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 synthesis and biochemical evaluation of estrone sulfatase inhibitors are described. Inhibitors were designed through modifications of the substrate estrone sulfate. An in vitro assay using the microsomal fraction isolated from human term placenta was used to evaluate sulfatase inhibitory activity. All the inhibitors (except sulfonyl chloride analog) exhibited low inhibitory activities in the screening assay. Sulfonyl chloride analog is a strong inhibitor, which caused 91.5% inhibition of the enzymatic activity at 300 microM.
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PMID:Synthesis and biochemical studies of estrone sulfatase inhibitors. 847 13

Estrone sulfatase is an important enzyme which catalyzes the production of estrone from estrone sulfate in a variety of human and animal tissues. We report, for the first time, on the presence of estrone sulfatase activity in thrombocytes from human blood. Incubation of [3H]estrone sulfate in the presence of human thrombocyte lysates resulted in the formation of [3H]estrone as assessed by two-dimensional TLC. Estrone sulfatase activity was localized in the mitochondrial-microsomal fraction in thrombocytes from human blood. The enzyme was thermostable and had an optimum pH of 5.60 in acetate buffer. The highest activity was obtained in the presence of 0.1% of either Nonidet P-40 or Triton X-100. Phosphate ions (1 mM) inhibited the enzyme activity by 64% and similar effects were observed in the presence of platelet-free plasma. Endogenous inhibitors had no effect on the observed enzyme activity under assay conditions as evidenced in this study. The apparent Km value was 3.16 +/- 0.08 microM for [3H]estrone sulfate and V was 188.5 +/- 2.6 (mean +/- SEM, n = 22) pmol.mg protein-1.h-1. Comparison between two thrombocyte preparative procedures provided evidence that thrombocyte estrone sulfatase activity should be measured in thrombocyte samples representing the whole thrombocyte population. This parameter appeared critical for accurate measurements of enzyme activity. The presence of estrone sulfatase activity in human thrombocytes provides a new non-invasive tool for the study of this activity both in physiological and pathological conditions which could be of potential clinical relevance.
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PMID:Characterization of estrone sulfatase activity in human thrombocytes. 866 70

In order to investigate the influence of estrogen metabolism on human breast cancer, estradiol 2- and 16 alpha-hydroxylase (2- and 16 alpha-OHase) activities were determined in the microsomal fractions of cancer tissues by using reverse phase HPLC. 2-OHase activity was detected in most cancer tissues and noncancerous tissues, but the activity was significantly lower in cancer tissues than in the paired noncancerous tissues (0.01 < p < 0.02). Interestingly the patients without lymph node metastasis had significantly higher 2-OHase activity in cancer tissues than those with lymph node metastasis (0.02 < p < 0.05). No correlation was observed between ER status and 2-OHase activity in cancer tissues. On the other hand, 16 alpha-OHase activity was detected only in one third of the breast cancer tissues examined. The activity was not significantly different from that in noncancerous tissues, although it was relatively higher in ER-positive cancer tissues when compared with that in ER-negative ones (0.05 < p < 0.1). Estrone sulfatase activity measured simultaneously in the cytosol fractions of some specimens was much higher in cancer tissues than in noncancerous tissues (0.02 < p < 0.05). We found, however, no correlation between estrone sulfatase activity and estradiol hydroxylase activity. Taken together, our results suggest that the increase in 2-OHase activity prevents the proliferation of breast cancer and that estradiol metabolism is regulated independently of the local biosynthesis of estrogen.
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PMID:Influence of estrogen metabolism on proliferation of human breast cancer. 911 18

We investigated the regional and subcellular distribution of neurosteroid sulfatase (NSS) in the bovine brain and its enzymatic properties by using dehydroepiandrosterone sulfate (DHEA-S) as a substrate. Bovine NSS was highly concentrated in the region of the midbrain and in the hypothalamus. The enzyme was found to be a microsomal enzyme. The optimal temperature of the enzyme was 50 degrees C, which was slightly lower than that of other steroid sulfatases. The optimal pH of bovine NSS was 7.4 with a second optimum at pH 4.0. The second optimal pH of 4.0 was the most characteristic property of bovine NSS. Employing DHEA-S as the substrate, apparent Km and Vmax values were 113 +/- 21 microM and 4.1 +/- 0.4 nmol/mg protein/h, respectively, whereas Km and Vmax values were found to be 1.6 +/- 0.2 M and 1.9 +/- 0.3 micromol/mg protein/h with p-nitrophenyl sulfate (NP-S) as the substrate. NSS has thus been shown to have a higher affinity for the steroid sulfate than the phenolic compound. When DHEA-S was used as the substrate, pregnenolone sulfate (Preg-S) was a competitive inhibitor with an apparent Ki value of 46 microM, and NP-S was a non-competitive inhibitor (apparent Ki=12 mM).
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PMID:Distribution and characterization of neurosteroid sulfatase from the bovine brain. 940 85

Inhibition of estrone sulfatase activity offers the potential for breast cancer prevention therapy by blocking a route to estrogen synthesis. We have investigated the inhibition of this activity by natural flavonoids in a human hepatic microsomal preparation in vitro. The majority of studies were performed with a male liver, but male and female livers exhibited comparable estrone sulfatase activities. The natural flavonoids, quercetin, kaempferol, and naringenin, significantly inhibited estrone sulfatase activity with I50 < 10 microM for the most potent, quercetin. Estrone sulfatase activity in the liver microsomes was biphasic, with a high affinity, low capacity, low concentration activity (Km 14.3 microM, Vmax 0.5 nmol/min/mg protein), probably steroid sulfatase-catalysed, and a low affinity, high capacity, high concentration activity (Km 1.5 mM, Vmax 21.5 nmol/min/mg protein), probably arylsulfatase C or E-catalysed. The former activity was inhibited uncompetitively by quercetin, the latter competitively. Quercetin, a natural dietary constituent, is a potent inhibitor of estrone sulfatase in vitro, and thus has the potential to express antiestrogenic activity in vivo.
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PMID:Inhibition of estrone sulfatase in human liver microsomes by quercetin and other flavonoids. 944

The missense mutation, L476P, in the N-acetylgalactosamine 4-sulfatase (4S) gene, has previously been shown to be associated with a severe feline mucopolysaccharidosis type VI (MPS VI) phenotype. The present study describes a second mutation, D520N, in the same MPS VI cat colony, which is inherited independently of L476P and is associated with a clinically mild MPS VI phenotype in D520N/L476P compound heterozygous cats. Biochemical and clinical assessment of L476P homozygous, D520N/L476P compound heterozygous, and D520N homozygous cats demonstrated that the entire range of clinical phenotypes, from severe MPS VI, to mild MPS VI, to normal are clustered within a narrow range of residual 4S activity from 0. 5% to 4.6% of normal levels. When overexpressed in CHO-KI cells, the secreted form of D520N 4S was inactivated in neutral pH conditions. In addition, intracellular D520N 4S protein was rapidly degraded and corresponded to 37%, 14.5%, and 0.67% of normal 4S protein levels in the microsomal, endosomal, and lysosomal compartments, respectively. However, the specific activity of lysosomal D520N 4S was elevated 22. 5-fold when compared with wild-type 4S. These results suggest that the D520N mutation causes a rapid degradation of 4S protein. The effect of this is partially ameliorated as a result of a significant elevation in the specific activity of mutant D520N 4S reaching the lysosomal compartment.
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PMID:Mild feline mucopolysaccharidosis type VI. Identification of an N-acetylgalactosamine-4-sulfatase mutation causing instability and increased specific activity. 959 74

In female rats, total estrone-3-sulfatase activity per liver in the nuclear fraction is comparable to the total activity per liver in the microsomal fraction. The combined estrone-3-sulfatase activity in the other fractions (lysosomal, mitochondrial, and cytosolic fractions) is negligible and only accounts for < 5% of the total nuclear or microsomal sulfatase activity. Nuclear and microsomal estrone-3-sulfatases have different pH optima (pH 8.0 and 7.2, respectively). The apparent Km values for the nuclear and microsomal estrone-3-sulfatases are 2.5 and 10.1 microM, respectively, suggesting that the nuclear sulfatase has a considerably higher affinity for estrone-3-sulfate than the microsomal sulfatase. Moreover, the nuclear estrone-3-sulfatase is more sensitive to inhibition by several steroids than the microsomal sulfatase. The results suggest that estrone-3-sulfatase in the nuclear fraction is a different isozyme than that in the microsomal fraction.
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PMID:Different biochemical properties of nuclear and microsomal estrone-3-sulfatases: evidence for the presence of a nuclear isozyme. 960 65

Rutin and quercetin absorption and metabolism were investigated in rats after in situ perfusion of jejunum plus ileum (15 nmol/min). In contrast to rutin, a high proportion of quercetin (two-thirds) disappeared during perfusion, reflecting extensive transfer into the intestinal wall. Net quercetin absorption was not complete (2.1 nmol/min), inasmuch as 52% were reexcreted in the lumen as conjugated derivatives (7.7 nmol/min). Enterohepatic recycling contribution of flavonoids was excluded by catheterization of the biliary duct before perfusion. After a 30-min perfusion period, 0.71 microM of quercetin equivalents were detected in plasma, reflecting a significant absorption from the small intestine. The differential hydrolysis of effluent samples by glucuronidase and/or sulfatase indicates that the conjugated forms released in the lumen were 1) glucuronidated derivatives of quercetin and of its methoxylated forms (64%) and 2) sulfated form of quercetin (36%). In vitro quercetin glucuronides synthetized using jejunal and ileal microsomal fractions were similar to those recovered in the effluent of perfusion. These data suggest that glucuronidation and sulfatation take place in intestinal cells, whereas no glucurono-sulfoconjugates could be detected in the effluent. The present work shows that a rapid quercetin absorption in the small intestine is very effective together with its active conjugation in intestinal cells.
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PMID:Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. 1040 58

In recent years, development of potent inhibitors for estrogen sulfatases has become an actively pursued strategy for chemoprevention and/or chemotherapy of estrogen-dependent human breast cancers. We report here our findings that pregnenolone 16alpha-carbonitrile (PCN) is a potent inhibitor of estrone-3-sulfatase activity of rats and also humans. PCN inhibited in a concentration-dependent manner the desulfation of estrone-3-sulfate catalyzed by liver microsomal and nuclear fractions of female Sprague-Dawley rats. The inhibition of estrone-3-sulfatase activity in these two subcellular fractions showed a biphasic pattern, with a highly sensitive phase seen at 78 nM to 1.25 microm of PCN followed by a markedly less-sensitive phase at > 2.5 microm of PCN. Interestingly, several of PCN's structural analogs without a 16alpha-nitrile group showed little or no inhibitory effect on rat liver microsomal E(1)-3-sulfatase activity. Double-reciprocal analysis showed that the inhibition of rat liver microsomal E(1)-3-sulfatase activity by PCN was essentially competitive in nature. When microsomes from six human term placentas were tested for their E(1)-3-sulfatase activity, PCN showed a similar biphasic inhibition of placental E(1)-3-sulfatase. Likewise, several of its structural analogs showed little or no inhibitory effect on placental E(1)-3-sulfatase activity. Computational analysis of the D-ring structure of PCN and other structurally similar analogs used in the study suggests that the potent sulfatase-inhibiting activity of PCN may be partly due to its unique steric orientation and size of the 16alpha-nitrile group. This knowledge may be useful for the rational design of more potent steroidal inhibitors of E(1)-3-sulfatase by introducing an additional nitrile group to their C16alpha-position.
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PMID:Strong inhibition of estrone-3-sulfatase activity by pregnenolone 16alpha-carbonitrile but not by several analogs lacking a 16alpha-nitrile group. 1097 31

In a previous study of nine human breast-derived cell lines, rates of metabolism of 17beta-estradiol (E(2)) were greatly enhanced when cultures were exposed to the aromatic hydrocarbon receptor agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin. Elevated rates of E(2) hydroxylation at the C-2, -4, -6alpha and -15alpha positions were observed concomitant with the induction of cytochromes P450 1A1 and 1B1. In each cell line, 2- and 4-hydroxyestradiol (2- and 4-OHE(2)) were converted to 2- and 4-methoxyestradiol (2- and 4-MeOE(2)) by the action of catechol O:-methyltransferase. In this study, conjugation of these estrogen metabolites was investigated. A comparison of the levels of metabolites determined with and without prior treatment of the media with a crude beta-glucuronidase/sulfatase preparation showed that most of the 2-MeOE(2) present was in conjugated form, whereas 4-MeOE(2), 6alpha-OHE(2) and 15alpha-OHE(2) were minimally conjugated. Inhibitor studies suggested that it was the sulfatase activity of the preparation that hydrolyzed the 2-MeOE(2) conjugates in MCF-7 cell media; the presence of 2-MeOE(2)-3-sulfate in MCF-7 culture media was confirmed by electrospray ion-trap mass spectrometry. To identify the enzyme catalyzing this conjugation, the expression of mRNAs encoding five sulfotransferases (SULT1A1, SULT1A2, SULT1A3, SULT1E1 and SULT2A1) was evaluated in the nine cell lines by use of the reverse transcription-polymerase chain reaction. Only expression of SULT1A1 mRNA correlated with the observed conjugation of nanomolar levels of 2-MeOE(2) in these cell lines. Cloning and sequencing of SULT1A1 cDNA from MCF-7 cells revealed that mRNAs encoding two previously identified allelic variants, SULT1A1*1 ((213)Arg) and SULT1A1*2 ((213)His), were expressed in these cells. Heterologous cDNA-directed expression of either variant in MDA-MB-231 cells, which do not normally express SULT1A1, conferred 2-MeOE(2) sulfonation activity. The SULT1A1 allelic variants were also expressed in SF:9 insect cells, from which post-microsomal supernatants were used to determine K:(m) values of 0.90 +/- 0.12 and 0.81 +/- 0.06 microM for SULT1A1*1 and SULT1A1*2, respectively, with 2-MeOE(2) as substrate. These results show that SULT1A1 is an efficient and selective catalyst of 2-MeOE(2) sulfonation and, as such, may be important in modulating the anticarcinogenic effects of 2-MeOE(2) that have been described recently.
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PMID:SULT1A1 catalyzes 2-methoxyestradiol sulfonation in MCF-7 breast cancer cells. 1106 53


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