conversion of 11-dehydrocorticosterone and cortisone to corticosterone and cortisol, respectively) is absent. RT/PCR analysis, using primers complementary to the human renal type 2 11 beta-HSD sequence, demonstrated that the high-affinity species of 11 beta-HSD expressed in human heart is indeed the same enzyme as that produced in the kidney. These findings strongly suggest that, as is the case in the distal portion of the nephron, type 2 11 beta-HSD plays an important role in the human heart to promote glucocorticoid metabolism and to confer MC specificity upon MR.
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PMID:High affinity NAD(+)-dependent 11 beta-hydroxysteroid dehydrogenase in the human heart. 873 5

The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension due to an inborn error of cortisol metabolism and is characterized by hypokalemia and low renin levels despite subnormal or normal levels of aldosterone and other known mineralocorticoids. The syndrome is attributable to congenital deficiency of the enzyme 11 beta-hydroxydehydrogenase (11 beta-HSD), which converts cortisol (F) to biologically inactive cortisone. This results in a prolonged half-life of F, which acts at the kidney level as a potent mineralocorticoid (MC). In fact, both F and aldosterone have similar affinities in vitro for type I MC receptor (MR), and 11 beta-HSD activity protects the MR in vivo from the higher circulating levels of F. The biochemical marker of this disorder is an increased ratio of tetrahydrocortisol (THF) + allo-THF/tetrahydrocortisone (THE) in the urine, which has been found in more than 20 patients described to date, together with evidence of a more general defect in steroid ring A reduction. Only a few cases (the so-called type II form) described in Italy differ from the classic form having a normal THF/THE ratio, but in both forms the ratio of free urinary F/E has recently been found to be similarly high. Dexamethasone is the treatment of choice but is often inadequate in long term control of high blood pressure. Acquired forms of AME are those consequent on abuse of licorice or carbenoxolone, which both inhibit 11 beta-HSD; the latter also inhibits the reverse 11-oxoreductase reaction leading to somewhat different abnormalities of urinary cortisol/cortisone. So far, two isoenzymes of 11 beta-HSD have been purified and cloned; 11 beta-HSD type 1 is NADP-dependent, abundant in liver, lung, and testis, and catalyzes both 11 beta-dehydrogenation and 11 beta-oxoreduction; no mutation in its gene was detected in patients with AME. A second NAD-dependent isoenzyme is present in kidney and placenta and catalyzes dehydrogenation only. Very recently (1995) two groups have independently demonstrated the presence of mutations in its gene, located in chromosome 16q22. New and co-workers found a point mutation in exon 6 of two affected siblings of an Iranian family, while White and co-workers in parallel studies showed point mutations or small deletions in both alleles in nine unrelated patients; importantly, expression studies showed minimal or absent activity for almost all the mutant sequences. No definite mutations have been so far identified in patients with AME type II. AME is thus the third single gene cause of human hypertension to be described, after glucocorticoid remediable aldosteronism in 1992 and Liddle's syndrome in 1994.
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PMID:Apparent mineralocorticoid excess: type I and type II. 873 99


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