Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) interconverts cortisol and cortisone. Congenital deficiency of the renal isoform of the enzyme results in hypertension, hypokalemia and suppression of the renin-angiotensin-aldosterone system--the apparent mineralocorticoid excess syndrome (AME). In these patients cortisol acts as a potent mineralocorticoid. Suppression of plasma cortisol with dexamethasone results in natriuresis, potassium retention and reduction in blood pressure. Ingestion of excess liquorice or taking carbenoxolone produces an acquired form of AME. The active component of liquorice is glycyrrhetinic acid (GE) and carbenoxolone is the hemisuccinate derivative. Both GE and carbenoxolone are potent inhibitors of 11 beta-OHSD. In vitro studies have shown that 11 beta-OHSD is present in aldosterone-selective tissues and acts as an autocrine mechanism which prevents cortisol from gaining access to the non-specific mineralocorticoid receptor (MR). Congenital or acquired absence of this enzyme allows cortisol to bind to MR resulting in AME. 11 beta-OHSD also appears to be important in controlling cortisol access to glucocorticoid receptors. Variable placental 11 beta-OHSD may alter foetal exposure to maternal cortisol and affect growth as indicated by the correlation between foetal weight and placental 11 beta-OHSD. Thus the tissue-specific distribution, ontogeny and modulation of this enzyme allows it to dictate glucocorticoid effects in addition to its key role in ensuring the specificity of the MR.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Congenital and acquired syndromes of apparent mineralocorticoid excess. 838 30

Prednisolone is metabolized in the perfused human placental lobule to prednisone, 20 alpha-dihydroprednisone, 20 beta-dihydroprednisone and 20 beta-dihydroprednisolone. The pathway of metabolite formation was defined in perfusions of placental lobules using prednisone and 20 beta-dihydroprednisone separately as substrates and with prednisolone co-perfused with glycyrrhetinic acid, a potent inhibitor of the 11-oxidase component of the 11 beta-hydroxysteroid dehydrogenase enzyme system. The pattern of metabolites identified from 6 h samples indicated a reversible formation of prednisone from prednisolone, the production of the 20 alpha- and 20 beta-dihydro metabolites of prednisone from prednisone, the formation of 20 beta-dihydroprednisolone from 20 beta-dihydroprednisone only and no direct formation of 20 beta-dihydroprednisolone from prednisolone. Kinetic analysis at two substrate concentrations confirmed that the formation of three of the four steroid metabolites followed first order kinetics. In perfusions with an initial prednisolone concentration of 1 microgram/ml (n = 4) or 100 ng/ml (n = 3), the rate constants obtained were (mean +/- SD, maternal compartment, h-1): prednisone, 1.97 +/- 0.49 and 2.25 +/- 0.15, P > 0.1; 20 alpha-dihydroprednisone, 0.0006 +/- 0.0004 and 0.0017 +/- 0.0006, P < 0.1; 20 beta-dihydroprednisone, 0.15 +/- 0.022 and 0.15 +/- 0.0077, P > 0.1. In contrast, the rate constant for formation of 20 beta-dihydroprednisolone at an initial prednisolone concentration of 100 ng/ml (0.083 +/- 0.0095 h-1) was significantly (P < 0.01) greater than the corresponding rate constant at the higher initial prednisolone concentration (0.039 +/- 0.015 h-1). A significant increase (P < 0.05) was observed for the formation of 20 beta-dihydroprednisolone at the end of 6 h perfusions at the lower initial substrate concentration (11.2 +/- 1.9%) compared with the 1 microgram/ml concentration (6.0 +/- 2.5%).
J Steroid Biochem Mol Biol 1993 Mar
PMID:Pathway and kinetics of prednisolone metabolism in the human placenta. 846 Dec 64

There is evidence for the presence in the kidney of more than one isoform of 11 beta-hydroxysteroid dehydrogenase (11HSD), an enzyme that interconverts cortisol and cortisone (in rodents, corticosterone and 11-dehydrocorticosterone). A specific isoform might arise from transcripts in the kidney that are known to originate in intron 1; translation from these transcripts is predicted to initiate at the codon that in the full-length rat enzyme encodes Met27. Alignment of the full-length rat and human 11HSD sequences with other members of the short chain dehydrogenase family suggests that initiation of translation at Met27 might yield a functional enzyme, since the amino-termini of most of these enzymes occur at equivalent positions. We confirmed that short transcripts are found in the kidney and are detectable at lower levels in the liver and lung. In vitro transcription and translation of short cDNA demonstrated that the AUG encoding Met27 is indeed a functional initiation codon. However, Chinese hamster ovary cells transfected with short cDNA in the pCMV4 vector expressed apparently low levels of the corresponding truncated polypeptide and had no 11HSD activity. Thus, the functional significance of transcripts originating in intron 1 is unclear.
Mol Endocrinol 1993 Feb
PMID:Transcripts originating in intron 1 of the HSD11 (11 beta-hydroxysteroid dehydrogenase) gene encode a truncated polypeptide that is enzymatically inactive. 846 31

In this review, we consider the relationship between the structure and function of 11 beta-hydroxysteroid dehydrogenase (11-HSD) purified from rat liver. The rat liver enzyme is a single domain glycoprotein with a unique active site and belongs to the short chain alcohol dehydrogenase family. Evidence supporting the presence in other tissues of 11-HSD isoforms is discussed.
J Steroid Biochem Mol Biol 1993 Apr
PMID:The forms and functions of 11 beta-hydroxysteroid dehydrogenase. 848 41

The enzyme, 11 beta-hydroxysteroid dehydrogenase converts the active glucocorticoids cortisol and corticosterone to their inactive 11-oxo metabolites cortisone and dehydrocorticosterone, respectively. The properties of the human placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) were studied. The enzyme was active in the oxidative and reductive directions. pH optimum for 11 beta-dehydrogenase activity was in the range of 7-10 and for 11-oxoreductase it was in the range of 5.5-6.0. The crude placental homogenate was unstable. Reductase activity was more labile than dehydrogenase activity. Removal of cytosol enabled the enzyme to retain activity. 11 beta-HSD a membrane bound enzyme was distributed in all particulate subcellular fractions. Addition of detergent released latent activity of 11 beta-dehydrogenase and inactivated 11-reductase activity. Both corticosterone and cortisol were substrates for the enzyme. The Km value with corticosterone as substrate was much lower than with cortisol. The Km values with cortisone and dehydrocorticosterone were similar.
J Steroid Biochem Mol Biol 1993 May
PMID:Characterization of 11 beta-hydroxysteroid dehydrogenase of human placenta: evidence for the existence of two species of 11 beta-hydroxysteroid dehydrogenase. 849 46

Excessive foetal exposure to glucocorticoids retards growth and "programmes" adult hypertension in rats. Placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which catalyses the conversion of corticosterone and cortisol to inert 11 keto-products, normally protects the foetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11 beta-HSD, and enzyme activity correlates with birth weight. Moreover, inhibition of placental 11 beta-HSD in the rat reduces birth weight and produces hypertensive adult offspring, many months after prenatal treatment with enzyme inhibitors; these effects are dependent upon maternal adrenal products. These data suggest that placental 11 beta-HSD, by regulating foetal exposure to maternal glucocorticoids, crucially determines foeto-placental growth and the programming of hypertension. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11 beta-HSD activity. Thus, deficiency of the placental barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and foeto-placental programming of later disease. These data may, at least in part, explain the human epidemiological observations linking early life events to the risk of subsequent hypertension. The recent characterization, purification and cDNA cloning of a distinct human placental 11 beta-HSD (type 2) will aid the further study of these intriguing findings.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Placental 11 beta-hydroxysteroid dehydrogenase and the programming of hypertension. 854 69

Effective glucocorticoid inactivation is currently thought to be an indispensable feature of mineralocorticoid target cells. The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) inactivates glucocorticoids and prevents them from binding to the non-selective mineralocorticoid receptor. In the kidney it is the NAD dependent high affinity isoform (11 beta-HSD2) which is thought to endow specificity on the receptor. The recent cloning of the human, sheep and rabbit 11 beta-HSD2 enzymes permits a comparison of the enzyme from the three species. Human and rabbit enzymes are 87% identical and of similar length, while the human and sheep enzymes have only 75% identity. The last 12 residues in all three species were found to be highly divergent, but most of the ovine dishomology can be accounted for by the deletion of a single nucleotide toward the C-terminus of the protein resulting in a shift in reading frame generating a protein 27 residues longer than the human isoform. Numerous other deletions were also observed in this region of the sheep cDNA sequence. Furthermore, the rabbit cDNA also displayed a large degree of dishomology with the human sequence a short distance downstream from the termination codon. Conserved overlapping cytoplasmic translocation signals were observed in all three species, suggesting a topology whereby the enzyme is anchored into the endoplasmic reticulum by multiple hydrophobic regions in the N-terminus and the bulk of the 11 beta-HSD2 peptide is sited in the cytoplasm. A polyclonal antibody generated against the C-terminus of human 11 beta-HSD2 was used to localize the enzyme within the kidney. A high level of immunoreactive was observed in distal tubules and collecting ducts, localizing the enzyme to the same part of the nephron as the mineralocorticoid receptor. Moderate levels of staining were also seen in vascular smooth muscle cells. These results support the notion that 11 beta-HSD2 is an autocrine protector of the mineralocorticoid receptor and that it plays an important role in cardiovascular homeostatic mechanisms.
J Steroid Biochem Mol Biol 1995 Dec
PMID:The human 11 beta-hydroxysteroid dehydrogenase type II enzyme: comparisons with other species and localization to the distal nephron. 854 70

Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyse the interconversion of active cortisol to inactive cortisone; 11 beta-HSD1 is a low affinity, NADP(H)-dependent dehydrogenase/oxo-reductase, and 11 beta-HSD2 a high affinity, NAD-dependent dehydrogenase. Because of the importance of 11 beta-HSD in regulating corticosteroid hormone action, we have analysed the distribution of the 11 beta-HSD isoforms in human adult and foetal tissues (including placenta), and, in addition have performed a series of substrate specificity studies on the novel, kidney 11 beta-HSD2 isoform. Using an RT-PCR approach, we failed to detect 11 beta-HSD1 mRNA in any human mid-gestational foetal tissues. In contrast 11 beta-HSD2 mRNA was present in foetal lung, adrenal, colon and kidney. In adult tissues 11 beta-HSD2 gene expression was confined to the mineralocorticoid target tissues, kidney and colon, whilst 11 beta-HSD1 was expressed predominantly in glucocorticoid target tissues, liver, lung, pituitary and cerebellum. In human kidney homogenates, 11-hydroxylated progesterone derivatives, glycyrrhetinic acid, corticosterone and the "end products" cortisone and 11-dehydrocorticosterone were potent inhibitors of the NAD-dependent conversion of cortisol to cortisone. Finally high levels of 11 beta-HSD2 mRNA and activity were observed in term placentae, which correlated positively with foetal weight. The tissue-specific distribution of the 11 beta-HSD isoforms is in keeping with their differential roles, 11 beta-HSD1 regulating glucocorticoid hormone action and 11 beta-HSD2 mineralocorticoid hormone action. The correlation of 11 beta-HSD2 activity in the placenta with foetal weight suggests, in addition, a crucial role for this enzyme in foetal development, possibly in mediating ontogeny of the foetal hypothalamo-pituitary-adrenal axis.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Type 2 11 beta-hydroxysteroid dehydrogenase in foetal and adult life. 854 71

We have used the X-ray crystallographic structures of rat and human dihydropteridine reductase and Streptomyces hydrogenans 20 beta-hydroxysteroid dehydrogenase to model parts of the 3-dimensional structure of human 11 beta- and 17 beta-hydroxysteroid dehydrogenases. We use this information along with previous results from studies of Drosophila alcohol dehydrogenase mutants to analyze the structures in binding sites for NAD(H) and NADP(H) in 11 beta-hydroxysteroid dehydrogenase-types 1 and 2. We also examine the structure of an alpha-helix at catalytic site of 17 beta-hydroxysteroid dehydrogenase-types 1, 2, 3, and 4. This alpha-helix contains a highly conserved tyrosine and lysine. Adjacent to the carboxyl side of this lysine is a site proposed to be important in subunit association. We find that 11 beta- and 17 beta-hydroxysteroid dehydrogenases-type 1 have the same residues at the "anchor site" and conserve other stabilizing features, despite only 20% sequence identity between their entire sequences. Similar conservation of stabilizing structures is found in the 11 beta- and 17 beta-hydroxysteroid dehydrogenases-type 2. We suggest that interactions of the dimerization surface of alpha-helix F with proteins or membranes may be important in regulating activity of hydroxysteroid dehydrogenases.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Structures important in mammalian 11 beta- and 17 beta-hydroxysteroid dehydrogenases. 854 86

Carbenoxolone (CX), the succinyl ester of glycyrrhetinic acid, causes hypokalemia and hypernatremia. Its pharmacological effects are believed to be due to its inhibition of 11 beta-hydroxysteroid dehydrogenase (11-HSD). There was a marked inhibition of this enzyme in the liver, kidney, pituitary, hippocampus, hypothalamus and amygdala 1 h after intraperitoneal administration of CX (100 mg kg-1) to intact male rats. Intracerebral injection of CX (1.5 mg kg-1) into the 3rd ventricle inhibited the oxidation of corticosterone to 11-dehydrocorticosterone by 11-HSD in the pituitary and hippocampus and produced marked behavioral hyperactivity but had no effect in the liver or kidney. Lower amounts of CX (10-50 micrograms/rat) given intracerebroventricularly (i.c.v) were without significant effect on 11-HSD in the pituitary or amygdala 1 h after infusion but inhibited this enzyme differentially in the hippocampus and hypothalamus. Inhibition of 11-HSD activity in the hippocampus and hypothalamus was observed up to 6 h after i.c.v. administration of CX (50 micrograms/rat) together with some decrease in activity of this enzyme in the pituitary at 3 h. The findings that low doses of CX given i.c.v. can alter the activity of 11-HSD in specific brain regions without affecting its activity in peripheral tissues, and only marginally in the pituitary, provides a method to study the central role of this enzyme independently of systemic effects.
J Steroid Biochem Mol Biol 1993 Aug
PMID:Differential inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues. 866 69


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