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

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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)

Benign meningioma tumors possess significant levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity. Two different 17 beta-HSDs were discovered in human placenta: one highly estrogen specific and using NADP+/NADPH as cofactors (type-1 17 beta-HSD), and a second one that utilizes both androgens and estrogens as substrates with NAD+/NADH (type-2 17 beta-HSD). Recently, two further human 17 beta-HSDs were isolated. A testis-specific 17 beta-HSD (type-3 17 beta-HSD) favors the reduction of delta 4-androstenedione to testosterone, and a ubiquitously expressed type-4 17 beta-HSD preferentially catalyzes the oxidation of estradiol and delta 5-androstenediol. In this study we characterize the expression levels of different types of 17 beta-HSD in a wide series of tumors. Using the Northern blotting method we show that type-1, -3, and -4 17 beta-HSDs are not detectable in meningiomas. In contrast, the type-2 17 beta-HSD RNA is present in 6 of 17 meningiomas and its abundance is directly correlated with estrogenic 17 beta-HSD activity (r2 = 0.74). The presence of type-2 17 beta-HSD is also demonstrated by in situ hybridization. RT-PCR and Western blots show that type-4 17 beta-HSD is also present, though at much lower levels. The progesterone receptor level, the epidermal growth factor receptor level, and the age of the patients are not correlated with the estrogenic 17 beta-HSD activity or type-2 17 beta-HSD mRNA expression level.
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PMID:17 beta-Hydroxysteroid dehydrogenase activity correlates with the type-2 17 beta-hydroxysteroid dehydrogenase mRNA abundance in human meningioma tumors. 881 69

Cytotoxic effect of progesterone on the neoplastic cells was investigated using POS cells, a cell line established from a spontaneous osteosarcoma in a dog. The 20 alpha-HSD activity of POS cells was 0.85 +/- 0.26 NADPH nmol/min mg protein, demonstrating that a considerable activity was present in this tumor cell. When progesterone was added to the medium and cultured for 48 hr, progesterone dose-dependently inhibited the cell growth, showing that progesterone was cytotoxic on this osteosarcoma cells in vitro. In order to assure the role of 20 alpha-HSD on the cell growth, various concentrations of four types of steroid derivatives, STZ 20, 23, 25, and 26, potent inhibitors of 20 alpha-HSD, were added to the medium with 0.1 microM progesterone. Then, the POS cell growth was more strongly inhibited, which may suggest that the cytotoxicity of progesterone was enhanced by inactivation of 20 alpha-HSD by STZs. From these results, POS osteosarcoma cells have 20 alpha-HSD, which might play an important role in tumor cell growth against the cell toxicity of progesterone.
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PMID:Effects of 20 alpha-hydroxysteroid dehydrogenase and its inhibitors on canine osteosarcoma cell growth in vitro. 884 97

Mineralocorticoid receptor (MR) selectivity for aldosterone is thought to be exerted by enzymes which inactivate competing glucocorticoids before they bind the receptor. Two different 11 beta-hydroxysteroid dehydrogenases (11 beta-HSD) have been described. 11 beta-HSD-1 is NADP(+)-dependent and has a Km in the micromolar range and bidirectional activity. 11 beta-HSD-2 is NAD(+)-dependent, has a Km in the nanomolar range, exhibits only oxidase activity, and colocalizes with the MR in the kidney, so is likely to serve as the gatekeeper for the MR. We have further characterized 11 beta-HSD activity in JEG-3 cells, a cell line derived from a human choriocarcinoma which was reported to have only the high affinity, NAD(+)-dependent 11 beta-HSD-2. We found that the Km for the conversion of corticosterone to 11-dehydrocorticosterone in intact cells and homogenates was about 16 nM. NAD(+)-dependent corticosterone conversion was equal in the nuclear and mitochondrial fractions and less, but significant, in the microsomal fraction. A high affinity, Km = 40 nM, NADP(+)-dependent enzyme was also found in homogenates. The subcellular distribution of this high affinity activity was greatest in the mitochondria, less in the nuclei, and even less, but still significant, in microsomes. Because of its cofactor dependency, high affinity, and different subcellular distribution, we suggest that this enzyme is neither the 11 beta-HSD-1 nor the 11 beta-HSD-2 and have named it 11 beta-HSD-3. Conversion of 11-dehydrocorticosterone to corticosterone did not occur in intact cells or in homogenates incubated with NADH or NADPH. Enzyme activity in intact cells was inhibited by glycyrrhetinic acid, carbenoxolone, progesterone, 5 beta-dihydroprogesterone, and 5 alpha-dihydroprogesterone, but not bile acids.
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PMID:11 beta-hydroxysteroid dehydrogenases of the choriocarcinoma cell line JEG-3 and their inhibition by glycyrrhetinic acid and other natural substances. 885 27

We have isolated, by screening a lambda gt11 human prostatic cDNA library, a cDNA clone that shows after transfection into transformed human embryonal kidney (293) cells high 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity that catalyzes efficiently the transformation of dihydrotestosterone to 5 alpha-androstane-3 alpha, 17 beta-diol. Chronologically, we name this enzyme type 3 3 alpha-HSD (3 alpha-HSD3). Surprisingly, human 3 alpha-HSD3 shares much higher amino acids sequence identity with human 20 alpha-HSD (97.8%) than with human type 1 and type 2 3 alpha-HSD (81.1 and 85.7% identity, respectively). DNA analysis predicts a protein of 323 amino acids with a molecular mass of 36,844. Alignment of the amino acid sequence of 3 alpha-HSD3 with other related 3 alpha- and 20 alpha-HSDs indicates that 3 alpha-HSD3 shares 68.1, 78.3, and 67.4% identity with rat 3 alpha-HSD and rabbit and rat 20 alpha-HSD, respectively. 3 alpha-HSD3 belongs to the aldo-keto reductase family and like almost all the members of this family preferred NADPH as cofactor.
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PMID:Molecular cloning of human type 3 3 alpha-hydroxysteroid dehydrogenase that differs from 20 alpha-hydroxysteroid dehydrogenase by seven amino acids. 892 Sep 37

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of biologically active cortisol to inactive cortisone in man, and corticosterone to 11-dehydrocorticosterone in rodents. As such, this enzyme has been shown to confer aldosterone-selectivity on the mineralocorticoid receptor and to modulate cortisol/corticosterone access to the glucocorticoid receptor (GR). Two kinetically distinct isoforms of this enzyme have been characterized in both rodents and man; a low-affinity NADP(H)-dependent enzyme (11 beta-HSD1) which predominantly acts as an oxoreductase and, more recently, a high-affinity NAD-dependent uni-directional dehydrogenase (11 beta-HSD2). In this study we have analysed the expression of both 11 beta-HSD1 and 11 beta-HSD2 isoforms in rat adrenal cortex and medulla and have investigated their possible roles with respect to glucocorticoid-regulated enzymes mediating catecholamine biosynthesis in adrenal medullary chromaffin cells. Using a rat 11 beta-HSD1 probe and a recently cloned in-house mouse 11 beta-HSD2 cDNA probe, Northern blot analyses revealed expression of mRNA species encoding both 11 beta-HSD1 (1.4 kb) and 11 beta-HSD2 (1.9 kb) in the whole adrenal. Consistent with this, 11 beta-dehydrogenase activity (pmol 11-dehydrocorticosterone formed/mg protein per h, mean +/- S.E.M.) in adrenal homogenates, when incubated with 50 nM corticosterone in the presence of 200 microM NAD, was 97.0 +/- 9.0 and with 500 nM corticosterone in the presence of 200 microM NADP, was 98.0 +/- 1.4. 11-Oxoreductase activity (pmol corticosterone formed/mg protein per h) with 500 nM 11-dehydrocorticosterone in the presence of 200 microM NADPH, was 187.7 +/- 31.2. In situ hybridization studies of rat adrenal cortex and medulla using 35 S-labelled antisense 11 beta-HSD1 cRNA probe revealed specific localization of 11 beta-HSD1 mRNA expression predominantly to cells at the corticomedullary junction, most likely within the inner cortex. In contrast, 11 beta-HSD2 mRNA was more abundant in cortex versus medulla, and was more uniformly distributed over the adrenal gland. Negligible staining was detected using control sense probes. Ingestion of the 11 beta-HSD inhibitor, glycyrrhizic acid (> 100 mg/kg body weight per day for 4 days) resulted in significant inhibition of adrenal NADP-dependent (98.0 +/- 1.4 vs 42.5 +/- 0.4) and NAD-dependent (97.0 +/- 9.0 vs 73.2 +/- 6.7) 11 beta-dehydrogenase activity and 11-oxoreductase activity (187.7 +/- 31.2 vs 67.7 +/- 15.3). However, while levels of 11 beta-HSD1 mRNA were similarly reduced (0.85 +/- 0.07 vs 0.50 +/- 0.05 arbitrary units), those for 11 beta-HSD2 remained unchanged (0.44 +/- 0.03 vs 0.38 +/- 0.01). Levels of mRNA encoding the glucocorticoid-dependent enzyme phenylethanolamine N-methyltransferase which catalyses the conversion of noradrenaline to adrenaline, were also significantly reduced in those rats given glycyrrhizic acid (1.12 +/- 0.04 vs 0.78 +/- 0.04), while those for the glucocorticoid-independent enzyme tyrosine hydroxylase (1.9 kb), which catalyses the conversion of tyrosine to DOPA, were unchanged (0.64 +/- 0.04 vs 0.61 +/- 0.04). In conclusion, the rat adrenal gland expresses both 11 beta-HSD1 and 11 beta-HSD2 isoforms. 11 beta-HSD1 gene expression is localized to the adrenal cortico-medullary junction, where it is ideally placed to regulate the supply of cortex-derived corticosterone to the medullary chromaffin cells. This, together with our in vivo studies, suggests that 11 beta-HSD1 may play an important role with respect to adrenocorticosteroid regulation of adrenaline biosynthesis. The role of 11 beta-HSD2 in the adrenal remains to be elucidated.
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PMID:11 beta-Hydroxysteroid dehydrogenase in the rat adrenal. 893 87

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyzes the interconversion of cortisol (F) to inactive cortisone (E) in man (corticosterone (B) to 11-dehydrocorticosterone (A) in rodents) and plays a crucial role in regulating corticosteroid hormone action. Two isoforms of this enzyme have been characterized; a low affinity NADP(H)-dependent enzyme (11 beta-HSD1) and a high affinity NAD-dependent dehydrogenase (11 beta-HSD2). We have analysed the expression of 11 beta-HSD in the rodent and human adrenal gland and have investigated its role with respect to glucocorticoid-mediated catecholamine biosynthesis. Our studies indicated higher expression of 11 beta-HSD2 mRNA in male versus female intact mouse adrenal. Both 11 beta-HSD isoforms were detected in intact male rat adrenal homogenates. For the 11 beta-HSD1 isoform, NADPH-dependent oxo-reductase activity exceeded that of NADP-dependent dehydrogenase activity (188 versus 98 pmol/mg.protein.hr). In situ hybridisation studies indicated specific localisation of 11 beta-HSD1 mRNA to cells at the corticomedullary junction. 11 beta-HSD2 mRNA was uniformly distributed across the cortex and was low/absent in the medulla. Administration of glycyrrhizic acid in vivo (> 100 mg/kg for 4 days) resulted in inhibition of 11 beta-HSD1 mRNA and activity and a decrease in mRNA levels for the glucocorticoid-dependent enzyme, phenylethanolamine N-methyltransferase, whilst levels of the glucocorticoid-independent enzyme, tyrosine hydroxylase were unchanged. No 11 beta-HSD expression was observed in the rat phaeochromocytoma cell line, PC12 cells, nor in human normal adrenal gland or phaeochromocytoma specimens. There are marked species and sex differences in the expression of 11 beta-HSD isoforms within the adrenal. The role of 11 beta-HSD within the adrenal gland remains obscure, but at least in the rat, the expression of the reductase enzyme, 11 beta-HSD1, to the corticomedullary junction may serve to maintain high medullary glucocorticoid concentrations required for catecholamine biosynthesis.
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PMID:Adrenal 11 beta-hydroxysteroid dehydrogenase. 896 40

17beta-Hydroxysteroid dehydrogenase (17beta-HSD) from the filamentous fungus Cochliobolus lunatus was purified in three steps, yielding a protein of an apparent molecular mass of 28 kDa. According to the obtained experimental data, the native form of the enzyme could be a dimer (60 kDa) and/or a tetramer (120 kDa). The enzyme was found to catalyse preferentially the reduction of steroid substrates using NADPH as an electron donor. Both androgens and estrogens are substrates for 17beta-HSD. Kinetic studies revealed the equilibrium ordered kinetic mechanism with NADPH as the first ligand to be bound to the enzyme followed by the addition of the substrate androstenedione. The purification and characterization of 17beta-HSD from Cochliobolus lunatus represents a step towards the elucidation of the role of this enzyme in fungal metabolism.
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PMID:Purification and characterization of 17beta-hydroxysteroid dehydrogenase from the filamentous fungus Cochliobolus lunatus. 901 Mar 36

Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) inactivate circulating steroid hormones, and in target tissues regulate the occupancy of steroid hormone receptors. Molecular cloning indicates that 3 alpha-HSDs are members of the aldo-keto reductase (AKR) superfamily and display high sequence identity (> 60%). Of these, the most extensively characterized is rat liver 3 alpha-HSD. X-ray crystal structures of the apoenzyme and the E.NADP+ complex have been determined and serve as structural templates for other 3 alpha-HSDs. These structures reveal that rat liver 3 alpha-HSD adopts an (alpha/beta)8-barrel protein fold. NAD(P)(H) lies perpendicular to the barrel axis in an extended conformation, with the nicotinamide ring at the core of the barrel, and the adenine ring at the periphery of the structure. The nicotinamide ring is stabilized by interaction with Y216, S166, D167, and Q190, so that the A-face points into the vacant active site. The 4-pro-(R) hydrogen transferred in the oxidoreduction of steroids is in close proximity to a catalytic tetrad that consists of D50, Y55, K84, and H117. A water molecule is within hydrogen bond distance of H117 and Y55, and its position may mimic the position of the carbonyl of a 3-ketosteroid substrate. The catalytic tetrad is conserved in members of the AKR superfamily and resides at the base of an apolar cleft implicated in binding steroid hormone. The apolar cleft consists of a side of apolar residues (L54, W86, F128, and F129), and opposing this side is a flexible loop that contains W227. These constraints suggest that the alpha-face of the steroid would orient itself along that side of the cleft containing W86. Site-directed mutagenesis of the catalytic tetrad indicates that Y55 and K84 are essential for catalysis. Y55S and Y55F mutants are catalytically inactive, but still form binary (E.NADPH) and ternary (E.NADH.Testosterone) complexes; by contrast K84R and K84M mutants are catalytically inactive, but do not bind steroid hormone. The reliance on a Tyr/Lys pair is reminiscent of catalytic mechanisms proposed for other AKR members as well as for HSDs that belong to the short-chain dehydrogenase/reductase (SDR) family, in which Tyr is the general acid, with its pKa being lowered by Lys. Superimposition of the nicotinamide rings in the structures of 3 alpha-HSD (an AKR) and 3 alpha, 20 beta-HSD (an SDR) show that the Tyr/Lys pairs are positionally conserved, suggesting convergent evolution across protein families to a common mechanism for HSD catalysis. W86Y and W227Y mutants bind testosterone to the E.NADH complex, with effective increases in Kd of 8- and 20-fold. These data provide the first evidence that the side of the apolar cleft containing W86 and the opposing flexible loop containing W227 are parts of the steroid-binding site. Detailed mutagenesis studies of the apolar cleft and elucidation of a ternary complex structure will ultimately provide details of the determinants that govern steroid hormone recognition. These determinants could provide a rational basis for structure-based inhibitor design.
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PMID:Structure and function of 3 alpha-hydroxysteroid dehydrogenase. 902 23

Whereas aldosterone is normally a much stronger mineralocorticoid than cortisol in vivo, mineralocorticoid receptors have identical in vitro affinities for these hormones. The in vivo specificity of the receptors is, at least in part, the result of activity of 11-HSD, an enzyme located in most mineralocorticoid target tissues that converts cortisol to cortisone. Cortisone is not a ligand for the receptor, whereas aldosterone is not a substrate of the enzyme. The syndrome of AME is a rare form of juvenile hypertension in which 11-HSD is defective. This deficiency allows mineralocorticoid receptors to be occupied by cortisol, leading to hypertension, because plasma concentrations of cortisol are much higher than those of aldosterone. Licorice, which contains 11-HSD inhibitors, causes a similar syndrome. There are two known isozymes of 11-HSD. The liver or type I isozyme is expressed at high levels in the liver, has a relatively low affinity for steroids (micromolar Km), catalyzes both dehydrogenation and the reverse reductase reaction, and utilizes NADP+ or NADPH as cofactors. The kidney or type 2 isozyme is expressed at high levels in the kidney and placenta, has a high affinity (nanomolar Km) for steroids, catalyzes only dehydrogenation, and utilizes NAD+ as a cofactor. Mutations in the HSD11B2 (HSD11K) gene encoding the kidney isozyme of 11-HSD have been detected in all kindreds with AME studied thus far. This gene represents a candidate locus for the common, "essential" form of hypertension.
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PMID:11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. 903 89

11beta-hydroxysteroid dehydrogenase (11beta-HSD) catalyzes the interconversion of cortisol to hormonally inactive cortisone (corticosterone (B) to 11-dehydrocorticosterone (A) in rodents), and as such is established as a pre-receptor signalling pathway for corticosteroid hormone action. To further evaluate the role of this enzyme in adult and fetal life we have characterized two isoforms of 11beta-HSD in mouse tissues. Mouse 'liver' or type 1 11beta-HSD is a bi-directional dehydrogenase/oxo-reductase (K(m) for B 1.9 microM, K(m) for A 0.73 microM). Oxo-reductase activity utilized only NADPH as a co-factor, whilst dehydrogenase activity increased with both NAD or NADP. Mouse 'kidney' or 11beta-HS3D2 activity was NAD-dependent with a K(m) for B of 0.11 microM. Dexamethasone was not a substrate. Using an in-house mouse 11beta-HSD2 cDNA and NAD-dependent activity studies, 11 beta-HSD2 was expressed in epithelial cells of colon, renal collecting ducts, ovary, and adrenal, but was absent in liver, spleen, testis and heart. With the exception of gonadal tissues, activity and mRNA levels were consistently higher in adult male versus female tissues. In fetal kidney and colon there was absent/low levels of 11beta-HSD2 expression from fetal day 15 to term (day 19/20). Placental 11beta-HSD2 mRNA and activity were highest on fetal day 13/14 and fell progressively to undetectable levels by term. Two isoforms of 11beta-HSD are present in mouse tissues in accordance with other mammalian species. The sexual-dimorphic expression 11 beta-HSD2 in kidney and colon may reflect male-female differences in sodium homeostasis, and the absent expression of 11 beta-HSD2 in late gestation may facilitate glucocorticoid-dependent maturation of mouse fetal tissues.
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PMID:Ontogeny and sexual dimorphic expression of mouse type 2 11beta-hydroxysteroid dehydrogenase. 909 7


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