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PubMed1997

Conversion of cysteine to formylglycine: a protein modification in the endoplasmic reticulum.

In sulfatases a Calpha-formylglycine residue is found at a position where their cDNA sequences predict a cysteine residue. In multiple sulfatase deficiency, an inherited lysosomal storage disorder, catalytically inactive sulfatases are synthesized which retain the cysteine residue, indicating that the Calpha-formylglycine residue is required for sulfatase activity. Using in vitro translation in the absence or presence of transport competent microsomes we found that newly synthesized sulfatase polypeptides carry a cysteine residue and that the oxidation of its thiol group to an aldehyde is catalyzed in the endoplasmic reticulum. A linear sequence of 16 residues surrounding the Cys-69 in arylsulfatase A is sufficient to direct the oxidation. This novel protein modification occurs after or at a late stage of cotranslational protein translocation into the endoplasmic reticulum when the polypeptide is not yet folded to its native structure.

Alanine↗

PubMed1978

Enzymatic and immunological characterization of the Mycobacterium fortuitum complex.

The arylsulfatase isozymes of Mycobacterium fortuitum, M. peregrinum, M. chelonei subsp. chelonei, and M. chelonei subsp. abscessus were examined to determine the isozymal and immunological relationship among the members of the M. fortuitum complex. Cell extracts were subjected to electrophoresis on agarose and polyacrylamide gel, and arylsulfatase activity was localized using beta-naphthyl sulfate as substrate. Unique zymograms were produced for M. fortuitum, M. peregrinum, and M. chelonei which were characteristic for each species. The immunological relationship among the sulfatases was assayed by using immunodiffusion and immunoelectrophoresis followed by sulfatase staining for the enzyme. One of the isozymes of M. fortuitum and M. peregrinum cross-reacted, showing immunological identity. Antisera to sulfatases of M. fortuitum and M. peregrinum did not react with sulfatases of M. chelonei. The characterization of sulfatase isozymes in extracts of organisms in the M. fortuitum complex suggests the division of the M. fortuitum complex into two species, M. fortuitum and M. chelonei, with subspecies designations.

Antigens, Bacterial↗

PubMedDate not supplied

[Biochemical diagnosis of mucosulfatidosis].

Biochemical anomalies in proband involved alterations in the spectrum of glycosaminoglycans (GAG) excreted with urine as well as a decrease in activity of lysosomal sulfatases (arylsulfatases A and B, heparan-N-sulfatase) in homogenates of leukocytes and cultivated fibroblasts. In healthy parents of the proband activity of the sulfatases was lower than in control donors but higher as compared with the proband. Antenatal diagnostics of mucosulfatidosis was carried out in fetus during the repeated pregnancy. The following biochemical anomalies were noted: alteration in the GAG spectrum in amniotic fluid, decrease in activity of lysosomal sulfatases in cultivated cells of the amniotic fluid. The pregnancy lead to a premature birth at 31st week of a girl. No alterations were observed in the spectrum of GAG's excreted with urine and in intracellular accumulation of 35S-GAG in the newborn child. Measurement of sulfatases activity in leukocytes enabled to identify conclusively that the child was a heterozygotic bearer mucosulfatidosis.

Child, Preschool↗

PubMed1976

Enzymes from human articular cartilage: isolation of arylsulfatase B and its comparison with arylsulfatase A.

This study describes the isolation of arylsulfatases A and B (arylsulfate sulfohydrolase EC 3.1.6.1) from human articular cartilage. These enzymes were extracted from collagenase digests of tissue homogenates. After fractionation with ammonium sulfate the enzymes were separated from each other by DEAE-cellulose chromatography and further purified by gel filtration on Sephadex G-200. Sulfatase B, subsequently chromatographed on CM-cellulose was apparently homogenous as judged by polyacrylamide gel electrophoresis in the presence and absence of sodium dodecyl sulfate. The enzyme has a pH optimum of 5.6, a molecular weight of 51,000 and Km of 2.6 mM for 4-nitrocatechol sulfate. Sulfatase A was found to be a glycoprotein with a pH optimum of 4.8, a molecular weight of 105,000 and a Km of 0.16 mM for 4-nitrocatechol sulfate. The competitive inhibition of both enzymes by inorganic sulfate, sulfite and phosphate support the likelihood of a common reaction mechanism. In contrast to sulfatase B which showed minimal inhibition, sulfatase A was totally inhibited by 5 mM N-ethylmaleimide.

Cartilage, Articular↗

PubMed1997

Identification by shotgun sequencing, genomic organization, and functional analysis of a fourth arylsulfatase gene (ARSF) from the Xp22.3 region.

We recently reported the isolation of two new members of the sulfatase gene family, arylsulfatase D (ARSD) and E (ARSE), located approximately 50 kb from each other in the Xp22.3 region. Mutation analysis indicated ARSE as the gene responsible for X-linked recessive chondrodysplasia punctata. Expression of the ARSE gene in COS cells resulted in a heat-labile arylsulfatase activity that was inhibited by warfarin. At the same time, we detected the presence of a 1.2-kb fragment located at approximately 60 kb from ARSD and ARSE with significant homology to these two genes, suggesting the existence of another sulfatase gene, arylsulfatase F (ARSF), in Xp22.3. We have used a combined approach of long-range genomic sequencing and screening of cDNA libraries to isolate the ARSF gene. Expression of the ARSF cDNA in COS cells resulted in a heat-labile arylsulfatase activity that is not inhibited by warfarin, supporting our hypothesis that only ARSE is specifically inhibited by warfarin and is most likely involved in warfarin embryopathy. Genomic analysis revealed that ARSF has an intron/exon organization highly similar to those of ARSD and ARSE, which is also shared by another Xp22.3 sulfatase gene, ARSC (arylsulfatase C, also known as steroid sulfatase), with the splice sites occurring at the same position in all four genes. The data obtained from sequence analysis and presented in this paper indicate that the ARSC, ARSD, ARSE, and ARSF genes are more similar to each other than to other members of the sulfatase gene family, supporting our hypothesis that they represent a subfamily of related proteins created through duplication events that occurred in an ancestral pseudoautosomal region.

Amino Acid Sequence↗

PubMed1996

The evolutionary conservation of a novel protein modification, the conversion of cysteine to serinesemialdehyde in arylsulfatase from Volvox carteri.

A novel post-translational protein modification has recently been described in two human sulfatases, by which a cysteine is replaced by a serinesemialdehyde (2-amino-3-oxopropionic acid) residue [Schmidt, B., Selmer, T., Ingendoh, A. & von Figura, K. (1995) Cell 82, 271-278]. This cysteine is conserved among all known eukaryotic sulfatases. Here we report the presence of this modification in arylsulfatase from the green alga Volvox carteri. The evolutionary conservation of this novel protein modification between sulfatases of V. carteri and man lends further support to the assumption that this modification is required for the catalytic activity of sulfatases and may be present in all sulfatases of eukaryotic origin.

Alanine↗

PubMed1994

Clinical implications of genetic and acquired defects in catecholamine synthesis and metabolism.

All major enzymes involved in catecholamine synthesis and metabolism have been cloned. In addition to some genetic defects of these enzymes responsible for well-defined clinical syndromes, several enzymatic abnormalities may be due to environmental (e.g. pharmacological and nutritional) or biological (e.g. aging) factors, which may modify genome expression. The enzymes involved in catecholamine metabolism either lead to metabolites which cannot be reconverted to the parent catecholamine (such as products of monoamine oxidation and catechol-O-methylation), or metabolites, which can be reconverted to the free catecholamine from which they are generated (such as products of sulfoconjugation). Reversible sulfoconjugation is partly regulated by the recently cloned enzyme, sulfatase. The importance of this reversible step is that it reconverts inactive into biologically active catecholamines. The balance of the sulfoconjugation-deconjugation interplay may have physiological implications; in addition to catecholamine release, it may determine the availability of free catecholamines during diurnal rhythms and stress or modify their renal excretion. Circumstantial evidence, including a close homology within the aryl sulfatases and steroid sulfatase gene, the first implicated in catecholamine metabolism, the second in steroid metabolism, suggests a genetic defect of sulfatases in essential hypertension. A similar, but secondary, sulfatase defect may affect catecholamine metabolism and action in chronic renal failure.

Animals↗

PubMed1983

Murine arylsulfatase C: evidence for two isozymes.

SWR/J mice possess high arylsulfatase C, estrone sulfatase, and dehydroepiandrosterone sulfatase activities in liver, spleen, and kidney compared to A/J mice. This interstrain activity variation appears to be determined by at least 1 autosomal gene. Murine arylsulfatase C activity occurs in both hydrophobic and hydrophilic forms which differ with respect to certain biochemical properties and exhibit different subcellular distributions. The hydrophilic isozyme is a major component in kidney and brain extracts and a minor isozyme in liver and spleen extracts. The hydrophobic arylsulfatase C isozyme appears to be identical to steroid sulfatase. The hydrophilic arylsulfatase C isozyme does not possess steroid sulfatase activity; however, hydrophilic and hydrophobic arylsulfatase C share certain properties, suggesting that they may be structurally related. The autosomal gene(s) affects both arylsulfatase isozymes.

Animals↗

PubMed1990

Sulfate derivatives of 2-phenylindoles as novel steroid sulfataseinhibitors. An in vitro study on structure-activity-relationship.

The growth of hormone-dependent mammary tumor cells is stimulated by non-conjugated estrogens. One important source of these hormones in the tumors could be the enzymatic hydrolysis of circulating estrogen sulfates by steroid sulfatase (EC 3.1.6.2). Inhibition of this enzyme may result in reduced levels of endogenous estrogens and, consequently, in a reduced proliferation rate of estrogen-dependent tumors. This paper reports on a series of inhibitors of steroid sulfatase based on sulfated derivatives of 2-phenylindoles, a new class of mammary tumor inhibiting compounds. Starting from hydroxy-substituted 2-phenylindoles, a number of mono- and disulfates were synthesized and tested for steroid sulfatase inhibiting properties. The enzymatic test was based on the measurement of [3H]estrone formed from [3H]estrone sulfate in the presence of various amounts of inhibitor. The concentrations which result in a 50% reduction of the rate of hydrolysis (IC50) were determined. Sulfates of hydroxylated 2-phenylindoles are substrates of steroid sulfatase. The most potent of these inhibitors show affinities which are comparable to the affinities of natural substrates. The test data further suggest that monosulfated compounds exhibit stronger enzyme-inhibiting properties than do disulfates.

Animals↗

PubMed1990

Steroid sulphatase activity in the human ovarian corpus luteum, stroma, and follicle: comparison to activity in other tissues and the placenta.

Steroid sulfatase activity was measured in 89 human samples, using dehydroepiandrosterone sulfate (DHEAS) as substrate. The lowest activity was that of follicular fluid which was significantly lower than that of other tissues tested (each P less than 0.01). The steroid sulfatase activity of ovarian tissue taken collectively (corpus luteum, stroma, and follicles) was higher than that of other tissues taken collectively (abdominal skin, uterus, and fallopian tube) (P less than 0.001), and the steroid sulfatase activity of either the follicle (P less than 0.01) or the stroma (P less than 0.05) was significantly greater than that of the corpus luteum. The geometric mean steroid sulfatase activity of the placenta was significantly higher than other tissues tested (each P less than 0.01) and was 22-fold higher than that of the follicle, the tissue with the next highest activity. These data indicate that the human ovary (particularly the stroma and follicle) is capable of utilizing DHEAS, an adrenal product, as a substrate for production of other androgens such as dehydroepiandrosterone (DHEA), androstenedione, and testosterone.

Arylsulfatases↗

PubMed1985

Purification of mammalian arylsulfatase A enzymes by subunit affinity chromatography.

Rabbit liver arylsulfatase A (arylsulfatase sulfohydrolase, EC 3.1.6.1) monomer was immobilized on cyanogen bromide-activated Sepharose-6MB and on Affi-Gel-10 under various experimental conditions in order to study the effects of variables in sulfatase monomer/oligomer subunit affinity chromatography. First, the number of reactive groups on activated Sepharose-6MB and Affi-Gel-10 was determined by a procedure involving spectrophotometric titration with L-tyrosine. After covalent coupling of sulfatase monomers to the gels, the enzyme binding capacities of the sulfatase subunit affinity gel matrixes were determined at pH 4.5. The maximum binding of free monomers from solution could be achieved when the Affi-Gel-10 protein monomer matrix was prepared at low degrees of covalent loading. The introduction of a batch technique for equilibration of the protein sample with the monomer affinity matrix also increased the efficiency of the subunit affinity gel in purification procedures. The effect of pH on the stability of the heterodimers formed between monomers of rabbit liver arylsulfatase A immobilized on Affi-Gel-10 and free monomers of arylsulfatase A enzymes from different tissues and organisms was studied using the batch technique. For all sulfatase A enzymes tested, the midpoint of the pH transition for subunit association was pH 6.2, suggesting that the amino acid residues involved in the dimerization are similar. The versatility of the Affi-Gel-10 monomer affinity matrix was further demonstrated by purifying 13 mammalian arylsulfatase A enzymes to homogeneity, as assessed by Sephacryl chromatography, native and SDS gel electrophoresis. The molecular weights of the homogeneous monomers and their peptide subunits were in the range of 110-180 KDa and 50-64 KDa, respectively. The amino acid compositions of these enzymes were also determined.

Animals↗

PubMed1984

Kinetic studies on the formation of estrogens from dehydroepiandrosterone sulfate by human placental microsomes.

Using microsomes isolated from term human placentae kinetic analyses of each of the enzymes involved in estrogen synthesis from dehydroepiandrosterone sulfate have been carried out and the following parameters were found: sulfatase, Michaelis-Menten constant (Km) = 16,000 +/- 5,000 nM, maximum velocity (Vm) = 2.0 +/- 0.5 nmol X min-1 X mg protein-1; 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), Km = 15 +/- 3 nM, Vm = 1.8 +/- 0.4 nmol X min-1 X mg protein-1; aromatase, Km = 14 +/- 4 nM, Vm = 0.12 +/- 0.02 nmol X min-1 X mg protein-1. From these values one can predict that, theoretically, the rate-limiting enzyme in estrogen synthesis from dehydroepiandrosterone sulfate (DS) should change from the sulfatase at low concentrations of substrate to the aromatase at higher concentrations. In order to test this hypothesis we developed a system which allowed the formation of estrogens from DS, dehydroepiandrosterone, and androstenedione to be measured and the appropriate intermediates to be isolated. The sulfatase was found to be rate limiting at concentrations of DS below 2 microM and the aromatase was found to be rate limiting at higher concentrations. These data may explain why previous perfusion studies of human placentae indicated the sulfatase was the rate-limiting enzyme in estrogen synthesis yet in vitro studies found that it was the aromatase. Steroids previously shown to inhibit the 3 beta-HSD were examined for their ability to inhibit the formation of estrogens from DS. Although 3 beta-HSD activity was markedly inhibited this had little effect on the overall conversion of DS to estrogens, until high concentrations of inhibitors were used. The data also underline the importance of studying enzyme systems rather than single enzymes when studying steroid synthesis.

3-Hydroxysteroid Dehydrogenases↗

PubMed1990

Phylogenetic conservation of arylsulfatases. cDNA cloning and expression of human arylsulfatase B.

A 2.2-kilobase cDNA clone for human arylsulfatase B (ASB) and several genomic clones were isolated and sequenced. The deduced amino acid sequence of 533 amino acids contains a 41-amino acid N-terminal signal peptide and a mature polypeptide of 492 amino acid residues. Overexpression of ASB in transfected baby hamster kidney (BHK) cells resulted in up to 68-fold higher ASB activity than in untransfected BHK cells. Pulse-chase labeling showed that ASB was synthesized and secreted as a 64-kDa precursor and processed to a 47-kDa mature form in BHK cells. The 47-kDa ASB form was located in dense lysosomes. Transport of ASB to the lysosomes was accomplished in a mannose 6-phosphate receptor-dependent manner. The ASB cDNA clone hybridizes to 4.8-, 2.5-, and 1.8-kilobase species of RNA from human fibroblasts. The same pattern was observed in RNA from fibroblasts of three Maroteaux-Lamy patients who were deficient in ASB activity, as well as in RNA from fibroblasts of three patients with multiple sulfatase deficiency, in which all known sulfatases were markedly diminished. Deduced amino acid sequences of human arylsulfatase A, human ASB, human steroid sulfatase, human glucosamine-6-sulfatase, and an arylsulfatase from sea urchin showed a substantial degree of similarity suggesting that they arose from a common ancestral gene and are members of an arylsulfatase gene family.

Amino Acid Sequence↗

PubMed1986

[Biochemical diagnosis of X chromosomal ichthyosis].

Steroid sulfatase (STS) and aryl sulfatase C (ASC) in leucocytes, as well as the electrophoretic mobility of the beta-lipoproteins, were analyzed in 34 patients with autosomal dominant ichthyosis (ADI), 18 patients with X-linked recessive ichthyosis (XRI), 7 patients with congenital nonbullous ichthyosis (CNBI), and 48 controls. The geometric means of both STS and ASC were significantly lower in the group of XRI by a factor of approximately 10. Analysis of ASC showed a clear separation of the whole group of XRI patients opposed to patients with ADI and CNBI and the controls, whereas an overlapping was observed for STS. With one exception, the clinical and biochemical diagnosis (sulfatase) was confirmed by the results of the lipoprotein electrophoresis (LPE). This case, clinically and biochemically diagnosed as XRI, exhibited normal electrophoretic mobility of beta-lipoproteins. We conclude: if the electrophoretic mobility of beta-lipoproteins is enhanced, XRI can be diagnosed; if the LPE is normal, XRI cannot be excluded; in this case, the diagnosis of XRI can be confirmed or rejected by analysis of the microsomal sulfatases.

Adult↗

PubMed1986

Dosage of the Sts gene in the mouse.

In this study we compared steroid sulfatase levels in XO, XX, and XY mice and carried out a clonal analysis in fibroblast cell cultures from mice heterozygous for the steroid sulfatase deficiency gene and heterozygous at the X-linked electrophoretic phosphoglycerate kinase locus. The combined results indicate that the murine steroid sulfatase locus is not dosage compensated and is not subject to X-inactivation. With respect to X-inactivation, it behaves in a somewhat different way from the closely linked sex-reversed gene and the human steroid sulfatase locus.

Alleles↗

PubMed1993

Estrone sulfate promotes human breast cancer cell replication and nuclear uptake of estradiol in MCF-7 cell cultures.

Estradiol levels in breast tumors from post-menopausal women are similar to those in pre-menopausal women even though plasma estrogens are much lower after the menopause. In situ estrogen production by the tumor provides a potential means of maintaining high estradiol levels in post-menopausal breast cancer tissue. The estrone sulfatase pathway has been proposed as the mediator of in situ estrogen production. A number of studies suggest that estrone sulfate may be converted into estradiol in breast tumors via the catalytic activity of estrone sulfatase and 17 beta-hydroxysteroid dehydrogenase. However, these studies used pharmacologic levels of estrogen sulfates and have not shown that physiologic levels can support biologic effects. Accordingly, the present study examined the dose relationship of estrone sulfate to a variety of biologic endpoints in MCF-7 breast cancer cells in culture. These cells converted physiologic concentrations of estrone sulfate to quantities of free estradiol capable of stimulating cell growth. Under these conditions, the nuclear steroids observed were free estrone and estradiol. Increase in cell number after 6 days of exposure to steroid required 100 nM estrone sulfate. However, S-phase, a more sensitive measure of cell proliferation, was stimulated by 0.1 nM estrone sulfate, a clearly physiologic concentration. Stimulation of estrogen-dependent protein markers such as pS2 and progesterone receptor required much higher concentrations of estrone sulfate. These effects were mediated through the estrogen receptor since the pure anti-estrogen, ICI 164384, blocked all effects produced by estrone sulfate. While it has been suggested that anti-estrogens may partly exert their effects by inhibition of sulfatase and 17 beta-hydroxysteroid dehydrogenase, this did not occur under our experimental conditions. These data provide evidence of the relevance of the estrone sulfatase pathway since biologic effects can be demonstrated in response to physiologic concentrations of estrone sulfate.

Biological Transport↗

PubMed1991

Characterization of arylsulfatase C isozymes from human liver and placenta.

Arylsulfatase C and steroid sulfatase were thought to be identical enzymes. However, recent evidence showed that human arylsulfatase C consists of two isozymes, s and f. In this study, the biochemical properties of the s form partially purified from human placenta were compared with those of the f form from human liver. Only the placental s form has steroid sulfatase activity and hydrolyses estrone sulfate, dehydroepiandrosterone sulfate and cholesterol sulfate. The liver f form has barely detectable activity towards these sterol sulfates. With the artificial substrate, 4-methylumbelliferyl sulfate, both forms demonstrated a similar KM but the liver enzyme has a pH optimum of 6.9 while the placental form displayed two optima at 7.3 and 5.5. The molecular weight of the native enzyme determined with gel filtration was 183,000 for the s form and 200,000 for the f form and their pI's were also similar at 6.5. However, the T50, temperature at which half of the enzyme activity was lost, was 49.5 degrees C for the f form and 56.8 degrees C for the s form. Polyclonal antibodies raised against the placental form reacted specifically against the s and not the f form. They immuno-precipitated concomitantly greater than 80% of the total placental arylsulfatase C and steroid sulfatase activities while less than 20% of the liver enzyme was immuno-precipitable. In conclusion, the two isozymes s and f of arylsulfatase C in humans purified from placenta and liver, respectively, have similar KM, pI' and native molecular weight. However, they are distinct proteins with different substrate specificity, pH optima, heat-lability and antigenic properties. Only the s form is confirmed to be steroid sulfatase.

Arylsulfatases↗

PubMed1995

Cholesterol sulfate is not degraded but does not accumulate in Epstein-Barr virus-transformed lymphoid cells from patients with X-linked ichthyosis.

The metabolism of cholesterol sulfate (CS) was investigated in immortalized, Epstein-Barr virus-transformed lymphoid cell lines derived from normal individuals and patients affected with recessive X-linked ichthyosis (XLI). Normal lymphoid cells expressed arylsulfatase C and steroid sulfatase (including cholesterol sulfatase) activities, and these two sulfohydrolases showed the same enzyme properties as in other human cells, e.g., leukocytes or skin fibroblasts. XLI-derived lymphoid cell lines exhibited extremely deficient activity of both arylsulfatase C and steroid sulfatase. While normal and XLI intact, living lymphoid cells could take up exogenous radiolabelled CS through a non-receptor-mediated process. XLI cells were completely unable to degrade CS to cholesterol. However, despite their defect in CS degradation, steroid sulfatase-deficient cells did not accumulate CS because of outflux of this sterol. The potential implications of these findings to the pathogenesis of increased CS content in plasma and epidermis of XLI patients are discussed. This study also demonstrates that immortalized lymphoid cell lines may represent a useful experimental model system for the study of XLI.

Adolescent↗