Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently described a progesterone receptor in the cytosol of ovaries of hypophysectomized, estrogen-primed, immature rats. This progesterone receptor was shown to be a thermolabile, saturable protein, which is specific for progestins (R5020 and progesterone), and elutes at the void volume of a Sephadex G-200 column. In the present study, we performed a more detailed analysis of the biochemical properties of this receptor and examined its cellular localization within the ovary. Treatment of the ovary cytosol with protamine sulfate and N-ethyl maleimide abolishes the specific binding of 3H-R5020, indicating that the receptor is an acidic protein containing cysteine residues necessary for binding. Gel exclusion chromatography shows the progesterone receptor to have a mean Stokes radius of 86 A and a molecular weight of approximately 300,000 daltons. Kinetic analysis indicates that the receptor--R5020 complex dissociates very rapidly, with a t1/2 of 10 minutes. The cytosol of isolated granulosa cells bind 3H-R5020 specifically, demonstrating that the ovarian progesterone receptor is present in the granulosa cell.
Steroids 1979 Oct
PMID:Progesterone receptor in the rat ovary: further characterization and localization in the granulosa cell. 57 72

The biologic actions of 1,25-(OH)2D3 are diverse, ranging from a major role in the regulation of mineral homeostasis in intestine, kidney, and bone to the control of such fundamental processes as myeloid progenitor cell differentiation. The central character in this action is the 1,25-(OH)2D3 receptor, a protein whose activity is focused at the level of the genome. The function of this polypeptide, by analogy with other steroid receptors, is to interact in a sequence-specific manner with unique regulatory elements of DNA, which serve to modify the activity of their respective promoters. The exact manner in which receptor binding to these sequences precipitates promoter activity is unclear. It is, however, a direct result of the structural organization of the steroid receptors, which represent a class of transcriptional controlling proteins. The deduced primary sequences emanating from the molecular cloning of estrogen, progesterone, glucocorticoid, and 1,25-(OH)2D3 receptors has revealed several important structure-function relationships. These include the identification of a highly conserved cysteine-rich domain that may interact with DNA and a steroid-binding domain that is hydrophobic and is located at the carboxy terminus of the protein. The similarity of this domain among heterologous steroid receptor species implies that each of these proteins belongs to a common gene family whose functional activities are similar if not identical. It is this structure within the 1,25-(OH)2D3 receptor that provides conclusive evidence that 1,25-(OH)2D3 is a steroid hormone that via its receptor modifies the activity of hormone-sensitive genes.
Steroids
PMID:Emerging concepts on the biologic role and mechanism of action of 1,25-dihydroxyvitamin D3. 284 97

Aromatase from human placenta has been purified to homogeneity (MW 55,000). Enzymatic activity can be reconstituted with reductase from pig liver in an aqueous buffer or after incorporation of the enzyme into liposomes. In both cases the enzyme converts androstenedione to estrone and testosterone to estradiol. Aromatase shows a typical CO-spectrum when reduced with dithionite and a type I spectral shift with both substrates. The NH2 terminal amino acid sequence is hydrophobic but shows no homology to that of other cytochromes P-450. Five cysteine peptides have been isolated by HPLC following tryptic digestion of the [14C]-carboxymethylated protein. Amino acid sequences of these peptides reveal that histidine is the carboxy-terminal amino acid of the protein and that significant homology exists with corresponding peptides from other cytochromes P-450. Unique oligonucleotides (62 and 30 MER) synthesized on the basis of a 45 amino acid sequence near the center of the molecular have been used to clone the aromatase gene from a cDNA expression library from human placenta in lambda gt11.
Steroids
PMID:Purification and characterization of aromatase from human placenta. 350 67

The effect of in vivo variation of hepatic glutathione (using diethyl maleate and L-cysteine) on in vitro cholesterol 7 alpha-hydroxylase activity was studied in male Sprague-Dawley rats. Cholesterol 7 alpha-hydroxylase activity in glutathione-depleted rats (ca. 10% of control glutathione) was significantly reduced compared to that in vehicle-injected controls. While L-cysteine treatment of glutathione-depleted animals increased glutathione levels somewhat (ca. 20% of control glutathione), they were still significantly less than control levels. Similarly, cholesterol 7 alpha-hydroxylase activity in the partially glutathione replete animals was approximately 50% greater than that in the glutathione-depleted animals, but still significantly less than that in the controls. The rate of 7 alpha-hydroxylation of cholesterol was found to be dependent on liver glutathione content. The calculated maximal rate was 34.4 picomoles/mg/min with a half maximal activity at 1.89 mumoles glutathione/gm liver. These results suggest that hepatic glutathione may be an important modulator of in vivo activity of cholesterol 7 alpha-hydroxylase.
Steroids 1984 Oct
PMID:Role of glutathione in the regulation of hepatic cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of bile acid biosynthesis. 654 72

Steroid sulfotransferase activity is present in the cytosol fraction of hamster epididymis. The activity of this enzyme is increased by magnesium ion. Cysteine is essential to assure optimal activity. Adenosine-3'-phosphate-5'-phosphosulfate is required as sulfate donor and an apparent Km of 62 microM was calculated. Inhibition studies suggest that this enzyme preferentially catalyzes the sulfurylation of the 3 beta-hydroxyl group of delta 5-steroids. An unusual feature of the enzyme is a pH optimum at pH 10.
Steroids 1981 Nov
PMID:Steroid sulfotransferase in hamster epididymis. 694 22

2,2-Dimethylandrost-4-ene-3,6,17-trione (5) and its 4-methoxy- (7) and 4-hydroxy- (8) derivatives were synthesized. 7 alpha-Acetoxy-4-ene-3,6-dione steroid 2 was also prepared by the improved method involving the lead tetraacetate oxidation of androst-4-ene-3,6,17-trione (1). These steroids along with the 2-acetoxy-(11 and 12), 2-substituted 1-ene- (9 and 10), and 4-substituted (13-15) derivatives of compound 1 were evaluated as inhibitors of human placental aromatase. All the steroids, except the 2-acetoxy-1-ene 10 and the 2 beta-acetate 11 of which Ki values were not determined because of their poor inhibitory activities, blocked aromatase in a competitive manner. Compounds 5 and 8 as well as the 4-hydroxy steroid 15 were potent inhibitors (Ki: 25-42 nM) whereas the inhibitory activities of steroids 2, 7, 9, 13, and 14 were good to fair, respectively (Ki: 160-810 nM). Inhibitors 2 and 15 inactivated the enzyme in a time-dependent manner in the presence of NADPH but the 2,3-dimethyl derivatives 5 and 8 did not. Androstenedione blocked the inactivation but L-cysteine did not. The results suggest that the 2 beta-methyl group would prevent the aromatase-catalyzed oxygenation at C-19 of the dimethyl steroids 5 and 8 most likely through the steric reasons.
Steroids 1994 Oct
PMID:A- or B-ring-substituted derivatives of androst-4-ene-3,6,17-trione as aromatase inhibitors. Structure-activity relationships. 787 85

A series of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their 7-deoxy derivatives, respectively, were synthesized and tested for their abilities to inhibit aromatase in human placental microsomes. All the steroids inhibited the enzyme in a competitive manner with Ki's ranging from 0.058 to 45 microM. The inhibitory activities of 17-oxo compounds were much more potent than those of the corresponding 17 beta-alcohols in each series. Steroids having an oxygen function (hydroxy or carbonyl) at C-19 were less potent inhibitors than the corresponding parent compounds having a 19-methyl group. 3,5-Dien-7-one 24 and its 19-hydroxy and 19-oxo derivatives (12 and 13) as well as 19-oxo-5-en-7-one 3 caused a time-dependent inactivation of aromatase only in the presence of NADPH in which the kinact values of 19-als 3 and 13 (0.143 and 0.189 min-1, respectively) were larger than those of the corresponding 19-methyl (23 and 24) and 19-hydroxy (1 and 12) steroids, respectively. 19-Nor-5-en-7-one 4 but not its 3,5-diene derivative 14 also inactivated the enzyme in a time-dependent manner. In contrast, 7-deoxy steroids 21 and 27, having a 19-methyl group, did not cause it. The inactivations were prevented by the substrate androstenedione, and no significant effects of L-cysteine on the inactivations were observed in each case. The results suggest that oxygenation at C-19 would be at least in part involved in the inactivations caused by the inhibitors 23 and 24. The conjugated enone structures should play a critical role in the inactivation sequences.
 ...
PMID:Synthesis of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their related 7-deoxy analogs as conformational and catalytic probes for the active site of aromatase. 803 27

In transient co-transfection assays, there is extensive cross-interaction between glucocorticoid receptor (GR) domains. For example, mutation of the conserved Ile residue at position 484 (rat GR map) to cysteine allows a net separation of transactivation and DNA binding. We also observed that the ligand binding domain plays a key role in cooperative transactivation. Furthermore, some carboxy-located mutations markedly alter the response of GR to agonists and antagonists. Finally, different reading frames of the CAG repeat that normally produces an amino-located poly-Gln repeat profoundly affect GR transactivation without altering DNA or ligand binding. This trans-dominant negative phenotype, seen when the CAG repeat yields a poly-Ala stretch, may turn out to be an excellent tool for functional analysis of GR in transgenic organisms.
Steroids 1994 Feb
PMID:Active, interactive, and inactive steroid receptor mutants. 819 45

Diastereomeric (19S)- and (19R)-19-ethynyl-19-acetoxy derivatives of androst-4-ene-3,6,17-trione (AT) (9 and 10) and 19,19-difluoro AT (12) were synthesized. The 19,19-difluoro compound (12) was an effective competitive inhibitor of human placental aromatase with an inhibition constant (ki) of 1.8 microM but the acetylenic 9 and 10 were poor inhibitors of the enzyme with k(is) of 75 and 67 microM, respectively. Inhibitor 12 caused a time-dependent, biphasic loss of aromatase activity in the presence of reduced nicotinamide-adenine-dinucleotide phosphate (NADPH) in air, whereas the other two caused a time-dependent, pseudo-first-order inactivation of the activity with rate constants for inactivation of 0.250, 0.077, and 0.065 min-1 for steroids 12, 9, and 10. NADPH was required for the time-dependent inactivation, and the substrate androst-4-ene-3,17-dione prevented it. L-Cysteine did not protect aromatase from the inactivation.
Steroids 1993 Jan
PMID:A time-dependent inactivation of aromatase by 19-substituted androst-4-ene-3,6,17-triones. 843 Apr 44

Experiments were carried out to determine the degree of solvent and reagent accessibility of the cysteines in the ligand-binding domain of the human estrogen receptor (hER LBD). The cysteine residues were alkylated when human ER LBD was present in its ligand (estradiol)-bound conformation. Direct electrospray ionization mass spectrometry (ESMS) as well as liquid chromatography coupled with ESMS, and matrix-assisted laser ionization desorption time-of-flight mass spectrometry were used to determine the location and the yield of the derivatized residues after proteolysis with trypsin. We observed that the cysteine 447 was protected against alkylation under these conditions, whereas cysteines 381, 417, and 530 were fully derivatized.
Steroids 1996 Jun
PMID:Carboxymethylation of the human estrogen receptor ligand-binding domain-estradiol complex: HPLC/ESMS peptide mapping shows that cysteine 447 does not react with iodoacetic acid. 877 99


1 2 3 Next >>