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)

Recent studies have demonstrated that the interconversion of active and inactive glucocorticoids plays a key role in determining the specificity of the mineralocorticoid receptor and controlling local tissue glucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified. 11 beta-HSD1 is NADPH-dependent and at its major site of action (the liver) is a reductase, converting cortisone to cortisol (11-dehydrocorticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-dependent, is present in tissues such as the kidney and placenta, and converts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produces the syndrome of apparent mineralocorticoid excess (SAME) in which cortisol gains access to the unprotected nonspecific mineralocorticoid receptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form results from inhibition of the enzyme by licorice, carbenoxolone, ACTH-dependent steroids in the ectopic ACTH syndrome, and possibly circulating inhibitors of the enzyme. This paper focuses on recent evidence, which suggest that low levels of placental 11 beta-HSD2 result in increased exposure of the fetus to maternal glucocorticoid and low birth weight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the level of placental 11 beta-HSD. Thus animals with low birth weight and large placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 beta-HSD activity or with the extent of cortisol inactivation by isolated perfused placental cotyledons. Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant rats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth weight of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocorticoid exposure of the fetus secondary to a failure of the normal inactivation of maternal glucocorticoid by the placental may be an important mechanism linking changes in the in utero environment and common adult diseases.
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PMID:11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. 873 12

The inactivation of physiological glucocorticoids by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) confers mineralocorticoid specificity to certain aldosterone target tissues. Both NADP, and NAD-dependent isoforms of 11 beta-HSD have been described. An NAD-dependent isoform of 11 beta-HSD (11 beta-HSD2) was recently cloned from human kidney. The present studies were designed to examine the cellular distribution of 11 beta-HSD2 in human kidney and colon, and to determine if the cellular distribution of 11 beta-HSD2 within the human kidney and colon is consistent with a role in conferring mineralocorticoid specificity. Using antibodies against a fusion protein containing a portion of the human 11 beta-HSD2, immunohistochemical staining of human kidney showed intense, specific staining of connecting tubules and cortical and medullary collecting tubules and less intense staining in the cortical thick ascending limb. No immunoreactivity was found in proximal tubules, glomeruli, or blood vessels. Within the collecting tubules staining was heterogeneous. The majority of cells showed intense cytoplasmic staining while alpha-intercalated cells displayed much less immunoreactivity. Within the colon, 11 beta-HSD2 immunoreactivity was found predominantly in surface epithelial cells but not in submucosal tissues. Thus, the distribution of the cloned NAD-dependent 11 beta-HSD2 parallels the distribution of mineralocorticoid receptors within the kidney and colon. These results support the view that the NAD-dependent isoform of 11 beta-HSD (11 beta-HSD2) provides mineralocorticoid specificity by inactivating glucocorticoids in an autocrine fashion.
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PMID:Immunolocalization of NAD-dependent 11 beta-hydroxysteroid dehydrogenase in human kidney and colon. 877 Sep 80

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) reversibly converts biologically active cortisol to inactive cortisone, and when present in placentae may act to protect fetuses from high concentrations of maternal glucocorticoids. Experiments were conducted to characterize placental 11 beta-HSD oxidative activity (conversion of cortisol to cortisone), to measure effects of gestational age and uterine environment on 11 beta-HSD, and to determine any associations between placental 11 beta-HSD and fetal size. Characterization of placental 11 beta-HSD at 100 days of gestation suggests the presence of two different isoforms, one that is NADP(+)-dependent and a second that is NAD(+)-dependent. The putative NAD(+)-dependent isoform has a lower Km (nM range) and a greater Vmax, and is likely to be more biologically relevant. Placentae were then obtained at 50, 75, and 100 days of gestation from uterine environments that subsequent to uterine ligations on Day 2 of gestation were either "crowded" (< or = 20 cm/potential embryo) or "roomy" (> or = cm/potential embryo). Fetal weight and length were increased (p < or = 0.015) in the roomy compared with the crowded uterine environment at each gestational age. Both NADP(+)- and NAD(+)-dependent 11 beta-HSD increased almost fivefold between 50 and 100 days of gestation (p < 0.02). At each gestational age, the amount of NAD(+)-dependent 11 beta-HSD was over twofold greater (p < 0.001) than that of NADP(+)-dependent 11 beta-HSD. Significant statistical interactions among gestational age, uterine environment, and fetal sex indicate that the effects of these factors on placental 11 beta-HSD activity are complex. When all factors associated with the experimental model were taken into account, there were no significant associations between fetal or placental size and placental 11 beta-HSD activity. These findings demonstrate the existence of porcine placental 11 beta-HSD activity, suggest the presence of two isoforms, indicate effects of gestational age, and suggest effects of uterine environment and fetal sex on these activities.
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PMID:Porcine placental 11 beta-hydroxysteroid dehydrogenase activity. 879 78

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

1. The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) converts glucocorticoids to their inactive 11-keto metabolites. The ubiquitous expression of the NADP-dependent isoform (11 beta HSD1) suggest an important role in modulating glucocorticoid action, but little is known about 11 beta HSD1 gene expression and enzymatic activity in the rat heart. 2. In the present study rat cardiac 11 beta HSD1 activity and ontogeny of gene expression have been characterized. The addition of NADP, but not NAD, to heart homogenates resulted in significant increases in the metabolism of both corticosterone and cortisol, with the former substrate displaying far greater metabolism. Both 11 beta HSD1 gene expression and enzyme activity increased in parallel from low levels at 1 week of age to maximal levels at 8 weeks, with no further change by 16 weeks of age. 3. We also compared the activity of 11 beta HSD1 in the hearts of male and female spontaneously hypertensive rats (SHR) with normotensive Wistar-Kyoto (WKY) controls. Enzyme activity in the pooled atria of female SHR was significantly higher than in male SHR atria (7.6 +/- 0.6% conversion of corticosterone vs 4.5 +/- 0.5%; P < 0.05). The left ventricles of female WKY rats contained significantly less 11 beta HSD activity than either male WKY rats or female SHR (8.6 +/- 0.8% conversion vs 17 +/- 1.4 and 13.6 +/- 0.5%, respectively; P < 0.05). In the right ventricle, female WKY rats also had significantly less enzyme activity than either female SHR or male WKY rats (4.9 +/- 0.7 vs 10.0 +/- 1.7 and 10.2 +/- 1.4%; P < 0.05). 4. These results clearly show that the rat heart contains significant amounts of the 11 beta HSD1 enzyme and that this activity is sexually dimorphic. Furthermore, significant differences were observed between a normotensive and hypertensive strain of rat. The relevance of these observations to the aetiology and maintenance of hypertension remains to be explored.
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PMID:11 beta-Hydroxysteroid dehydrogenase type I enzyme in the hearts of normotensive and spontaneously hypertensive rats. 888 82

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

Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) regulate steroid hormone levels. cDNA cloning indicates that the rat and human liver isoforms display high sequence identity and that they belong to the aldo-keto reductase (AKR) superfamily. Of these the most extensively characterized is rat liver 3 alpha-HSD. The recently solved X-ray crystal structure shows that this enzyme adopts an (alpha/beta)8-barrel scaffold (Hoog et al. 1994). NAD(P)H binds in an extended anti-conformation and lies along the inner surface of the barrel. The nicotinamide ring is stabilized by interaction with Y216. The 4-pro(R)-hydrogen transferred in the reaction is in close proximity to Y55. K84, D50 and H117 which are implicated in catalysis. These residues are located at the base of a hydrophobic pocket which is presumed to be involved in binding steroid hormone. This catalytic tetrad is conserved in members of the AKR superfamily. Mutant enzymes support roles for Y55 in steroid binding and for K84 as the general acid involved in catalysis. The gene for rat 3 alpha-HSD has been cloned and is 47 kb in length and contains 9 exon-intron boundaries which are highly conserved in the human gene(s). The 5'-flanking regions of the rat and human genes contain consensus sequences for AP-1, Oct-1 and multiple copies of perfect and imperfect steroid hormone response elements (REs) (estrogen, glucocorticoid (GRE), and progesterone) which may comprise a steroid response unit (SRU) (Lin & Penning 1995). Constitutive and regulated expression of the rat 3 alpha-HSD gene has been studied by transiently transfecting reporter gene (chloramphenicol acetyltransferase, CAT) constructs into human hepatoma (HepG2) cells. With respect to the transcription start-site (+1), a proximal (-498 to -199bp) and distal (-20 to -4.0kb) enhancer, as well as a powerful silencer (-755 to -498 bp) were located in the promoter. Band-shift and supershift assays provide evidence that Oct-1 binds to the silencer. Tandem repeats of the imperfect proximal and distal GREs that reside in the SRU were inserted into tk-CAT vectors and transiently transfected. Stimulation of transfected cells with dexamethasone resulted in robust CAT activity. These data indicate that glucocorticoids may positively regulate transcription of the rat 3 alpha-HSD gene from the SRU.
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PMID:3 alpha-hydroxysteroid dehydrogenase: three dimensional structure and gene regulation. 894 1

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

Mutagenetic replacements of conserved residues within the active site of the short-chain dehydrogenase/reductase (SDR) superfamily were studied using prokaryotic 3 beta/17 beta-hydroxysteroid dehydrogenase (3 beta/17 beta-HSD) from Comamonas testosteroni as a model system. The results provide novel data to establish Ser 138 as a member of a catalytically important "triad" of residues also involving Tyr151 and Lys155. A Ser-->Ala exchange at position 138 results in an almost complete (> 99.9%) loss of enzymatic activity, which is not observed with a Ser-->Thr replacement. This indicates that an essential factor for catalysis is the ability of side chain 138 to form hydrogen bond interactions. Mutations in the NAD(H) binding region, in strands beta A, beta D, and adjacent turns, reveal two additional residues, Thr12 and Asn87, which are important for correct binding of the coenzyme and with a differential effect on the reactions catalyzed. Thus, mutation of Thr12 to Ala results in a complete loss of the 3 beta-dehydrogenase activity, whereas the 3-oxoreductase activity remains unchanged. On the other hand, a T12S substitution yields a protein with unaltered catalytic constants for both reactions, revealing that a specific hydrogen bond is critical for the dehydrogenase activity. Our interpretation of the available crystal structure of 3 alpha/20 beta-HSD from Streptomyces hydrogenans suggests a hydrogen bond in that enzyme between the Thr12 side chain and the backbone NH of Asn87 rather than the coenzyme, indicating that this hydrogen bond to the beta D strand might determine a crucial difference between the reductive and the oxidative reaction types. Similarly, mutation of Asn87 to Ala results in an 80% reduction of kcat/Km in the dehydrogenase direction but also unchanged 3-oxoreductase properties. It appears that the binding of NAD+ to the protein is influenced by local structural changes involving strand beta D and turn beta A to alpha B.
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PMID:Active site directed mutagenesis of 3 beta/17 beta-hydroxysteroid dehydrogenase establishes differential effects on short-chain dehydrogenase/reductase reactions. 899 15

Corticosteroids (glucocorticoids and mineralocorticoids) have multiple actions in the brain which are mediated via specific intracellular receptors. Recently, a novel and important control of glucocorticoid action has been identified in peripheral tissues; prereceptor metabolism by 11beta-hydroxysteroid dehydrogenase (11beta-HSD). This enzyme catalyses the conversion of the active glucocorticoids corticosterone and cortisol to inert 11 keto-products (11-dehydrocorticosterone, cortisone), thus regulating access of glucocorticoids to receptors. Two distinct isozymes occur. 11beta-HSD-1 is a widespread, NADP(H)-dependent enzyme, which shows bidirectional activity in tissue homogenates and microsomal preparations, but may predominantly function as an 11beta-reductase (regenerating active glucocorticoids) in intact cells. 11beta-HSD-2 is a much higher affinity, NAD-dependent, exclusive 11beta-dehydrogenase (glucocorticoid inactivating enzyme), which, when colocalized with otherwise nonselective mineralocorticoid receptors (MR), ensures selective access for aldosterone in vivo. Accumulating evidence indicates widespread expression of 11beta-HSD-1 in the brain. The highest levels are found in cerebellum, hippocampus, cortex, and pituitary, but detectable activity is also present in the hypothalamus (including the paraventricular nucleus) and other regions of neuroendocrine interest. 11beta-HSD-1 protein has been detected on Western blots of brain and immunostaining is widespread, localized predominantly in neurons and their processes. The mRNA encoding 11beta-HSD-1 is also widely expressed in the brain, its distribution broadly paralleling enzyme bioactivity and immunostaining. 11beta-HSD-1 expression is regulated during late prenatal and postnatal ontogeny and by glucocorticoids and stress, prompting suggestions that this isoform may play a role in protecting the brain from the deleterious consequences of glucocorticoid excess. However, in primary cultures of hippocampal neurons, 11beta-HSD-1 functions as a predominant 11beta-reductase, reactivating inert corticoids and thus potentiating neurotoxicity. The functions of 11beta-HSD-1 in the CNS are not defined, but may relate to mood, neuronal survival, and glucocorticoid feedback. The identification of aldosterone-selective actions in the brain (upon blood pressure and salt appetite) predict the presence of 11beta-HSD-2. This isozyme has very limited expression in the adult brain, probably confined to the subregions of the brain stem and the subcommissural organ, where some aldosterone-selective actions may be mediated. However, the midgestation fetal brain highly expresses 11beta-HSD-2, which might modulate glucocorticoid effects on CNS development. Studies with licorice-derived enzyme inhibitors indicate functional effects for 11beta-HSD in the adult brain, notably in the periventricular hypothalamus and limbic system. Thus, 11beta-HSD represents a novel and potentially important level of control of glucocorticoid action in the CNS. Enzyme modulation by pharmacological or other agents may provide a useful means to target increased or attenuated glucocorticoid action to specific sites in the brain.
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PMID:11beta-Hydroxysteroid dehydrogenase in the brain: a novel regulator of glucocorticoid action? 900 Apr 59


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