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PubMed2002

Sulfotransferases and sulfatases in mycobacteria.

Analysis of the genomes of M. tuberculosis, M. leprae, M. smegmatis, and M. avium has revealed a large family of genes homologous to known sulfotransferases. Despite reports detailing a suite of sulfated glycolipids in many mycobacteria, a corresponding family of sulfotransferase genes remains uncharacterized. Here, a sequence-based analysis of newly discovered mycobacterial sulfotransferase genes, named stf1-stf10, is presented. Interestingly, two sulfotransferase genes are highly similar to mammalian sulfotransferases, increasing the list of mycobacterial eukaryotic-like protein families. The sulfotransferases join an equally complex family of mycobacterial sulfatases: a large family of sulfatase genes has been found in all of the mycobacterial genomes examined. As sulfated molecules are common mediators of cell-cell interactions, the sulfotransferases and sulfatases may be involved in regulating host-pathogen interactions.

Amino Acid Sequence↗
PubMed2003

Carbonic anhydrase inhibitors. Inhibition of cytosolic isozymes I and II and transmembrane, tumor-associated isozyme IX with sulfamates including EMATE also acting as steroid sulfatase inhibitors.

A series of sulfamates or bis-sulfamates incorporating aliphatic, aromatic, polycyclic (steroidal), and sugar moieties in their molecules has been synthesized and assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of the cytosolic isozymes CA I andII, and the transmembrane, tumor-associated isozymes CA IX. Some of these compounds were previously reported to act as inhibitors of steroid sulfatases, among which estrone sulfatase (ES) and dehydroepiandrosterone sulfatase (DHEAS) are the key therapeutic targets for estrogen-dependent tumors. Very potent (nanomolar) inhibitors were detected against the three investigated CA isozymes. Best CA I inhibitors were phenylsulfamate and some of its 4-halogeno derivatives, as well as the aliphatic compound n-octyl sulfamate. Against CA II, low nanomolar inhibitors (1.1-5 nM) were phenylsulfamate and some of its 4-halogeno/nitro derivatives, n-octyl sulfamate, and estradiol 3,17beta-disulfamate among others. All the investigated sulfamates showed efficient CA IX inhibitory properties, with inhibition constants in the range of 18-63 nM. The best CA IX inhibitor detected so far was 4-chlorophenylsulfamate. These data are critical for the design of novel antitumor properties, mainly for hypoxic tumors that overexpress CA IX, which are nonresponsive to radiation or chemotherapy. The antitumor properties of the ES/DHEAS inhibitors in clinical trials may on the other hand also be due to their potent inhibitory properties of CA isozymes involved in tumorigenicity, such as CA II and CA IX.

Antigens, Neoplasm↗
PubMed1997

In vitro correction of iduronate-2-sulfatase deficiency by adenovirus-mediated gene transfer.

Hunter syndrome is a lethal lysosomal storage disorder caused by the deficiency of iduronate-2-sulfatase and characterized by severe skeletal and neurological symptoms. Only symptomatic treatments are available and, although bone marrow transplantation has been suggested, no encouraging results have been obtained so far. Therefore, gene therapy might be a route to be pursued for treatment of the disease. In this respect, one major goal to achieve is the generation of an overexpressing vector able to correct, in particular, central nervous system (CNS) cells. Adenoviruses have been shown to infect CNS cells efficiently with minor or even absent immunological response. We describe the generation of a replication-defective adenoviral vector, AdRSVIDS, which is able to express in vitro high levels of iduronate-2-sulfatase. After infection, accumulation of mucopolysaccharides in treated Hunter cells was normalized. Furthermore, endocytosis of the transduced IDS did occur via the mannose-6-phosphate (M6P) receptor. Since no animal model for the disease is available, we developed a system based on the generation of derma-equivalents which enabled us to verify the expression of high levels of sulfatase up to 30 days after infection.

Adenoviridae↗
PubMed2004

Confocal fluorescence detection expanded to UV excitation: the first continuous fluorimetric assay of human steroid sulfatase in nanoliter volume.

Steroid sulfatase is an enzyme that currently enjoys considerable interest as a potential drug target in the treatment of estrogen- and androgen-dependent diseases, in particular breast cancer. We have purified human steroid sulfatase to apparent homogeneity from recombinant Chinese hamster ovary cells, and we established an assay with a new fluorogenic substrate, 3,4-benzocoumarin-7-O-sulfate (1). Substrate 1 features a K(m) value of 22.5 microM, which is close to the value for the natural substrate dehydroepiandrosterone sulfate (26 microM) and much lower than the K(m) values of other synthetic substrates (276-736 microM). Importantly, the cleavage of substrate 1 can be monitored continuously during the enzymatic cleavage, since a change in fluorescence intensity is detectable at the pH where the enzyme is active; in contrast, all other synthetic substrates described so far require alkalization to reveal a measurable absorbance or fluorescence signal. The adaptation of the assay to the 96-well format allows continuous monitoring of multiple wells in a microplate fluorescence reader. Applications of the assay for the determination of IC(50) and K(i) values of novel steroid sulfatase inhibitors are presented. Most importantly the assay was transferred to the nanoscale format (1-microl assay volume) in 2080-well plates with confocal fluorescence detection. This miniaturization will permit screening with a minimum throughput of 20000 compounds per day. The system presented demonstrates that the confocal detection platform used for nanoscreening can be successfully adapted to assays for which conventional ultraviolet dyes like coumarins are necessary. This strongly broadens the application range of confocal readers in drug screening.

Algorithms↗
PubMed1994

Pseudopregnancy-dependent accumulation of cholesterol sulfate due to up-regulation of cholesterol sulfotransferase and concurrent down-regulation of cholesterol sulfate sulfatase in the uterine endometria of rabbits.

The uterine endometria of rabbits induced into pseudopregnancy by intramuscular injection of 17 beta-estradiol, followed by intravenous injection of human chorionic gonadotropin, expressed cholesterol sulfate at a significantly high concentration. The highest concentration of cholesterol sulfate was observed 4 days after the injection of gonadotropin for formation of the corpus luteum, being 10 times higher than that in nonpregnant endometria, and 15.2% of the total cholesterol in the endometrium was converted to the sulfated form, whose percentage in nonpregnant endometrium was 3.2%. However, no significant change in the concentration of gangliosides was observed during the period of pseudopregnancy. In the pseudopregnant endometria, the activity of cholesterol sulfotransferase, a cytosolic thiol enzyme, was increased thirtyfold over that in the nonpregnant endometria, whereas cholesterol sulfate sulfatase, a microsomal enzyme, exhibited approximately one-tenth of the activity in nonpregnant endometria. Arylsulfatase C, but not arylsulfatases A and B, exhibited the same change in activity as cholesterol sulfate sulfatase. Thus, the striking increase in cholesterol sulfate after induction of pseudopregnancy was found to be due to the activation of cholesterol sulfotransferase and the simultaneous inhibition of cholesterol sulfate sulfatase.

Animals↗
PubMed2006

Apoptosis related to steroid sulfatase at the cone-shaped projection in nephron morphogenesis.

Steroid sulfatase (STS) is a microsomal enzyme catalysing the hydrolysis of steroid 3beta-sulfates, including estrogen sulfate, at organ target sites. Steroid sulfatase activity, as well as the activity of various estrogens, has been reported to influence the development of organs. In the kidney, progenitor cells of nephrons develop from mesenchymal cells and finally attach to the ureteric duct at the region termed the cone-shaped projection. However, the mechanisms of this process have not been fully investigated. In the present study, STS-related apoptosis occurring between the renal vesicle and ureteric duct was examined using immunohistochemical techniques. Immunoreactivity to STS was demonstrated at the cortical metanephric mesenchyme surrounding new vessels and was pronounced at the junction between the renal vesicle and ureteric duct (cone-shaped junction). Steroid sulfatase-transfected LLC-RK1 cells (rat proximal cell line) were also examined in vitro. Apoptosis occurred when an estrogen precursor (ELS) was added at concentrations between 10(-4) and 10(-2) mol/L. These results indicate that STS is synthesized in the progenitor cells of proximal tubules. Moreover, STS may be related to apoptosis occurring at the junction between the renal vesicle and ureteric duct in a manner proportional to the availability of STS precursors.

Animals↗
PubMed1986

Enzymatic control of estrogen production in human breast cancer: relative significance of aromatase versus sulfatase pathways.

One-third of the cases of breast cancer in postmenopausal women are hormone-dependent and the lesions regress upon treatment with antiestrogens or inhibition of estrogen biosynthesis. In these patients, estrogens are synthesized in extraglandular tissues from adrenal precursors and re-enter plasma to produce estrone levels of 52 +/- 6.5 pg/ml (mean +/- SEM) and estradiol concentrations of 13.1 +/- 0.7 pg/ml. However, the fact that the levels of estrogen in breast tumor tissue are an order of magnitude higher than plasma levels suggested the possibility of in situ estrogen production. To address this possibility, we measured several enzymes involved in estradiol biosynthesis in human tumors. Forty-eight of 61 tumors contained aromatase (estrogen synthetase) activity ranging from 5-80 pg/gm protein per hour. By comparison, the levels of estrone sulfatase were 10(6) higher, ranging from 0.8-125 micrograms/gm protein per hour. Because the sulfatase enzyme was of lower affinity (i.e., Km = 27 microM) than that of aromatase (i.e., 0.027 microM), the amount of estrogen formed under conditions of similar substrate concentrations was compared and found to be 10-fold higher via the sulfatase enzyme. In 41 additional tumors, the 17 beta-hydroxysteroid dehydrogenase enzyme, catalyzing the conversion of estrone to estradiol, was uniformly present. To test the biologic relevance of the estrone sulfate to estrone to estradiol pathway, estrogen-dependent nitrosomethylurea rat mammary tumors were grown in soft agar in the presence of estrone sulfate. Concentrations of estrone sulfate of 10(-6) microM significantly (p less than 0.01) stimulated colony formation in this system in which 75.5-98.6% of estrone sulfate was converted to estrone and 0.2 to 6% to estradiol. These data support the hypothesis that mammary carcinomas can synthesize estradiol in situ from circulating estrogen precursor and that local conversion is biologically important. On the basis of comparative data, the estrone sulfate to estrone to estradiol pathway is quantitatively more important than that involving androstenedione to estrone to estradiol.

17-Hydroxysteroid Dehydrogenases↗
PubMed1982

Isolation of a bile salt sulfatase-producing Clostridium strain from rat intestinal microflora.

Bile acid sulfates, formed in human and rat livers, are desulfated by the intestinal microflora. In our study we first isolated from conventional rat feces an unnamed bacterium, termed strain S1, which desulfated the 5 beta-bile salt 3 alpha-sulfates in vitro and in vivo after association with gnotobiotic rats. Strain S1 also possessed 12 alpha-hydroxysteroid dehydrogenase and bile salt-deconjugating activities. The strain was a strict anaerobic, CO2-requiring, gram-negative, sporeforming rod and was designated as belonging to the genus Clostridium. Growth was scarce in culture media, unless in the presence of 0.1% taurine, a sulfur-containing amino acid. Addition of this substance raised the number of bacteria in thioglycolate and peptone yeast media from 10(4) per ml to 10(6) to 10(7) per ml and increased the colony diameter on agar medium from 0.2 mm to 0.5 to 0.9 mm. Sulfatase activity was specific for the 5 beta-bile salt sulfates, leaving the 5 alpha-bile salt sulfates unchanged. In addition, the sulfatase activity was cell bound, and its production was dependent on the composition of the culture medium, although no minimal sulfur medium was required for sulfatase activity.

Animals↗
PubMed1999

Ontogeny of estrogen sulfatase activity in ovine fetal hypothalamus, hippocampus, and brain stem.

Ovine parturition is initiated by increases in fetal hypothalamus-pituitary-adrenal (HPA) axis activity, which in turn increase placental estrogen biosynthesis and ultimately increase uterine contractility. In addition to the action in the uterus, estrogens augment fetal ACTH secretion. In late gestation, estrone sulfate is more abundant in fetal plasma than is unconjugated estrone. We studied hypothalamus, hippocampus, and brain stem tissue from fetal, neonatal, and adult sheep to test the hypothesis that the ovine brain contains estrogen sulfatase activity. We found that the activity in the hippocampus was significantly increased in late-gestation fetuses compared with both younger and older animals. No significant change in either hypothalamus or brain stem was revealed; however, the activity in all brain areas was high. Immunohistochemistry revealed the presence of estrogen sulfatase in the paraventricular nucleus of the hypothalamus, the nucleus of the solitary tract, and the rostral ventrolateral medulla. We conclude that ovine fetal hypothalamus, hippocampus, and brain stem contain estrogen sulfatase activity and that the activity in the hippocampus is developmentally regulated.

Aging↗
PubMed1992

Saudi variant of multiple sulfatase deficiency.

We describe eight patients with multiple sulfatase deficiency (MSD, or Austin's disease) who differ phenotypically from classic neonatal-, childhood-, or juvenile-onset MSD. The age of onset was in childhood. The patients presented with somatic and facial features of mucopolysaccharidosis reminiscent of Maroteaux-Lamy and Morquio syndromes. They differed from classic MSD by the presence of corneal cloudiness, macrocephaly, severe dysostosis multiplex, and gibbus and the absence of ichthyosis, retinal degeneration, severe deafness, severe mental retardation, and dementia. The main neurologic presentation was cervical cord compression due to axis abnormalities. Despite neuroradiologic evidence of white-matter changes, neurologic presentation was not like metachromatic leukodystrophy. The sulfatase deficiencies were more marked than in the classic juvenile form of MSD, but less marked than in the classic childhood-onset form of MSD. Steroid sulfatase activity was spared except in one patient. This Saudi variant of MSD accounts for 5% of all lysosomal storage diseases in the Cell Repository Registry of our Inborn Errors of Metabolism Laboratory.

Child↗
PubMed1980

Sulfatase activity of keratinizing tissues in X-linked ichthyosis.

Arylsulfatases A and B were measured in the stratum corneum of four normal controls and two individuals with sex-linked ichthyosis. For arylsulfatase A, the mean delta optical density/hr/mg protein value was 1.6 for controls and 2.0 for patients, whereas for arylsulfatase B values of 1.5 for controls and 1.4 for patients were observed. Assay of arylsulfatase C in the callus of four normal controls showed a mean delta optical density/hr/100 mg callus of 0.63, whereas no or trace activity was detected in callus from four patients with x-linked ichthyosis. The assay of steroid sulfatase is best for studying microsomal sulfatase activity. Table 1 shows the activity of this enzyme in nails, callus, and hair bulbs from controls and patients with x-linked ichthyosis. No steroid sulfatase could be demonstrated in patients with x-linked ichthyosis. The values in normal controls and obligate heterozygotes are compared in Table 2. The mean value of the two groups is statistically different with P less than or equal to 0.05 using the Student t test.

Arylsulfatases↗
PubMed1987

Variations in estrone sulfatase activity in human leukocytes.

Peripheral blood leukocytes isolated from men and women were studied for their capacity to metabolize estrone (E1) sulfate. Fresh human leukocytes (granulocytes and mononuclear cells) were incubated in phosphate buffer, pH 7.4, containing [3H]E1S for 1 h at 37 C. The samples were extracted with chloroform for measurement of the [3H]E1 formed, and the results were corrected for nonenzymatic hydrolysis. The mean E1 sulfatase activity in leukocytes isolated from normal women in the follicular phase of their cycle was 75% higher than that during the luteal [1840 +/- 179 (+/- SE) vs. 1048 +/- 101 fmol E1 micrograms protein-1 h-1; P less than 0.004] and higher than that in normal men (875 +/- 123; P less than 0.002), but was not different from that in menopausal (1349 +/- 151) or hirsute women (1700 +/- 222). In pregnant women, the mean leukocyte E1 sulfatase activity was significantly lower (861 +/- 147) than that in nonpregnant women in the follicular phase (P less than 0.003). These results suggest that progesterone may modulate E1 sulfatase activity, whereas estrogens do not.

Adult↗
PubMed2003

Structure-activity relationship determination within a group of substituted phenyl sulfamate based compounds against the enzyme oestrone sulfatase.

The enzyme oestrone sulfatase (ES) is responsible for the conversion of the stored (sulfated) form of oestrogens to the active form, namely oestrone. In our continuing quest to synthesize potent inhibitors of oestrone sulfatase and to determine the structural requirements for such inhibition, we have synthesized and evaluated several derivatives of phenyl sulfamate. We report the results of the synthesis and biochemical evaluation of a series of 3- and 4-aminosulfonated derivatives of phenol in an effort to investigate the role of the acid dissociation constant (pK(a)), and therefore the stability of the phenoxide ion, on the inhibitory activity of compounds against this enzyme. The results showed that there was a strong correlation between the observed pK(a) and inhibitory activity within the aminosulfonated compounds considered. This suggested that in the inhibition of oestrone sulfatase by these compounds, pK(a) was an important physicochemical property, and as such, the stability of the O(-) ion was a crucial factor in the inhibition, and therefore the drug design process.

Enzyme Inhibitors↗
PubMedDate not supplied

Effectiveness of calcium and magnesium on testicular sulfatase activity.

Nucleotides and calcium ions have been implicated in the regulation of biosynthesis of steroids, although the exact locus of calcium activity is not yet known. The administration of Ca2+ to Leydig cells increases testosterone production. Steroid sulfatase activity is reported to be enhanced by adenine nucleotides. In the present study the testicular sulfatase was evaluated in subcellular fractions by conversion of sulfate to free steroids in the presence or absence of Ca2+ and Mg2+ ions. The specific activity of the enzyme, which was located predominantly in submitochondrial fraction, showed a positive correlation with calcium, increasing 1.5-fold in the presence of 2.54 mM of calcium (62 nmol/h mg protein-1). In contrast, magnesium inhibited the enzymatic activity 1.79-fold in presence of 1.18 mM (23 nmoles/h mg protein-1). It would appear that testicular sulfatase is predominantly located in the mitochondria, which is recognized as one of the major sites of control of intracellular metabolism, and that its enzymatic activity could be modulated by calcium regulating the levels of potentially active androgens.

Animals↗
PubMed2000

In vivo inhibition of estrone sulfatase activity and growth of nitrosomethylurea-induced mammary tumors by 667 COUMATE.

The development of potent steroid sulfatase inhibitors is an important new therapeutic strategy for the treatment of postmenopausal women with breast cancer. A series of tricyclic coumarin sulfamates were synthesized, and their inhibitory properties were examined in vitro and in vivo. In a placental microsomal assay system, 667 COUMATE emerged as the most potent inhibitor with an IC50 of 8 nM. Administration of a single dose (10 mg/kg, p.o.) of 667 COUMATE inhibited rat liver estrone sulfatase activity by 93%. 667 COUMATE was devoid of estrogenicity, as indicated by its failure to stimulate the growth of uteri in ovariectomized rats. In vivo, estrone sulfate-stimulated growth of uteri in ovariectomized rats was inhibited by 667 COUMATE. Using the nitrosomethylurea-induced mammary tumor model, we found that 667 COUMATE caused regression of estrone sulfate-stimulated tumor growth in a dose-dependent manner. The identification of 667 COUMATE as a potent steroid sulfatase inhibitor will enable the therapeutic potential of this type of therapy to be evaluated.

Animals↗
PubMedDate not supplied

Dydrogesterone (Duphaston) and its 20-dihydro-derivative as selective estrogen enzyme modulators in human breast cancer cell lines. Effect on sulfatase and on 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity.

Estradiol (E2) is one of the main factors which control the growth and evolution of breast cancer. Consequently, to block the formation of E2 inside cancer cells has been an important target in recent years. Breast cancer cells possess all the enzymatic systems (e.g. sulfatase, aromatase, 17beta-hydroxysteroid dehydrogenase [17beta-HSD]) involved in the conversion of estrogen precursors into E2. Sulfotransferase, which converts estrogen to its sulfate, is also present in this tumoral tissue. Duphaston is a synthetic progestogen with properties similar to the natural progesterone. In the present study we examined the effect of Duphaston and its 20-dihydro-metabolite on the sulfatase and 17beta-HSD activities in MCF-7 and T-47D breast cancer cells. The cells were incubated with estrone sulfate (E1S) (5x10(-9)M) in the absence or presence of Duphaston or its 20-dihydro-metabolite (5x10(-5) to 5x10(-9)M) for 24h at 37 degrees C. In another series of experiments, estrone (E1) (5x10(-9)M) was incubated with T-47D cells in the absence or presence of the two progestogens (5x10(-5) to 5x10(-9)M) for 24h at 37 degrees C. E1S, E1 and E2 were characterized by thin layer chromatography and quantified using the corresponding standard. Duphaston and its 20-dihydro-metabolite, at concentrations of 5x10(-7) and 5x10(-5)M, inhibited the conversion of E1S to E2 by 14% and 63%, 65% and 74%, respectively, in MCF-7 cells; the values were 15% and 48% and 31% and 51%, respectively, in T-47D cells. In another series of experiments it was observed that, after 24-h incubation, E1 (5x10(-9)M) was converted in a great proportion to E2 in the T-47D cells and that this transformation was significantly inhibited by Duphaston and its 20-dihydro-metabolite. The IC50 value, corresponding to 50% of the inhibition in the conversion of 1 to E2, was 9x10(-6)M for 20-dihydro-metabolite in this cell line. It was concluded that the progestogen Duphaston and its 20-dihydro-metabolite are potent inhibitory agents on sulfatase and 17beta-HSD activities in breast cancer cells. Duphaston is a progestogen with properties similar to the endogenous progesterone. The data open interesting perspectives to study the biological responses of these progestogens in clinical trials of patients with breast cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed1987

Substrate specific sulfatase activity from hair follicles in recessive X-linked ichthyosis.

Recessive X-linked ichthyosis (RXLI) has its biochemical basis in a defect of the enzyme steroid sulfatase. Since several studies have reported a simultaneous deficiency of arylsulfatase C and steroid sulfatase it has been hypothesized that both enzymes are identical. In human hair follicles, however, hydrolytic activity for 4-methylumbelliferone sulfate, the substrate for arylsulfatase C, is found, while dehydroepiandrosterone sulfate is not hydrolyzed at all. These findings suggested the possible existence of two different enzymes. In the present paper structure-activity studies and molecular energy calculations are used for the demonstration that the remaining sulfatase activity in hair follicles of RXLI patients can be explained on the basis of the assumption that the enzyme has not lost its total function but has become less efficient.

Adolescent↗