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:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E(1)S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17alpha of estradiol (E(2)), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17alpha-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17alpha-decyl-E(2) and 17alpha-dodecyl-E(2), a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC(50) = 440 nM), but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17alpha-(benzyl substituted)-E(2) derivatives studied, the 3'-bromobenzyl, 4'-tert-butylbenzyl, 4'-butylbenzyl, and 4'-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E(1)S into E(1) (IC(50) = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E(2) nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E(1)S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).
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PMID:Structure-activity relationships of 17alpha-derivatives of estradiol as inhibitors of steroid sulfatase. 1108 71

Localization of steroid sulfatase, a membrane-bound microsomal enzyme, in human fallopian tubes was immunohistochemically investigated, and expression of RNA was confirmed by competitive RT-PCR. Human fallopian tubes were obtained from 10 patients in follicular and early luteal phases during gynecological laparotomy. An anti-human rabbit polyclonal antibody was prepared against sulfatase protein purified from human placenta. Total RNA was isolated from epithelium of fallopian tubes. A heterologous RNA competitor was designed, and competitive RT-PCR was carried out. Steroid sulfatase was localized to the cytoplasm of epithelial cells. With respect to the positive staining of cells, the number of positive secretory cells was higher than that of ciliated cells. A significantly higher number of positive cells was found in tissue obtained from the early luteal phase than that found in tissue from the follicular phase. An abundant expression of sulfatase mRNA in early luteal phase was also observed. This study demonstrates, for the first time, that steroid sulfatase is localized to human epithelial cells and that steroid sulfatase staining and mRNA expression changes with the menstrual cycle. These results suggest that sulfatase in the fallopian tube may be involved in controlling the local steroid environment, which appears to regulate aspects of the physiological reproductive function of the fallopian tube.
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PMID:Localization and expression of steroid sulfatase in human fallopian tubes. 1114 87

The intestinal bioavailability and biotransformation of 3-hydroxybenzo(a)pyrene, a major metabolite of benzo(a)pyrene in many animal species, was investigated in an in situ isolated intestinal preparation from the channel catfish, and in vitro with preparations of catfish intestine and blood. 3-Hydroxybenzo(a)pyrene was a good substrate for adenosine 3'-phosphate 5'-phosphosulfate (PAPS)-sulfotransferase and UDP-glucuronosyltransferase in cytosol or microsomes prepared from intestinal mucosa. The benzo(a)pyrene-3-glucuronide and 3-sulfate conjugates were only very slowly hydrolyzed by intestinal beta-glucuronidase and sulfatase. The K(m) values for PAPS-sulfotransferase and UDP-glucuronosyltransferase were 0.4 and 1 microM, respectively, and V(max) were 1.61 +/- 1.08 nmol benzo(a)pyrene-3-sulfate/min/mg of cytosolic protein and 1.08 +/- 0.54 nmol benzo(a)pyrene-3-glucuronide/min/mg of microsomal protein. Hydrolytic enzyme activities were three orders of magnitude slower. In the in situ intestinal preparation, [(3)H]3-hydroxybenzo(a)pyrene was readily metabolized to the glucuronide and sulfate conjugates. After 1 h of incubation of 2 or 20 microM [(3)H]3-hydroxybenzo(a)pyrene in the in situ preparation, the luminal contents contained 3-hydroxybenzo(a)pyrene, benzo(a)pyrene-3,6-dione, benzo(a)pyrene-3-sulfate, and benzo(a)pyrene-3-glucuronide. Mucosal samples contained these components, as well as some unextractable material. The blood contained mainly benzo(a)pyrene-3-sulfate and an as yet unidentified metabolite of 3-hydroxybenzo(a)pyrene bound to hemoglobin. Some, but not all, blood samples contained small amounts of 3-hydroxybenzo(a)pyrene, benzo(a)pyrene-3-glucuronide, and benzo(a)pyrene-3,6-dione. These studies demonstrate the rapid phase 2 conjugation of a phenolic benzo(a)pyrene metabolite in intestinal mucosa, and the transfer of the phase 2 sulfate and glucuronide conjugates to blood.
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PMID:Intestinal bioavailability and biotransformation of 3-hydroxybenzo(a)pyrene in an isolated perfused preparation from channel catfish, Ictalurus punctatus. 1130 39

To gain further information on the biological role of the high amounts of conjugated estrone (E1S) secreted by the bovine placenta, an in vitro assay system was developed to measure oestrogen sulfotransferase (OST) and oestrogen sulfatase (OS) activities in caruncular and cotyledonary homogenates and the respective subcellular fractions. Placental tissue was obtained from 150 (n = 3), 220 (n = 4), 240 (n = 3) and 270 days (n = 3) pregnant and parturient cows (n = 4). 3H-E1 and 3H-E1S served as substrates and 4-nitrophenyl sulfate potassium salt was used as a competitive inhibitor to block OS when testing for OST activity. OST-activity did not change during pregnancy and parturition and was higher (p < 0.001) in cotyledonary than in caruncular tissue with mean conversions (median) of 61.8% and 41.6% after 30 min of homogenate incubation. On a subcellular level OST-activity was clearly associated with the cytosol. OS-activity was higher (p < 0.001) in caruncular than in cotyledonary homogenates; it was constant during pregnancy (median of conversion: 88.0% and 66.4%, resp.), but was significantly decreased (p < 0.05) at parturition (median of conversion: 48.1% and 30.6%, resp.). On a subcellular level in both the cotyledon and the caruncle highest OS-activities were detected in the microsomal and the mitochondrial fractions. The decreased placentomal OS-activities in parturient cows are inconsistent with a substantial role of OS in the prepartal increase of free oestrogens. These results also suggest that bovine placental oestrogens may largely exert their action locally within the placentomes during most time of gestation as the enzymes catalyzing sulfoconjugation (i.e. inactivation of free oestrogens) and desulfation (i.e. activation of conjugated oestrogens) are expressed in close proximity to each other. In this respect the finding of oestrogen receptors in caruncular stromal cells is of particular interest.
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PMID:Investigations on the activity of bovine placental oestrogen sulfotransferase and -sulfatase from midgestation to parturition. 1150 54

C(alpha)-formylglycine is the key catalytic residue in the active site of sulfatases. In eukaryotes formylglycine is generated during or immediately after sulfatase translocation into the endoplasmic reticulum by oxidation of a specific cysteine residue. We established an in vitro assay that allowed us to measure formylglycine modification independent of protein translocation. The modifying enzyme was recovered in a microsomal detergent extract. As a substrate we used ribosome-associated nascent chain complexes comprising in vitro synthesized sulfatase fragments that were released from the ribosomes by puromycin. Formylglycine modification was highly efficient and did not require a signal sequence in the substrate polypeptide. Ribosome association helped to maintain the modification competence of nascent chains but only after their release efficient modification occurred. The modifying machinery consists of soluble components of the endoplasmic reticulum lumen, as shown by differential extraction of microsomes. The in vitro assay can be performed under kinetically controlled conditions. The activation energy for formylglycine formation is 61 kJ/mol, and the pH optimum is approximately 10. The activity is sensitive to the SH/SS equilibrium and is stimulated by Ca(2+). Formylglycine formation is efficiently inhibited by a synthetic sulfatase peptide representing the sequence directing formylglycine modification. The established assay system should make possible the biochemical identification of the modifying enzyme.
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PMID:Characterization of posttranslational formylglycine formation by luminal components of the endoplasmic reticulum. 1160 May 3

In conditions associated with high serum iodothyronine sulfate concentrations, e.g. during fetal development, desulfation of these conjugates may be important in the regulation of thyroid hormone homeostasis. However, little is known about which sulfatases are involved in this process. Therefore, we investigated the hydrolysis of iodothyronine sulfates by homogenates of V79 cells expressing the human arylsulfatases A (ARSA), B (ARSB), or C (ARSC; steroid sulfatase), as well as tissue fractions of human and rat liver and placenta. We found that only the microsomal fraction from liver and placenta hydrolyzed iodothyronine sulfates. Among the recombinant enzymes only the endoplasmic reticulum-associated ARSC showed activity toward iodothyronine sulfates; the soluble lysosomal ARSA and ARSB were inactive. Recombinant ARSC as well as human placenta microsomes hydrolyzed iodothyronine sulfates with a substrate preference for 3,3'-diiodothyronine sulfate (3,3'-T(2)S) approximately T(3) sulfate (T(3)S) >> rT(3)S approximately T(4)S, whereas human and rat liver microsomes showed a preference for 3,3'-T(2)S > T(3)S >> rT(3)S approximately T(4)S. ARSC and the tissue microsomal sulfatases were all characterized by high apparent K(m) values (>50 microM) for 3,3'-T(2)S and T(3)S. Iodothyronine sulfatase activity determined using 3,3'-T(2)S as a substrate was much higher in human liver microsomes than in human placenta microsomes, although ARSC is expressed at higher levels in human placenta than in human liver. The ratio of estrone sulfate to T(2)S hydrolysis in human liver microsomes (0.2) differed largely from that in ARSC homogenate (80) and human placenta microsomes (150). These results suggest that ARSC accounts for the relatively low iodothyronine sulfatase activity of human placenta, and that additional arylsulfatase(s) contributes to the high iodothyronine sulfatase activity in human liver. Further research is needed to identify these iodothyronine sulfatases, and to study the physiological importance of the reversible sulfation of iodothyronines in thyroid hormone metabolism.
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PMID:Characterization of iodothyronine sulfatase activities in human and rat liver and placenta. 1186 2

Estrone sulfatase (ES; 562 amino acids), one of the key enzymes responsible for maintaining high levels of estrogens in breast tumor cells, is associated with the membrane of the endoplasmic reticulum (ER). The structure of ES, purified from the microsomal fraction of human placentas, has been determined at 2.60-A resolution by x-ray crystallography. This structure shows a domain consisting of two antiparallel alpha-helices that protrude from the roughly spherical molecule, thereby giving the molecule a "mushroom-like" shape. These highly hydrophobic helices, each about 40 A long, are capable of traversing the membrane, thus presumably anchoring the functional domain on the membrane surface facing the ER lumen. The location of the transmembrane domain is such that the opening to the active site, buried deep in a cavity of the "gill" of the "mushroom," rests near the membrane surface, thereby suggesting a role of the lipid bilayer in catalysis. This simple architecture could be a prototype utilized by the ER membrane in dictating the form and the function of ER-resident enzymes.
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PMID:Structure of human estrone sulfatase suggests functional roles of membrane association. 1265 38

Activities of hepatic microsomal and cytosolic epoxide hydrolases, accumulation of dieldrin in liver, and in vivo metabolism and disposition of the polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BP), were examined in rainbow trout pretreated with dieldrin, a chlorinated cyclodiene insecticide. Rainbow trout were fed 0.3 mg dieldrin/kg/day for 9 weeks and the same dose of dieldrin for 9 weeks, followed by 3 weeks on control diet (12 weeks). Fish then received an intraperitoneal (ip) challenge dose of 14C-BP (10 micromol/kg). Dieldrin pretreatment significantly elevated the concentration of 14C-BP in bile (142% and 200% at 9 and 12 weeks, respectively), but not liver or fat. Extraction of bile subsamples confirmed dieldrin pretreatment significantly stimulated total biliary excretion of 14C-BP polar metabolites (244% and 221% at week 9 and 12, respectively). The complex metabolism of BP characterized the in vivo state of the CYP system, UDP-glucuronyltransferases, and sulfotransferases. Bile was extracted and then hydrolyzed by beta-glucuronidase and arylsulfatase to regenerate BP metabolites conjugated by phase II enzymes. Evaluation of biliary polar metabolite profiles of 14C-BP revealed no significant differences between control and dieldrin-fed fish. There was no selective enhancement of any particular metabolite, or formation of a novel metabolite with dieldrin pretreatment. This research confirmed that enhanced biliary excretion, following chronic dieldrin exposure, was not explained by induction of xenobiotic metabolizing enzymes. The results are consistent with induction of hepatic intracellular trafficking proteins in dieldrin-fed fish.
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PMID:Dieldrin stimulates biliary excretion of 14C-benzo[a]pyrene polar metabolites but does not change the biliary metabolite profile in rainbow trout (Oncorhyncus mykiss). 1288 87

Two sulfatase isoforms, a soluble one with an optimum pH of 5.0, and a microsomal one with an optimum pH of 7.6, were observed in digestive gland, gonads, mantle and gills of the oyster C. virginica. The highest sulfatase activity was recorded in the digestive gland cytosol and is likely to interfere with the in vitro determination of sulfotransferase activity. Indeed, the sulfatase inhibitor Na(2)SO(3) led to an increase of measured sulfotransferase activity (31+/-9%), suggesting that those sulfatases might be partially responsible for the low sulfotransferase activities found in C. virginica.
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PMID:Sulfatase activity in the oyster Crassostrea virginica: its potential interference with sulfotransferase determination. 1596 77

Estrogen sulfatase is a microsomal enzyme and is ubiquitously distributed in several mammalian tissues, among which the liver, placenta, and endocrine tissues exhibit relatively high activity. Because the major circulating precursors of estrogen are estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, estrogen sulfatase plays an important role not only in their incorporation and metabolism, but also in the controls of estrogen activity by regulating the binding potential of estrogen as to its receptor through sulfoconjugation and desulfation reactions. Accordingly, an increase in sulfoconjugation through transfection of the sulfotransferase gene or inhibition of estrogen sulfatase by specific inhibitors has been successfully applied to abolish the estrogen activity in estrogen-dependent breast cancer- and uterine endometrial adenocarcinoma-derived cells. Inhibitors of estrogen sulfatase are expected to be developed as new drugs for estrogen-dependent cancer therapy, particularly in postmenopausal women.
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PMID:Estrogen sulfatase. 1639 56


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