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)

Steroid sulfatase (STS; E.C. 3.1.6.2) is an enzyme involved in the local production of estrogens and androgens in target organs. Inhibitors of steroid sulfatase activity are considered novel therapeutic agents for the treatment of different pathologic conditions, including cancers of breast, endometrium, and prostate and disorders of the pilosebaceous unit. Evaluation of steroid sulfatase inhibition in cells up to now has been a cumbersome process, involving the extraction of a radioactive cleavage product into organic solvents. Here, we describe a rapid, nonradioactive cellular assay in microtiter plate format, using 4-methylumbelliferyl sulfate as a substrate. The reaction product, 4-methylumbelliferone, is read in a fluorescence microtiter plate reader. Several cell lines were assayed for sulfatase activity. To increase the sensitivity of the assay, we developed a Chinese hamster ovary (CHO) cell line stably transfected with a cDNA encoding the human steroid sulfatase. The steroid sulfatase activity in transfected cells correlated with the presence of the enzyme in these cells, as determined by immunofluorescence. For most STS inhibitors tested, including estrone-3-O-sulfamate, the results from the CHO cellular assay were in good agreement with those from a standard cell-free assay.
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PMID:Microtiter plate cellular assay for human steroid sulfatase with fluorescence readout. 1281 32

X-linked ichthyosis (XLI) is a relatively common genetic disorder that occurs in about one in every 2000-6000 male births. Clinically, XLI is characterized by a generalized scaling of the skin, with large, polygonal, dark brown scale, and more prominent on the extensor aspects of the limbs. It is known that an undetectable maternal serum, unconjugated estriol, associated with placental steroid sulfatase (STS) deficiency, may be the cause of cause of XLI. In most case, STS deficiency is caused by a complete or partial deletion of the STS gene mapped on chromosome Xp22.3. We describe here the prenatal detection of a male fetus affected with STS deficiency as a result of an undetectable unconjugated estriol in the second-trimester maternal serum screening. Microdeletion of the STS gene was confirmed by fluorescence in situ hybridization analysis of cultured amniotic fluid.
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PMID:Prenatal diagnosis for placental steroid salfatase deficiency with fluorescence in situ hybridization: a case of X-linked ichthyosis. 1464 95

Disorders of cornification are a group of diseases that share abnormalities in the manufacture or desquamation of corneocytes. This paper reviews the major and a few of the rarer ones with a concentration on their therapy. Ichthyosis vulgaris is probably a post-translational defect in pro-filaggrin expression. It shows fine white flaky scales of the extensor surfaces, trunk, flank, lower legs but spares the folds and wet areas. Treatment is with aggressive moisturization. Hydrocortisone creams may be needed to control itch. Recessive X-linked ichthyosis is due to a deficiency of cholesterol sulfatase. Boys with this condition show small dark scales around the ears, sides of the neck, extensor surfaces of the arms and legs, and the peri-umbilical region. It spares the folds and face. Treatment is with moisturizers, topical retinoid creams or with topical cholesterol-based creams. Checking for signs of contiguous gene disorders (Kallman or Conradi-Hunermann syndromes) is necessary. Bullous congenital ichthyosiform erythroderma is caused by mutations in keratins 1 and/or 10. These patients are born as bright red babies with large blisters and erosions. Slowly, a porcupine quill-like waxy scaling develops. Blistering continues throughout life. Secondary infections of the skin cause pain, debility, and a very foul odor. Treatment is difficult. Topical moisturizers, descalers and retinoid creams help a little. Oral retinoids help a lot but can cause increased blistering. Controlling the odor is an ongoing issue using antibacterial washes, absorbing powders, and masking fragrances. Autosomal recessive ichthyosis is a term for both lamellar ichthyosis and congenital ishthysosiform erythroderma. They are caused by various mutations in transglutaminase-1 gene. In both instances patients are born as 'collodion babies'. Lamella ichthyosis has the very recognizable plate-like scale over the entire body. Children with congenital ishthysosiform erythroderma are red all over with a finer scale in some places and plate-like scales in others. Treatment is with topical moisturizers, retinoid creams, descalers, and in some cases oral retinoids. Palmar plantar keratodermas occur in conjunction with some ichthyoses, but also by themselves. Some are diffuse and others have discrete, corn-like hardenings. Treatment with topical acids, propylene glycol and retinoid creams help to some extent.Throughout the article pearls from my practice are included to assist the clinician in the day-to-day handling of these patients. A short section on genetic counseling concludes this article.
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PMID:Disorders of keratinization: diagnosis and management. 1497 40

Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.
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PMID:Steroid sulfatase: molecular biology, regulation, and inhibition. 1556 2

X-linked ichthyosis is an inherited genetic disorder of the skin that results from steroid sulfatase (STS) deficiency. Seven critical point mutations have been previously reported for the STS gene, six leading to amino acid substitutions and one to a premature termination of the polypeptide chain. The three-dimensional structure of the full-length human enzyme has been recently determined. Amino acid substitutions due to point mutations in X-linked ichthyosis are mapped onto the three-dimensional structure of human STS. In each case, the substitution appears to cause disruption of the active site architecture or to interfere with the enzyme's putative membrane-associating motifs crucial to the integrity of the catalytic cleft, thereby providing an explanation for the loss of STS activity.
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PMID:Mutations in X-linked ichthyosis disrupt the active site structure of estrone/DHEA sulfatase. 1560 12

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenocortical insufficiency, especially in children, and may be an underestimated cause of neonatal death. Early postnatal diagnosis may prevent hypoglycemic seizures, Addisonian crises, and death. There are also occasional reports of prenatal diagnosis of IAD by findings on the maternal triple-marker screen (TMST), a combined serum analyte test that measures levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol for the detection of Down syndrome and open neural-tube defects. An isolated low estriol level is usually correlated with compromised uteroplacental perfusion and frequently associated with fetal death. A low estriol level in the context of normal fetal sonography and growth, after exclusion of placental sulfatase deficiency and Smith-Lemli-Opitz syndrome, should raise the suspicion of deficient fetal steroidogenesis, which leads to decreased production of adrenal dehydroepiandrosterone sulfate. We describe 2 brothers with adrenal insufficiency resulting from IAD. The parents are first cousins whose first son is healthy. During the pregnancy of the second son, who died at the age of 7 weeks as a result of presumed cardiomyopathy, a low estriol level on the TMST was ignored because of a normal fetal ultrasound. In the third pregnancy, a low level was found again, and the mother was referred to our tertiary center. Ultrasonography revealed no abnormalities, and karyotype was normal. Normal levels of steroid sulfatase activity and 7-dehydrocholesterol ruled out X-linked ichthyosis and Smith-Lemli-Opitz syndrome, respectively. Postnatally, basal and stimulated cortisol and ACTH levels were low. Other pituitary functions were normal, suggesting the diagnosis of IAD. The patient was treated with a stress dose of hydrocortisone on day 2 of life, which was tapered to a maintenance dose. At the time of this writing, he was 7 months old, with normal growth and development. Recently, loss-of-function mutations in the human TPIT gene were detected in autosomal recessive IAD. TPIT is a cell-restricted T-box transcription factor that is important for the terminal differentiation of pituitary corticotrophs. Therefore, we performed molecular analysis of the TPIT gene, which revealed a new mutation (IVS4+1G>A) that affects the first nucleotide of the splice site at the 5' end of the fourth intron. This stop codon probably leads to loss of TPIT function by nonsense-mediated mRNA decay, as it does for other TPIT nonsense mutations. We recommend that pregnant women with an isolated low estriol level of unexplained etiology be referred for additional evaluation by a multidisciplinary team that includes a geneticist and pediatric endocrinologist. Prompt ACTH testing in the first postnatal days will allow for early diagnosis. The immediate institution of glucocorticoid therapy, with proper instructions for stress management, can prevent unnecessary neonatal death secondary to an easily treatable disease.
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PMID:Low estriol levels in the maternal triple-marker screen as a predictor of isolated adrenocorticotropic hormone deficiency caused by a new mutation in the TPIT gene. 1639 Sep 21

The sulfatase family of enzymes catalyzes the hydrolysis of sulfate ester bonds of a wide variety of substrates. Nine human sulfatase proteins and their genes have been identified, many of which are associated with genetic disorders leading to reduction or loss of function of the corresponding enzyme. A catalytic cysteine residue, strictly conserved in prokaryotic and eukaryotic sulfatases, is modified posttranslationally into a formylglycine. Hydroxylation of the formylglycine residue by a water molecule forming the activated hydroxylformylglycine (a formylglycine hydrate or a gem-diol) is a necessary step for sulfatase activity of the enzyme. Crystal structures of three human sulfatases, arylsulfatases A and B (ARSA and ARSB) and C, also known as steroid sulfatase or estrone/dehydroepiandrosterone sulfatase (ES), have been determined. In addition, the crystal structure of a homologous bacterial arylsulfatase from Pseudomonas aeruginosa (PAS) is also available. While ARSA, ARSB, and PAS are water-soluble enzymes, ES has a hydrophobic domain and is presumed to be bound to the endoplasmic reticulum membrane. This chapter compares and contrasts four sulfatase structures and revisits the proposed catalytic mechanism in light of available structural and functional data. Examination of the ES active site reveals substrate-specific interactions previously identified in another steroidogenic enzyme. Possible influence of the lipid bilayer in substrate capture and recognition by ES is described. Finally, mapping the genetic mutations into the ES structure provides an explanation for the loss of enzyme function in X-linked ichthyosis.
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PMID:Three-dimensional structures of sulfatases. 1639 55

A 13-year-old boy presented with a lifelong history of tightly-adherent, brown, polygonal scales that covered the extensor surfaces of the extremities, lateral aspects of the trunk, and neck. The clinical presentation and the history of a similar skin condition in the patient's male maternal relatives helped establish the diagnosis of X-linked recessive ichthyosis (XLI). Systemic manifestations of the steroid sulfatase (STS) deficiency underlying XLI include cryptorchidism, asymptomatic corneal opacities, and maternal failure to progress during labor. Most cases of XLI are caused by deletions of the STS gene, and contiguous gene syndromes may occur when the deletions extend to neighboring genes on the distal short arm of the X chromosome.
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PMID:X-linked recessive ichthyosis. 1640 84

Steroid sulfatase (STS) is localized in the endoplasmic reticulum and catalyzes desulfation of 3beta-hydroxysteroid sulfates. X-linked ichthyosis (XLI) is an inherited skin disorder caused by deficiency of STS enzyme activity. We previously reported a case in which XLI with a one-base change in the STS gene and variation in amino acid Q560P developed. In this study, we performed molecular analysis to determine the importance of terminal regions of STS and the effect of mutant STS on STS enzyme activity. To examine the effect of terminal truncated STS on the enzyme activity, N- and C-terminal truncated STS expression vectors were transfected into COS-1 cells. The activity of truncated STS lacking the N-terminal regions declined, and the activity of C-terminal-truncated STS declined with extension of the truncated C-terminal region. Although the results of pulse-chase experiments showed that a one-base mutant STS (Q560P) and C-terminal-truncated STS (deltaC2 (1-559)) had no effects on protein synthesis and degradation, the mutant STS and C-terminal-truncated STS have dominant negative effect on STS enzyme activity when the STS mutant or truncated STS protein and a wild-type STS protein coexist in cells. Results of coprecipitation of the truncated STS with an STS-FLAG fusion protein showed that STS formed a dimer conformation in cells. In this study, we have shown that both the N-terminal region and C-terminal region are important for STS enzyme activity. The C-terminal mutant has a dominant negative effect on wild-type STS.
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PMID:Both N-terminal and C-terminal regions of steroid sulfatase are important for enzyme activity. 1646 62

Sulfatase enzymes have important roles in metabolism of steroid hormones and of glycosaminoglycans (GAGs). The activity of five sulfatase enzymes, including steroid sulfatase (STS; arylsulfatase C), arylsulfatase A (ASA; cerebroside sulfatase), arylsulfatase B (ASB; N-acetylgalactosamine-4-sulfatase), galactose-6-sulfatase (GALNS), and iduronate-2-sulfatase (IDS), was compared in six different mammary cell lines, including the malignant mammary cell lines MCF7, T47D, and HCC1937, the MCF10A cell line which is associated with fibrocystic disease, and in primary epithelial and myoepithelial cell lines established from reduction mammoplasty. The effects of estrogen hormones, including estrone, estradiol, estrone 3-sulfate, and estradiol sulfate on activity of these sulfatases were determined. The malignant cell lines MCF7 and T47D had markedly less activity of STS, ASB, ASA, and GAL6S, but not IDS. The primary myoepithelial cells had highest activity of STS and ASB, and the normal epithelial cells had highest activity of GALNS and ASA. Greater declines in sulfatase activity occurred in response to estrone and estradiol than sulfated estrogens. The study findings demonstrated marked variation in sulfatase activity and in effects of exogenous estrogens on sulfatase activity among the different mammary cell types.
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PMID:Steroid sulfatase, arylsulfatases A and B, galactose-6-sulfatase, and iduronate sulfatase in mammary cells and effects of sulfated and non-sulfated estrogens on sulfatase activity. 1706 91


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