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PubMedDate not supplied

Ocular features of multiple sulfatase deficiency and a new variant of metachromatic leukodystrophy.

Multiple sulfatase deficiency, a newly recognized autosomal recessive disorder caused by a deficiency of several sulfatase enzymes, is characterized by psychomotor retardation, ichthyosis, and mild organomegaly. Patients with metachromatic leukodystrophy, also an autosomal recessive disorder, have a deficiency of a single sulfatase enzyme, arysulfatase A. The ocular features of a patient with multiple sulfatase deficiency and a patient with a new biochemical variant of metachromatic leukodystrophy are described. The patient with multiple sulfatase deficiency had a unique, peripheral lens opacity and a panretinal degeneration. The patient with a new variant of metachromatic leukodystrophy exhibited a cherry-red spot.

Cataract↗

PubMed2003

Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase.

The present study describes the biological in vitro and in vivo evaluation of 2-methoxy derivatives of estrogenic inhibitors of steroid sulfatase, namely 3-sulfamoyloxy-17alpha-p-tert-butylbenzyl(or benzyl)-1,3,5 (10)-estratrien-17beta-ols. The addition of the 2-methoxy group conserves the potent inhibitory effect on steroid sulfatase activity (IC(50)s of 0.024 and 0.040 nM) while removing the estrogenic action. Using an ovariectomized mouse model, we show that the first generation of steroid sulfatase inhibitors tested, 3-sulfamoyloxy-17alpha-p-tert-butylbenzyl(or benzyl)estra-1,3,5 (10)-trien-17beta-ols and estrone-3-O-sulfamate, are estrogenic compounds stimulating estrogen-sensitive uterine growth. Interestingly, the 2-methoxy-3-sulfamoyloxy-17alpha-benzylestra-1,3,5 (10)-trien-17beta-ol (7) has no estrogenic activity but efficiently blocks (s.c. and p.o.) uterine growth induced by estrone sulfate, which is converted into estrone and then estradiol by steroid sulfatase and type 1 17beta-hydroxysteroid dehydrogenase, respectively. This report clearly shows that a steroid sulfatase inhibitor can efficiently block estrogen action from the inactive precursor estrone sulfate, in vitro and in vivo.

Animals↗

PubMed1986

[Demonstration of a cytosolic inhibitory of membrane estrone sulfatase activity in guinea pig liver].

Estrone sulfatase is a membrane-bound enzyme hydrolysing estrone sulfate. In normal and pathological tissues, estrone sulfatase is required for the conversion of estrone sulfate into physiologically active estrogens. In the hepatic cytosol of Guinea-pig, we have demonstrated the existence of a soluble inhibitor of uterine and hepatic microsomal estrone sulfatase. This inhibitor has approximatively a molecular weight of 7,600 and acts as a non-competitive inhibitor of estrone sulfatase. It seems to be a soluble intra-cellular effector of membrane-bound estrone sulfatase.

Animals↗

PubMed1987

Isolation and characterization of rat hepatic ascorbic acid-2-sulfatases.

Ascorbic acid-2-sulfatase was isolated from rat liver by a multistep procedure. DEAE Sephacel ion-exchange chromatography resolved crude ascorbic acid-2-sulfatase into cationic and anionic fractions. These fractions were purified 75- and 230-fold, respectively. The comparative biochemical properties suggest that arylsulfatase B is responsible for the cationic ascorbic acid-2-sulfatase activity, while arylsulfatase A appears to be responsible for the anionic ascorbic acid-2-sulfatase activity. Partially purified arylsulfatase A hydrolyzed ascorbic acid-2-sulfate at 4% the rate of p-nitrocatechol sulfate hydrolysis, while arylsulfatase B hydrolyzed ascorbic acid-2-sulfate at 0.6% the p-nitrocatechol sulfate rate.

Animals↗

PubMed1988

Multiple sulfatase deficiency.

Multiple sulfatase deficiency is an inherited disorder characterized by a deficiency of several sulfatases and the accumulation of sulfatides, glycosaminoglycans, sphingolipids, and steroid sulfates in tissues and body fluids. The clinical manifestations represent the summation of two diseases: late infantile metachromatic leukodystrophy and mucopolysaccharidosis. We present a 9-year-old girl with a phenotype similar to a mucopolysaccharidosis: short stature, microcephaly, and mild facial dysmorphism, along with dysphagia, retinal degeneration, developmental arrest, and ataxia. We discuss the importance of measuring the sulfatase activities in the leukocytes, and the instability of sulfatases in the cultured skin fibroblasts.

Cerebroside-Sulfatase↗

PubMed1982

Galactose 6-sulfate sulfatase activity in Morquio syndrome.

We have prepared a new substrate (o-beta-D-sulfo-galactosyl-(1-4)-beta-D-6-sulfo-2-acetamido-2-deoxyglucosyl- (1-4)-D-[1-3H]galactitol), from shark cartilage keratan sulfate, for the assay of galactose 6-sulfate sulfatase activity. Using this substrate, we found there was a striking deficiency of galactose 6-sulfate sulfatase activity, in addition to the known deficiency of N-acetylgalactosamine 6-sulfate sulfatase, in the cultured skin fibroblasts of patients with Morquio syndrome. Our results could be explained by the hypothesis that accumulation of keratan sulfate and chondroitin 6-sulfate in Morquio syndrome is due to a deficiency of galactose 6-sulfate sulfatase and N-acetylgalactosamine 6-sulfate sulfatase activity, which are necessary for the degradation of these two mucopolysaccharides.

Animals↗

PubMed1987

Hunter syndrome: presence of material cross-reacting with antibodies against iduronate sulfatase.

Polyclonal antibodies were obtained from rabbits by injection of iduronate sulfatase purified 35,000-fold from human placenta, after elution of the enzyme from sodium dodecyl sulfate (SDS) polyacrylamide gels. The specificity of these antibodies towards iduronate sulfatase was demonstrated by immunoprecipitation of enzyme activity; the level of other lysosomal hydrolases and sulfatases remained constant. Immunoblot of iduronate sulfatase from various human sources showed that the antibody recognises a polypeptide of mol. wt. 72,000 daltons in placenta and serum, and a form of mol. wt. 60,000 daltons in fibroblasts. No immunoprecipitable peptide was found in urine or in the culture medium of fibroblasts. Polypeptides of the same molecular weight were recognised in serum and in fibroblasts of Hunter patients. The presence of altered proteins in these patients was also shown by competition experiments. The addition of Hunter proteins alters the binding of normal enzyme to the antibody.

Animals↗

PubMedDate not supplied

Placental steroid metabolism in a case of placental sulfatase deficiency.

The importance of the placental 3 beta-steroid sulfatase for placental biosynthesis of estrogens is demonstrated by a case report of a placental sulfatase deficiency. The absolute deficiency of this enzyme in our case is demonstrated in vivo by the intravenous dehydroepiandrosterone sulfate loading test and in vitro by placental enzyme tests. Steroid concentrations in serum after injection of dehydroepiandrosterone sulfate (DHEA-S) are compared with those in a group of pregnant women without placental enzyme defects and in a group of nonpregnant women. Placental in vitro tests demonstrate the intact 3 beta-hydroxysteroid dehydrogenase-delta 4,5 isomerase-aromatase-system in the placenta with sulfatase deficiency. The lack of placental hydrolysis results in low concentrations of estrone and estradiol-17 beta in the maternal serum, which are only 5.9% and 12.5%, respectively, of the mean values of the control group. This indicates that more than 90% of estrone and more than 85% of estradiol-17 beta measured in the maternal serum are from DHEA-S as precursor. The remaining concentrations are converted mainly from dehydroepiandrosterone (DHEA), which needs no hydrolysis. Maternal serum concentrations of estriol are under the detection limit of the radioimmunoassay. This is due to the absence of the so called "neutral pathway" and the "phenolic pathway" with 16 alpha-hydroxydehydroepiandrosterone sulfate (16 alpha-OH-DHEA-S) and DHEA-S respectively as precursors. The insignificance of the "placental pathway" for the total biosynthesis of estriol is demonstrated. The placental sulfatase seems to have no great importance for the biosynthesis of the C21-steroids.

Androstenedione↗

PubMed1989

Steroid sulfate sulfatase in human benign prostatic hyperplasia: characterization and quantification of the enzyme in epithelium and stroma.

Characteristics and activities of estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHAS) sulfatases were studied in epithelium and stroma of benign hyperplastic tissues from human prostates. Tissues were obtained by suprapubic prostatectomy, and epithelium and stroma were separated mechanically by standard techniques. The assay procedure comprised homogenization in Tris-buffer, incubation of the homogenate with [3H]E1S or [3H]DHAS, separation of free steroids from nonhydrolyzed steroid sulfates by extraction with ether, and their final quantification by LSC. The main results were: (1) The pH-optimum of the sulfatase was found at pH 7.0. (2) The highest specific sulfatase activity was found in the epithelium and was associated with its nuclear fraction. (3) Michaelis-Menten constants Km (microM) were 8.7 +/- 1.4 (7) and 4.3 +/- 0.8 (5), maximum velocity rates Vmax (nmol/h x mgDNA) were 47.4 +/- 8.8 (7) and 8.4 +/- 1.5 (5) for E1S and DHAS, respectively (means +/- SEM (n]. (4) The enzymatic cleavage of E1-sulfate was competitively inhibited by DHA-sulfate and vice versa with inhibition constants Ki (microM) of 4.0 +/- 0.5 (2) for E1S and 2.7 +/- 0.4 (2) for DHAS. On the basis of these findings, possible roles of steroid sulfate-sulfatases in forming precursors of active androgens and estrogens from the high amounts of E1S and DHAS in blood are discussed.

Aged↗

PubMed1998

Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase.

Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (> 99% at 0.1 microM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site-directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8-Tetrahydronaphthalene 2-O-sulfamate (7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 microM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) were prepared to extend this series of nonsteroidal inhibitors, and COUMATE reduces the E1-STS activity in placental microsomes by > 90% at 10 microM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) were also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4-dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 nM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed.

Arylsulfatases↗

PubMed1983

Identification of an autosomal locus affecting steroid sulfatase activity among inbred strains of mice.

We have found an activity variant for testicular and liver steroid sulfatase among inbred strains of mice that is not X-linked. C57BL/6J, SM/J and SWR/J testicular extracts hydrolyze 3H-dehydroepiandrosterone sulfate twice as rapidly as do A/J extracts. The C3H/HeJ and DBA/2J strains were intermediate. The Km values for C57BL/6J and A/J are 2.29 +/- 0.10 and 1.01 +/- 0.02 microM, respectively. The F1 values in both directions were intermediate, which argues against X-linkage of this trait. F2 values show scattered high-intermediate-low values compatible with assay variation superimposed on the segregation of codominant alleles. When assayed for both testicular and liver steroid sulfatase, nine recombinant inbred lines between A/J and C57BL/6J segregate to near the parental strain values. Thus, this activity variation for steroid sulfatase appears to be determined by a single gene, which is not X-linked. Sex and steroidal hormone differences in liver steroid sulfatase activity were not present in the A/J strain, but females of the C57BL/6J and some recombinant inbred lines had higher levels. Electrophoretic studies only disclosed a variant in the SM/J strain, which seems to be secondary to the well-known neuraminidase variation in SM/J.

Animals↗

PubMed1982

Purification and some properties of human liver iduronate sulfatase.

Iduronate sulfatase was purified from human liver for an investigation of the degradative pathway of dermatan sulfate. An overall 80-fold purification was achieved and, more importantly, the preparation was free of alpha-L-iduronidase, beta-glucuronidase, N-acetylgalactosamine 4-sulfate sulfatase (arylsulfatase B) and highly enriched in beta-N-acetylhexosaminidase. The liver enzyme appeared to be composed of several molecular species. The enzyme activity was optimal at pH 4.0 and its Km was 10--20 microM with sulfoiduronyl sulfoanhydromannitol. Chloride was inhibitory at high concentration and among divalent metal ions, only copper was inhibitory. Nitrocatechol sulfate was not a substrate, but did show competitive inhibition. Its Ki for iduronate sulfatase was similar to its Km for arylsulfatase, suggesting a similarity in the substrate binding sites of iduronate sulfatase and arylsulfatases.

Chemical Phenomena↗

PubMed1981

Steroid sulfatase of human leukocytes and epidermis and the diagnosis of recessive X-linked ichthyosis.

Patients with recessive X-linked ichthyosis, one of the inherited types of excessive stratum corneum cohesion, have deficient steroid sulfatase in fibroblasts grown from their dermis. Because of the expense and long period required to grow such cells, we have assayed this enzyme in peripheral blood leukocytes and found it to be undetectable in those from patients with this type of ichthyosis, but normal in those from patients with other hereditary or acquired types of ichthyosis. In addition, steroid sulfatase activity is less in leukocytes from women who are carriers of this disease than normal women, and this assay can be used to detect such carriers. Despite previous studies demonstrating that the gene for this enzyme escapes the inactivation of other x-chromosome genes, normal women have leukocyte steroid sulfatase activity only 1.3 times that of normal men, suggesting that some gene dosage compensation occurs. Normal human epidermis, the tissue most affected clinically, also expresses steroid sulfatase activity. The epidermal enzyme is similar in its subcellular localization, its molecular size, and kinetically to that of placenta, leukocytes, and fibroblasts.

Cells, Cultured↗

PubMed2000

Profile of glycosaminoglycan-degrading glycosidases and glycoside sulfatases secreted by human articular chondrocytes in homeostasis and inflammation.

OBJECTIVE: To determine enzymatic activities of the 8 key glycosaminoglycan-degrading glycosidases and glycoside sulfatases in cultured human articular chondrocytes and in synovial fluid from patients with osteoarthritis. METHODS: The following enzymes were analyzed: hexosaminidase and its isoenzyme A, N-acetyl-alpha-D-glucosaminidase, beta-galactosidase, beta-glucuronidase, alpha-L-iduronidase, aryl sulfatase, and galactose-6-sulfate sulfatase. Activity of the selected enzymes was analyzed by fluorometry with the aid of 4-methylumbelliferryl derivatives of the appropriate monosaccharides. RESULTS: Hexosaminidase was found to be the dominant enzyme released by chondrocytes into the extracellular compartment. Stimulation of chondrocytes with interleukin-1beta resulted in a selective increase of the extracellular hexosaminidase activity and, to a lesser degree, of the extracellular beta-galactosidase activity, without significant changes in the activity of the other studied enzymes. Analysis of the pH dependency of the enzymatic activities revealed that even at neutral pH, hexosaminidase expressed a measurable activity, much higher than the activity of the other studied enzymes. Chondrocyte apoptosis did not result in increased extracellular glycosidase activities, including hexosaminidase activity. The spectrum of glycosidase and glycoside sulfatase activities in the synovial fluid from patients with osteoarthritis was similar to that in cultured human articular chondrocytes. CONCLUSION: These data support the concept that lysosomal glycosidases, in particular hexosaminidase, represent a distinct subset of cartilage matrix-degrading enzymes that are activated by proinflammatory stimuli.

Apoptosis↗

PubMed1998

A superfamily of metalloenzymes unifies phosphopentomutase and cofactor-independent phosphoglycerate mutase with alkaline phosphatases and sulfatases.

Sequence analysis of the probable archaeal phosphoglycerate mutase resulted in the identification of a superfamily of metalloenzymes with similar metal-binding sites and predicted conserved structural fold. This superfamily unites alkaline phosphatase, N-acetylgalactosamine-4-sulfatase, and cerebroside sulfatase, enzymes with known three-dimensional structures, with phosphopentomutase, 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, phosphoglycerol transferase, phosphonate monoesterase, streptomycin-6-phosphate phosphatase, alkaline phosphodiesterase/nucleotide pyrophosphatase PC-1, and several closely related sulfatases. In addition to the metal-binding motifs, all these enzymes contain a set of conserved amino acid residues that are likely to be required for the enzymatic activity. Mutational changes in the vicinity of these residues in several sulfatases cause mucopolysaccharidosis (Hunter, Maroteaux-Lamy, Morquio, and Sanfilippo syndromes) and metachromatic leucodystrophy.

Alkaline Phosphatase↗

PubMed1997

Daidzein sulfoconjugates are potent inhibitors of sterol sulfatase (EC 3.1.6.2).

Recent studies have associated high dietary isoflavone intake with low incidence of breast cancer. Since estrogenic steroids are important factors in the evolution of breast cancer, and in breast tumors they are derived mainly from the sterol sulfatase pathway, we have therefore investigated effects of the isoflavone daidzein and its sulfoconjugates, daidzein-4'-O-sulfate and daidzein-7,4'-di-O-sulfate, on sterol sulfatase acitivity using dehydroepiandrosterone sulfate as substrate. While daidzein does not affect sterol sulfatase, its sulfoconjugates are potent inhibitors of this enzyme. Kinetic analyses reveal that daidzein-4'-O-sulfate and daidzein-7,4'-di-O-sulfate inhibit sterol sulfatase competitively with respect to the steroid substrate and with Ki values of 5.9 and 1 microM, respectively. Daidzein sulfo-conjugates also inhibit hydroxysteroid and phenol sulfotransferases but at much higher concentrations. These results provide a biochemical basis for the putative chemopreventive role of dietary isoflavones against breast cancer.

Animals↗

PubMed1997

Inhibition of morphogenetic movement during Xenopus gastrulation by injected sulfatase: implications for anteroposterior and dorsoventral axis formation.

In order to explore the role of morphogenetic movement in the establishment of anteroposterior and dorsoventral axes, we sought to identify novel in vivo inhibitors of gastrulation movements in Xenopus laevis. Injection of hydrolytic sulfatase into the blastocoels of gastrula stage embryos resulted in severe anteroposterior truncation, without a corresponding truncation of the dorsoventral axis. Confocal microscopy of whole embryos revealed that gastrulation movements are severely disrupted by sulfatase; in addition, sulfatase dramatically inhibited chordomesodermal cell elongation and convergent extension movements in planar dorsal marginal zone explants. The phenotype of anteroposterior reduction elicited by sulfatase is distinctly different from commonly generated dorsoanterior phenotypes (e.g., ultraviolet irradiation of the vegetal cortex prior to cortical rotation or suramin injection), and the two varieties of phenotype appear to result from inhibition of distinct, separable components of the axis-generating machinery.

Animals↗

PubMed1979

Clinical and biochemical investigations on patients with partial deficiency of placental steroid sulfatase.

We report on three independent cases with a partial deficiency of placental steroid sulfatase (E.C.3.1.6.2). Upon routine pregnancy monitoring these patients were detected on the basis of low estriol excretion and failing induction of labor. In all three cases a male was delivered and subsequently the diagnosis of partial deficiency of placental steroid sulfatase was confirmed enzymatically in placenta homogenates. In one case, fibroblast cultures were established from skin explants of mother and son. In fibroblasts of the child, as in placental tissue, the activity of steroid sulfatase was only 34% of normal. Similar values were obtained for arylsulfatase C, though this enzyme is clearly separable from steroid sulfatase by electrophoresis. In cells of the mother, enzyme activities were unremarkable.

Arylsulfatases↗