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Mucopolysaccharidoses (MPS) comprise a group of 12 metabolic disorders where defects in specific enzyme activities lead to the accumulation of glycosaminoglycans (GAGs) within lysosomes. This classification expands to 13 when considering MPS IIIE. This type of MPS, associated with pathogenic variants in the ARSG gene, has thus far been described only in the context of animal models. However, pathogenic variants in this gene also occur in humans, but are linked to a different disorder, Usher syndrome (USH) type IV, which is sparking increasing debate. This paper gathers, discusses, and summarizes arguments both for and against classifying dysfunctions of arylsulfatase G (due to pathogenic variants in the ARSG gene) in humans as another subtype of MPS, called MPS IIIE. Specific difficulties in diagnostics and the classification of some inherited metabolic diseases are also highlighted and discussed. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) has the third highest incidence and second mortality rate of malignant tumors globally, highlighting the urgency to explore the mechanisms underlying CRC progression for refined treatment of this patient population. Methods: R Studio was used for data sorting and analysis. Cell apoptosis and cell cycle detection were performed by flow cytometry. Quantitative real-time PCR (qRT-PCR) was used to explore mRNA expression levels. Western blotting was used to explore protein expression levels. CCK8, EdU, and colony formation assays were performed to explore the proliferation capacity of CRC cells. Transwell invasion and migration assays, along with the wound healing assay, were used to explore the invasive and migratory abilities of CRC cells. Subcutaneous Xenograft Assay was utilized to evaluate the tumorigenic capacity of CRC cells in vivo. Results: SULF1 was highly expressed in CRC samples and cell lines. The knockdown of SULF1 inhibited the proliferation, invasion, and migration of CRC and increased the rate of cell apoptosis. Meanwhile, we demonstrated that SULF1 could negatively regulate ARSH through the FAK/PI3K/AKT/mTOR pathway. Conclusion: We demonstrated that SULF1 could promote CRC progression by regulating ARSH. The SULF1/ARSH/FAK/PI3K/AKT/mTOR signaling pathway represents a promising target for the treatment of this patient population. Simple summary: Colorectal cancer (CRC) has the third highest incidence and second mortality rate of malignant tumors globally. Sulfatase 1 (SULF1) belongs to the sulfatase family, The function of SULF1 in CRC remains elusive. Our study demonstrated that the knockdown of SULF1 could inhibit the proliferation, invasion, and migration of CRC. Meanwhile, our findings indicated that SULF1 could interact with Arylsulfatase Family Member H (ARSH) to regulate the proliferation, invasion, and migration of CRC via the FAK/PI3K/AKT/mTOR signaling pathway. Taken together, our findings suggest that SULF1 might be a new therapeutic target in CRC. [ABSTRACT FROM AUTHOR]

The effects of the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B, ARSB), which removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate, on the expression of PD-L1 were determined, and the underlying mechanism of PD-L1 expression was elucidated. Initial experiments in human melanoma cells (A375) showed that PD-L1 expression increased from 357 ± 31 to 796 ± 50 pg/mg protein (p < 10−11) when ARSB was silenced in A375 cells. In subcutaneous B16F10 murine melanomas, PD-L1 declined from 1227 ± 189 to 583 ± 110 pg/mg protein (p = 1.67 × 10−7), a decline of 52%, following treatment with exogenous, bioactive recombinant ARSB. This decline occurred in association with reduced tumor growth and prolongation of survival, as previously reported. The mechanism of regulation of PD-L1 expression by ARSB is attributed to ARSB-mediated alteration in chondroitin 4-sulfation, leading to changes in free galectin-3, c-Jun nuclear localization, HDAC3 expression, and effects of acetyl-H3 on the PD-L1 promoter. These findings indicate that changes in ARSB contribute to the expression of PD-L1 in melanoma and can thereby affect the immune checkpoint response. Exogenous ARSB acted on melanoma cells and normal melanocytes through the IGF2 receptor. The decline in PD-L1 expression by exogenous ARSB may contribute to the impact of ARSB on melanoma progression. [ABSTRACT FROM AUTHOR]

The enzymatic activity of soil arylsulfatase and β-glucosidase enzymes are biological parameters used to measure the biological activity of soils, an important tool for identifying disturbances in agricultural systems, as they are more sensitive to differentiate changes in soil management when compared to physical and chemical attributes. Thus, the aim was to evaluate arylsulfatase and β-glucosidase levels in different succession systems. Soil samples were collected in agricultural areas with 5 years of experimentation, with four treatments: (1) soybean/corn + brachiaria (Urochloa ruzizienses), (2) soybean/corn, (3) soybean/brachiaria (Urochloa ruzizienses) and (4) soybean/millet. Routine chemical analyses were performed, and the determination of β-glucosidase and arylsulfatase was carried out according to the p-nitrophenyl colorimetric method. As a result, both enzymes presented higher average values in treatment 3. In the biological IQS, treatment 3 differed from treatments 1 and 2. Under the study circumstances, the use of soil with soybean, corn, millet and brachiaria crops provided adequate sustainability conditions, providing high arylsulfatase and β-glucosidase levels. [ABSTRACT FROM AUTHOR]

Background: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. Late-infantile, juvenile and adult clinical subtypes are defined by symptom onset at ≤ 2.5, > 2.5 to < 16 and ≥ 16 years, respectively. Epidemiological data were sought to address knowledge gaps and to inform decisions regarding the clinical development of an investigational drug. Methods: To synthesize all available estimates of MLD incidence and birth prevalence worldwide and in selected countries, Ovid MEDLINE and Embase were searched systematically (March 11, 2022) using a population, intervention, comparator, outcome, time and setting framework, complemented by pragmatic searching to reduce publication bias. Where possible, results were stratified by clinical subtype. Data were extracted from non-interventional studies (clinical trials, non-clinical studies and case reports were excluded; reviews were used for snowballing only). Results: Of the 31 studies included, 14 reported birth prevalence (13 countries in Asia–Pacific, Europe, the Middle East, North America and South America), one reported prevalence and none reported incidence. Birth prevalence per 100,000 live births ranged from 0.16 (Japan) to 1.85 (Portugal). In the three European studies with estimates stratified by clinical subtypes, birth prevalence was highest for late-infantile cases (0.31–1.12 per 100,000 live births). The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. Conclusions: This review provides a foundation for further analysis of the regional epidemiology of MLD. Data gaps indicate the need for better global coverage, increased use of epidemiological measures (e.g. prevalence estimates) and more stratification of outcomes by clinical and genetic disease subtype. [ABSTRACT FROM AUTHOR]

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12.Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in CEP78, CEP250, ARSG, or ABHD12.CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12-related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe.This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

Background: Arylsulfatase D (ARSD) belongs to the sulfatase family and plays a crucial role in maintaining the proper structure of bone and cartilage matrix. Although several researches have revealed the functions of ARSD in tumor progression, the prognostic value of ARSD in glioma and the related mechanisms have not been fully investigated. Methods: We performed a pan-cancer analysis of ARSD, and investigated the relationship between expression of ARSD and overall survival (OS) in multiple glioma datasets. ROC curves and nomograms were created to investigate the predictive capacity of ARSD. Immune and analysis were conducted to investigate the mechanisms underlying the roles of ARSD in glioma. Glioma tissue samples were collected to verify the expression of ARSD in glioma, while the functions of ARSD were explored using cell experiment. M2 macrophage infiltration assay was used to determine the relation between ARSD and tumor immune microenvironment. Results: Survival analysis indicated that individuals with high ARSD expression in glioma had a shorter survival time. Cox analysis showed that ARSD had a good ability for predicting prognosis in glioma. Immune analysis suggested that ARSD could regulate immune cell infiltration and affect the Cancer-Immunity Cycle to create an immunosuppressive environment. Combined with cell experiment and bioinformatic analysis, we found that ARSD can promote glioma progression through regulation of JAK2/STAT3 pathway and M2 macrophage infiltration. Conclusion: Our study found that ARSD can promote glioma development by regulating immune microenvironment and JAK2/STAT3 signaling pathway, which provided a potential therapy target for glioma treatment. [ABSTRACT FROM AUTHOR]

Arylsulfatases exhibit great potential in industry for desulfation applications, but less is known about the metallo-β-lactamase (MBL) fold arylsulfatases. To learn more about them, an MBL fold arylsulfatase from Pseudoalteromonas atlantica T6c (PaAst) was identified and characterized, and its structure was elaborated in this study. PaAst was sequence analyzed, heterologously expressed in E. coli, purified by Ni2+-NTA resin affinity chromatography and size-exclusion chromatography, functionally studied by p-nitrophenyl sulfate (pNPS), and crystallized for structure determination. The MBL fold arylsulfatase was identified by sequence analysis and confirmed by enzymatic assay on pNPS with Km 1.00 mM and Vmax 60.80 U/mg at 50 °C and pH 7.5. Furthermore, its crystals were obtained in 0.2 M sodium thiocyamate, 20% PEG3350, and its structure was determined at 2.0 Å that formed a dimer with MBL fold. Our work highlighted the MBL fold arylsulfatases from structural insights and could be the theoretical foundation for investigations into their catalytic mechanism. [ABSTRACT FROM AUTHOR]

Antimony (Sb), a toxic metalloid, is ubiquitous in the environment and threatens human and ecological health. Soil arylsulfatase (ARS) activity indicates heavy metal pollution. However, the enzyme's substrate concentration can affect the toxicity evaluation of heavy metals using enzyme activity. Enzyme kinetic parameters directly reflect the potency of heavy metals, and the magnitude of these parameters does not change with the substrate concentration of soil enzyme. In this work, seventeen soils were exposed to Sb contamination to investigate the change of kinetic parameters of soil arylsulfatase under Sb stress. Results showed that Sb inhibited soil arylsulfatase activity. The maximum reaction rate (Vmax) of soil arylsulfatase was reduced by 11.58–46.72% in 16 tested soils and unchanged in S15 when exposed to Sb. The Michaelis constant (Km) presented three trends: unchanged, increased by 28.46–41.27%, and decreased by 19.71–29.91% under Sb stress. The catalytic efficiency (Ka as the ratio of Vmax to Km) decreased by 12.56–55.17% in all soils except for S12 and S16. Antimony acted as a non-competitive and linear mixed inhibitor by decreasing ARS activity in S1–S12, S14, and S17–S18 soils, as an uncompetitive inhibitor in S13 and S16 soils and as a competitive inhibitor in S15. The competitive and uncompetitive inhibition constants (Kic and Kiu) were 0.058–0.142 mM and 0.075–0.503 mM. The ecological dose values of Sb to catalytic efficiency (Ka) of ARS (ED10-Ka) ranged from 50 to 1315 mg kg−1. Soil pH and total phosphorus (TP) contents were the dominant factors responsible for Sb toxicity on Ka by affecting the interaction of inhibitor (Sb) with enzyme-substrate (ES) complex. The findings of this study advance the current knowledge on Sb toxicity to soil enzymes and have significant implications for the risk assessment of Sb in soils. [ABSTRACT FROM AUTHOR]

Sulfur is a required macroelement for all organisms, and sulfate deficiency causes growth and developmental defects. Arylsulfatases (ARS) hydrolyze sulfate from sulfate esters and make sulfate bioavailable for plant uptake. These enzymes are found in microorganisms and animals; however, plant genomes do not encode any ARS gene. Our database searches found nineteen ARS genes in the genome of Chlamydomonas reinhardtii. Among these, ARS1 and ARS2 were studied in the literature; however, the remaining seventeen gene models were not studied. Our results show that putative polypeptide sequences of the ARS gene models all have the sulfatase domain and sulfatase motifs found in known ARSs. Phylogenetic analyses show that C. reinhardtii proteins are in close branches with Volvox carterii proteins while they were clustered in a separate group from Homo sapiens and bacterial species (Pseudomonas aeruginosa and Rhodopirellula baltica SH1), except human Sulf1, Sulf2, and GNS are clustered with algal ARSs. RT‐PCR analyses showed that transcription of ARS6, ARS7, ARS11, ARS12, ARS13, ARS17, and ARS19 increased under sulfate deficiency. However, this increase was not as high as the increase seen in ARS2. Since plant genomes do not encode any ARS gene, our results highlight the importance of microbial ARS genes. [ABSTRACT FROM AUTHOR]

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We found the activity of arylsulfatase in the midgut contents of the silkworm, Bombyx mori. We identified a 60-kDa protein that comigrates with the activity on a column chromatography following ammonium sulfate precipitation. Based on its partial amino acid sequence, we searched for its coding gene using Basic Local Alignment Search Tool (BLAST) and identified KWMTBOMO05106. Transcriptional data suggest a specific expression of the gene in middle silk glands. The majority (80%) of arylsulfatase activity was found in the silk glands, concurring the specific transcription in the silk gland. Observing the feeding behaviour of the silkworm, we found that silkworms smear a mucus secretes from the spinneret on the food pellet as they feed on. Arylsulfatase activity was also detected in the food pellet bitten by the silkworm as well as in the gut content. Furthermore, arylsulfatase activity was not detected either in the food pellet and in the gut content when silkworms had obstructed the spinneret. These results suggest that arylsulfatase is secreted from the silk glands and may contribute to digestive function. [ABSTRACT FROM AUTHOR]

Sulfate is an essential macroelement for all living organisms. However, sulfate can be limited in agricultural settings. Microorganisms change their gene expression to acclimate to sulfate deficient conditions. Green microalga Chlamydomonas reinhardtii expresses and secretes extracellular arylsulfatase (ARS) under sulfate deficient conditions. Our results show that C. reinhardtii ARS can hydrolyze both sulfate monoester (5-bromo-4-chloro-3 indolyl sulfate; X-SO42-) and phosphate monoester (5-bromo-4-chloro-3 indolyl phosphate; X-PO43-) providing evidence that ARS enzyme has promiscuous activity. C. reinhardtii is found in soil and fresh water habitats in nature. This promiscuous activity can be beneficial in making both sulfate and phosphate bioavailable for uptake by soil organisms and plant roots. [ABSTRACT FROM AUTHOR]

• First report for transformation of estradiol to estrone by commercial arylsulfatase. • Acetate could efficiently inhibit the transformation. • Underestimation of estradiol and overestimation of estrone may occur. This work for the first time reported the complete transformation of 17β-estradiol (E2) to estrone (E1) by unknown wild-type enzyme present in the widely used commercial arylsulfatase derived from Helix pomatia. It was found that acetate could effectively inhibit the unknown enzyme with a half inhibitory concentration (IC 50) of 140.9 μM, while phosphate and citrate showed no inhibition. Since the buffer solutions with phosphate and citrate have been used in the enzymatic hydrolysis of natural estrogen conjugates for decades, the transformation of E2 to E1 likely occurred during such procedure, inevitably leading to overestimated E1, but underestimated E2. It was further suggested that acetate should be used to prevent this undesirable transformation during the enzymatic hydrolysis of natural estrogen conjugates. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Subsequent accumulation of sulfatides leads to demyelination and neurodegeneration in the central and peripheral nervous system. To date MLD is classified based on the age at onset, however, especially for late onset forms this classification provides only limited projection regarding the clinical disease course. Moreover, evolving newborn screening approaches raise the need to predict the disease onset and course in pre-symptomatic individuals. Here, we correlate the ARSA activity and the ARSA -genotype with clinical parameters in a large cohort of 96 affected individuals. Clinical data of 96 affected individuals with genetically and/or biochemically confirmed MLD were collected from a national database. Leukocyte samples from 69 affected individuals were re-analyzed for the ARSA activity using p-nitrocatecholsulfate as substrate with a refined ARSA assay towards the lower limit of detection. For 84 individuals genetic sequencing was conducted by Sanger or next generation sequencing (NGS). The adapted ARSA assay revealed the discriminatory power to differentiate MLD subtypes as the residual enzyme activity was low in late infantile and early juvenile forms, and clearly higher in late juvenile and adult MLD (p < 0.001). A residual enzyme activity below 1% compared to controls predicted an early onset (late-infantile or early-juvenile) and rapid disease progression. A firm genotype-phenotype correlation was proven as reliable for bi-allelic protein-truncating variants in the ARSA gene resulting in minimal residual ARSA activity, an early onset of the disease and initial decline of motor functions. Although the impact of missense variants was equivocal, few variants with a recognizable clinical spectrum were identified. ARSA activity in leukocytes as well as the ARSA genotype can predict the age of disease onset and the dynamic of disease progression for most of the early onset forms. This knowledge is relevant for patient counseling and to guide treatment decisions, especially when identifying pre-symptomatic individuals, e.g., in newborn screening. However, due to the high cumulative frequency of rare disease-causing missense variants in the ARSA gene that lead to highly variable residual enzyme activity, reiterated biochemical and genetic studies are needed to improve disease course prediction. [ABSTRACT FROM AUTHOR]

The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). The newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. The regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights. [ABSTRACT FROM AUTHOR]

Agricultural gypsum can improve the chemical quality of low fertility soil, providing calcium and sulphur. In this study, we evaluated the effects of agricultural gypsum application at five dosage rates (0, 3, 6, 9 and 12 Mg ha−1) on the chemical and microbial soil characteristics of an acid oxisol (0–0.1 m and 0.1–0.2 m layers) and the impact on wheat grain yield. Increasing agricultural gypsum dosage rates increased Ca, S as well as the Ca/Mg ratio and microbial biomass of carbon in the 0–01 m soil layer. In the 0.1–0.2 m soil layer, agricultural gypsum affected organic C (Corg), Ca and the Ca/Mg ratio. The microbial biomass of carbon had positive correlations with most chemical and microbial variables. In the 0–0.1 m soil, the microbial biomass of C and N had negative relationships with arylsulphatase and β‐glucosidase, respectively. At 0.1–0.2 m depth, arylsulphatase activity correlated negatively with Corg and positively with Al. Agricultural gypsum soil amendments increased the microbial biomass of carbon, especially at the highest application rate (12 Mg ha−1). The highest biochemical index activity was found in the 3 Mg ha−1 (0–0.1 m) and 9 Mg ha−1 (0.1–0.2 m) treatments. At 70 months after application, we found that maximum wheat grain yield was rendered by an agricultural gypsum application rate close to 3 Mg ha−1. [ABSTRACT FROM AUTHOR]

Arylsulfatase and β-glucuronidase are the two substantial enzymes having a significant role in the cleavage of conjugated natural estrogens (C-NEs). The present study reports that arylsulfatase and β-glucuronidase have been abundantly found in the digestive tracts of Cipangopaludina chinensis; in which, their corresponding activities were 60 and 5 U/g wet waste, respectively. The arylsulfatase from Cipangopaludina chinensis could show high activity at low temperatures. Hence, its activity still remained at 53.2% of maximal activity even at an extremely low temperature of 4 ℃; while the corresponding activities of arylsulfatase from Helix pomatia or activated sludge were less than 20% and 10%, respectively. The arylsulfatase and β-glucuronidase from Cipangopaludina chinensis could efficiently cleave C-NEs suggesting that they could be alternative enzymes derived from Helix pomatia that are used for cleavage of conjugated compounds in environmental or biological sample analysis. Meanwhile, they might also be used to enhance the cleavage of C-NEs in municipal wastewater. [ABSTRACT FROM AUTHOR]

Brassicaceae products have been extensively studied for their biofumigant activity; despite this, few investigate their effect on soil proprieties. This paper aims to describe the effect on soil fertility by adding the seed meal of Brassica carinata at three different doses corresponding to field dose (3 tons/ha), 10 and 100 fold this dose in organic soil. The organic carbon balance was evaluated by analysing the oxidisable, humified and mineralised carbon fractions. Microbial activity was measured by enzymes linked to the carbon, phosphorous and sulphur cycles—β-glucosidase, phosphatase and arylsulphatase, respectively. The amount corresponding to 30 t/ha was the best solution for the mineralised carbon and humic carbon ratio. In contrast, there was a substantial increase in the organic substance's mineralisation level at the maximum dose, not offset by a relative rise in humification. No repression was observed in the metabolic activity of the microorganisms, their abundance or the main enzymatic activities and, in the conditions tested, a release of only a volatile isothiocyanate occurred, limiting the biofumigant effect. Therefore, these combined factors allow us to assert that the amendment with this type of material at the intermediate dose could positively affect the phosphorus cycle, the soil structure, and fertility. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Arylsulfatases and neuraminidases modulate engagement of CCR5 by chemokines by removing key electrostatic interactions" published in Scientific Reports. The correction addresses an error in Figure 1, panel B, where the label "Hek/1/85a (sulfation-insensitive)" was incorrectly given as "Hek/1/85a (sulfation-sensitive)". The original article has been corrected. The authors of the article are Inês Pinheiro, Nicolas Calo, Marianne Paolini-Bertrand, and Oliver Hartley. [Extracted from the article]

The study aimed to assess the effects of fungicide QuadrisR on activities of soil enzymes contributed to soil nutrient turnover. A batch laboratory experiment with QuadrisR-amended (0 mg/kg ds (dry soil) - 35.00 mg/kg ds) loamy sand soil was conducted, and shifts in soil physical environments and enzyme activities (beta-glucosidase, urease, acid and alkaline phosphatases, arylsulfatase and dehydrogenase) were evaluated on experimental days 1, 30, 60, 90 and 120. The results indicated that QuadrisR changed both soil properties and enzyme activities. The most sensitive environmental parameter to fungicide input was soil pH. The most suscaptable to QuadrisR enzymes were dehydrogenase and arylsulfatase, and the most resistant - urease. The mean overall dehydrogenase activity decreased by 33%, whereas the profile of arylsulfatase activity tended to permanent decrease over time. The general pattern of enzyme responses to QuadrisR was an immediate-early (days 1 - 30) decline of enzyme activities after fungicide application, except that of arylsulfatase. Beta-glucosidase manifested a temporal profile of steady-state stimulation under the lowest (2.90 mg/kg ds) and low sensitivity to the higher (14.65 mg/kg ds and 35.00 mg/kg ds) fungicide concentrations. [ABSTRACT FROM AUTHOR]

The degradation of glycosaminoglycans (GAGs) involves a series of exolytic glycosidases and sulfatases that act sequentially on the nonreducing end of the polysaccharide chain. Enzymes have been cloned that catalyze all of the known linkages with the exception of the removal of the 2-O-sulfate group from 2-sulfoglucuronate, which is found in heparan sulfate and dermatan sulfate. Here, we show using synthetic disaccharide substrates that arylsulfatase K is the glucuronate-2-sulfatase. Arylsulfatase K acts selectively on 2-sulfoglucuronate and lacks activity against 2-sulfoiduronate, whereas iduronate-2-sulfatase (IDS) desulfates synthetic disaccharides containing 2-sulfoiduronate but not 2-sulfoglucuronate. As arylsulfatase K has all of the properties expected of a lysosomal enzyme, we conclude that arylsulfatase K is the long sought lysosomal glucuronate-2-sulfatase, which we designate GDS.

Vegetable production is characterized by a strong dependence on external inputs and intense tillage, which can harm soil health (SH) by reducing organic matter levels, soil biota diversity, and overall ecosystem functions. Tools to assess SH affected by organic and conventional vegetable production systems are crucial and still scarce. This study aimed to develop a practical and reliable SH assessment tool for vegetable production systems in tropical soils by integrating Cornell's Comprehensive Assessment of Soil Health (CASH) with the four-quadrant model (4QM). Furthermore, the study evaluated the relationship between management practices and SH status. Arylsulfatase (ARYL) and β-glucosidase (GLU) activities, and soil organic carbon (SOC) were analyzed in 90 soil samples (0 to 10 cm depth) collected from 53 organic and conventional vegetable farms in the Federal District, Brazil. The adoption of practices aimed at improving or maintaining SH was significantly greater on organic farms than on conventionally managed farms, resulting in a SOC content and ARYL activity 27 % and 86 % higher in organic farms than in conventional systems, respectively (P < 0.05). ARYL proved to be more accurate in separating organic and conventional fields than GLU, highlighting its potential for SH evaluation in vegetable production systems. The integration of CASH and the 4QM, along with ARYL, GLU, and SOC measurements, effectively addressed the complexity of both organic and conventional vegetable production systems. This combined approach facilitated differentiation between systems based on varying levels of adoption of best management practices (BMPs). Further research is needed to assess the performance of this approach across different soil types and regions where vegetables are cultivated. [Display omitted] • A novel soil health (SH) assessment tool for vegetable cropping systems investigated • Soil samples from 90 field sites under organic and conventional systems assessed • Comprehensive Assessment of Soil Health (CASH) and four-quadrant model (4QM) merged • Organic sites showed higher arylsulfatase and organic carbon than conventional. • Combination of CASH and 4QM allows evaluation of SH in vegetable cropping systems. [ABSTRACT FROM AUTHOR]

Arylsulfatase and β‐glucuronidase are two important enzymes in wastewater and surface water, which play important roles on cleavage of sulfate/glucuronide estrogens. In this work, a high‐performance liquid chromatography (HPLC)‐based new method was firstly established for arylsulfatase/β‐glucuronidase with determination of p‐nitrophenyl sulfate (pNPS)/p‐nitrophenyl‐β‐D‐glucuronide (pNPG). The limits of detections (LODs) of the developed method for pNPS and pNPG were 0.164 and 0.098 μM, respectively. Intraday and interday reproducibility expressed as relative standard deviation (RSD) values of retention times and peak areas was 0.39%–3.68% and 0.23%–4.74%, respectively. The respective recovery efficiencies of this HPLC‐based method spiking at three different concentrations for p‐nitrophenol (pNP), pNPS, and pNPG in activated sludge were 76.5%–88.1%, 79.2%–93.1%, and 84.2%–96.1%, with RSD below 3.9%. The HPLC‐based method was finally applied to estimate the enzyme activity of arylsulfatase/β‐glucuronidase in one activated sludge system and along which the classical spectrophotometric method was also evaluated. Compared with the classic spectrophotometric analytical method, the HPLC‐based new method could simultaneously measure arylsulfatase/β‐glucuronidase one time, which was convenient and time‐saving. Moreover, the developed method could effectively avoid possible underestimation that the spectrophotometric method might encounter. Practitioner points: A new HPLC‐based method for activity estimation of arylsulfatase and β‐glucuronidase was developed.The HPLC‐based method can simultaneously estimate enzyme activity of both arylsulfatase and β‐glucuronidase.The HPLC‐based method can avoid possible underestimation that spectrophotometric method may encounter. [ABSTRACT FROM AUTHOR]

Steroid arylsulfatase is an important enzyme in human, which plays an important role in dynamic equilibrium of natural estrogens. On the other hand, sulfite can be endogenously produced as a consequence of human body's metabolism of sulfur-containing amino acids, while its main sources to human are mainly derived from food as it is a widely used additive. Sulfite-sensitivity is a well-known phenomenon to a small proportion of populations. However, its potential adverse effects on healthy individuals have been hardly reported. It was for the first time reported in this study that sulfite could effectively inhibit arylsulfatase, and its IC50 values for the snail- and human urine–derived arylsulfatase were determined to be 71.9 and 142.8 µM, which were lower than the concentration of sulfite in some healthy population. Consequently, it appears that sulfite might disrupt estrogen homeostasis in human, and this deserves further investigation. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA's enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes. Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, but the connecting pathophysiological mechanisms are incompletely understood. Here the authors identify arylsulfatase A as a NASH-induced hepatokine that inhibits hepatic lysophosphatidylcholine and lysophosphatidic acid secretion, and improves muscle insulin action and systemic glucose homeostasis. [ABSTRACT FROM AUTHOR]

This research evaluated the effects of coffee cultivation with two different water regimes associated or not with liming and the presence/absence of brachiaria as intercrop on the activities of the soil enzymes β-glucosidase, arylsulfatase and acid phosphatase. The study was carried out at the experimental farm of Embrapa Cerrados, using the cultivar IAC 144 (Coffea arabica L.), under a clayey dystrophic Cerrado Oxisol. Two water regimes (WR) were considered, WR1 with irrigation shifts throughout the year and WR3 with controlled water stress, for about 70 days, in the dry season. In each water regime, effects of lime application (with/without) and the presence/absence of brachiaria cultivated between the lines of coffee plants were evaluated. The activities of the enzymes β-glucosidase, arylsulfatase and acid phosphatase were evaluated during the rainy and dry seasons. Liming and intercropped brachiaria positively affected the activities of the three enzymes assessed in this study at varying degrees, depending on season and/or the WR. Our findings evidenced that intercropped brachiaria in coffee rows was the factor that most positively impacted soil enzymes activities. [ABSTRACT FROM AUTHOR]

The preconditioning of human sperm with sublethal nitrosative stress before cryopreservation can potentially improve the thawed sperm quality. However, the underlying mechanisms behind this protective strategy are not entirely understood. We compared the cryosurvival of human sperm exposed to 0.01 μM nitric oxide (NO) throughout the cryopreservation and used multiplexed quantitative proteomics approach to identify changes in the proteome profile of preconditioned sperm cells. Semen samples were obtained from 30 normospermia donors and then each sample was divided into three equal parts: fresh (F), frozen-control (C), and frozen exposed to nitric oxide (NO). The sperm undergoing mild sublethal stress showed higher values for motility and viability compared to the frozen control sperm. Moreover, out of 2912 identified proteins, 248 proteins were detected as differentially abundant proteins (DAPs) between cryopreserved groups and fresh group (F) (p < 0.05). Gene ontology (GO) analysis of differentially abundant proteins indicated that the abundance of proteins associated with glycolysis, gluconeogenesis, and fertilization processes was reduced while oxidative phosphorylation pathway was increased in abundance in cryopreserved sperm compared to the fresh sperm. Moreover, redox protein such as thioredoxin 17 was increased in abundance in the NO group compared to the control freezing group. Therefore, the pre-conditioning of sperm prior to cryopreservation may play an important role in maintaining the redox balance in mitochondria of sperm after freezing. Overall, our results indicate that arylsulfatase A (ARSA), serine protease 37 (PRSS37), and sperm surface protein (SP17) may potentially serve as protein biomarkers associated with screening the fertilization potential of the thawed sperm. [ABSTRACT FROM AUTHOR]

Steroid sulfate esters are important metabolites for anti-doping efforts in sports, pathology and research. Analysis of these metabolites is facilitated by hydrolysis using either acid or enzymatic catalysis. Although enzymatic hydrolysis is preferred for operating at neutral pH, no known enzyme is capable of hydrolyzing all steroid sulfate metabolites. Pseudomonas aeruginosa arylsulfatase (PaS) is ideal for the hydrolysis of β-configured steroid sulfates but like other known class I sulfatases it is inefficient at hydrolyzing α-configured steroid sulfates. We have used directed evolution with liquid chromatography mass spectrometry screening to find variants capable of hydrolyzing a α-configured steroid sulfate: etiocholanolone sulfate (ECS). After targeting two regions of PaS, four residues were identified and optimized to yield a final variant with a total of seven mutations (DRN-PaS) capable of hydrolyzing ECS ~80 times faster than the best PaS variant previously available. This DRN-PaS also shows improved activity for other α-configured steroid sulfates. Simultaneous mutagenesis was essential to obtain DRN-PaS due to complementarity between targeted residues. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by an arylsulfatase A (ARSA) deficiency and characterized by severe neurological symptoms resulting from demyelination within the central and peripheral nervous systems. We investigated the feasibility and efficacy of intrathecal administration of a type 9 adeno-associated viral vector encoding ARSA (AAV9/ARSA) for the treatment of 6-week-old MLD model mice, which are presymptomatic, and 1-year-old mice, which exhibit neurological abnormalities. Immunohistochemical analysis following AAV9/ARSA administration showed ARSA expression within the brain, with highest activities in the cerebellum and olfactory bulbs. In mice treated at 1 year, alcian blue staining and quantitative analysis revealed significant decreases in stored sulfatide. Behaviorally, mice treated at 1 year showed no improvement in their ability to traverse narrow balance beams as compared to untreated mice. By contrast, MLD mice treated at 6 weeks showed significant decreases in stored sulfatide throughout the entire brain and improved ability to traverse narrow balance beams. These findings suggest intrathecal administration of an AAV9/ARSA vector is a promising approach to treating genetic diseases of the central nervous system, including MLD, though it may be essential to begin therapy before the onset of neurological symptoms. [ABSTRACT FROM AUTHOR]

Most antibiotics, insecticides, and other chemicals used in agricultural and fishery production tend to persist in the environment. Fenvalerate, sulfide gatifloxacin, and ridomil are widely used in aquaculture as antibacterial, antifungal, and antiparasitic drugs; however, their toxicity mechanism remains unclear. Thus, we herein analyzed the effects of these three drugs on the hepatopancreas of Procambarus clarkii at the transcriptome level. Twelve normalized cDNA libraries were constructed using RNA extracted from P. clarkii after treatment with fenvalerate, sulfide gatifloxacin, or ridomil and from an untreated control group, followed by Kyoto Encyclopedia of Genes and Genomes pathway analysis. In the control vs fenvalerate and control vs sulfide gatifloxacin groups, 14 and seven pathways were significantly enriched, respectively. Further, the effects of fenvalerate and sulfide gatifloxacin were similar on the hepatopancreas of P. clarkii. We also found that the expression level of genes encoding senescence marker protein-30 and arylsulfatase A was downregulated in the sulfide gatifloxacin group, indicating that sulfide gatifloxacin accelerated the apoptosis of hepatopancreatocytes. The expression level of major facilitator superfamily domain containing 10 was downregulated, implying that it interferes with the ability of the hepatopancreas to metabolize drugs. Interestingly, we found that Niemann pick type C1 and glucosylceramidase-β potentially interact with each other, consequently decreasing the antioxidant capacity of P. clarkii hepatopancreas. In the fenvalerate group, the downregulation of the expression level of xanthine dehydrogenase indicated that fenvalerate affected the immune system of P. clarkii ; moreover, the upregulation of the expression level of pancreatitis-associated protein-2 and cathepsin C indicated that fenvalerate caused possible inflammatory pathological injury to P. clarkii hepatopancreas. In the ridomil group, no pathway was significantly enriched. In total, 21 genes showed significant differences in all three groups. To conclude, although there appears to be some overlap in the toxicity mechanisms of fenvalerate, sulfide gatifloxacin, and ridomil, further studies are warranted. • We herein explored the toxicity mechanism of three drugs on P. clarkii hepatopancreas. • Sulfide gatifloxacin and fenvalerate showed similar mechanism of action. • Hepatopancreas toxicity of fenvalerate was higher than that of the other two drugs. • Fenvalerate treatment downregulated most cell senescence- and apoptosis-related genes. • In the sulfide gatifloxacin group, SMP-30 and NPC1 showed a synergistic effect. [ABSTRACT FROM AUTHOR]

The lysosomal degradation of heparan sulfate is mediated by the concerted action of nine different enzymes. Within this degradation pathway, Arylsulfatase G (ARSG) is critical for removing 3-O-sulfate from glucosamine, and mutations in ARSG are causative for Usher syndrome type IV. We developed a specific ARSG enzyme assay using sulfated monosaccharide substrates, which reflect derivatives of its natural substrates. These sulfated compounds were incubated with ARSG, and resulting products were analyzed by reversed-phase HPLC after chemical addition of the fluorescent dyes 2-aminoacridone or 2-aminobenzoic acid, respectively. We applied the assay to further characterize ARSG regarding its hydrolytic specificity against 3-O-sulfated monosaccharides containing additional sulfate-groups and N-acetylation. The application of recombinant ARSG and cells overexpressing ARSG as well as isolated lysosomes from wild-type and Arsg knockout mice validated the utility of our assay. We further exploited the assay to determine the sequential action of the different sulfatases involved in the lysosomal catabolism of 3-Osulfated glucosamine residues of heparan sulfate. Our results confirm and extend the characterization of the substrate specificity of ARSG and help to determine the sequential order of the lysosomal catabolic breakdown of (3-O-)sulfated heparan sulfate. [ABSTRACT FROM AUTHOR]

The presence of sulfate groups in agar compromises the agar quality by affecting the crosslinking during gelling process. Some arylsulfatases can catalyze the hydrolysis of sulfate bonds in agar to improve the agar quality. Immobilized arylsulfatases prove beneficial advantages for their industrial applications. Here, a previously characterized mutant arylsulfatase K253H/H260L was immobilized on the synthesized magnetic Fe3O4 nanoparticles after functionalization by tannic acid (MNPs@TA). The surface properties and molecular structures of the immobilized arylsulfatase (MNPs@TA@ARS) were examined by scanning electron microscopy and Fourier transform infrared spectroscopy. Enzymatic characterization showed that MNPs@TA@ARS exhibited shifted optimal temperature and pH with deviated apparent Km and Vmax compared to its free counterpart. The immobilized arylsulfatase demonstrated improved thermal and pH stability and enhanced storage stability with modest reusability. In addition, MNPs@TA@ARS displayed enhanced tolerance to various inhibitors and detergents. The utilization of the immobilized arylsulfatase for agar desulfation brought the treated agar with improved quality. [ABSTRACT FROM AUTHOR]

Newborn screening (NBS) for metachromatic leukodystrophy (MLD) is based on first-tier measurement of sulfatides in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A in the same DBS. This approach is very precise with 0–1 false positives per ∼30,000 newborns tested. Recent data reported here shows that the sulfatide molecular species with an α-hydroxyl, 16‑carbon, mono-unsaturated fatty acyl group (16:1-OH-sulfatide) is superior to the original biomarker 16:0-sulfatide in reducing the number of first-tier false positives. This result is consistent across 4 MLD NBS centers. By measuring 16:1-OH-sulfatide alone or together with 16:0-sulfatide, the estimated false positive rate is 0.048% and is reduced essentially to zero with second-tier arylsulfatase A activity assay. The false negative rate is predicted to be extremely low based on the demonstration that 40 out of 40 newborn DBS from clinically-confirmed MLD patients are detected with these methods. The work shows that NBS for MLD is extremely precise and ready for deployment. Furthermore, it can be multiplexed with several other inborn errors of metabolism already tested in NBS centers worldwide. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD. [ABSTRACT FROM AUTHOR]

A novel enzyme cleavable linker for antibody–drug conjugates is reported. The 3-O-sulfo-β-galactose linker is cleaved sequentially by two lysosomal enzymes – arylsulfatase A and β-galactosidase – to release the payload in targeted cells. An α-HER2 antibody–drug conjugate synthesised using this highly hydrophilic dual-cleavable linker exhibited excellent cytotoxicity and selectivity. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) has emerged as a sensitive matrix for the screening of biomarkers for diagnosis and clinical follow-up of diseases with neurological manifestations, including some lysosomal storage disorders. In this study, we assessed the range of values of arylsulfatase A (ARSA) activity in the CSF of pediatric and adult donors, and in pediatric patients who underwent gene therapy for metachromatic leukodystrophy (MLD). Methods: A cohort of 56 CSF samples was included in the study: pediatric donors (n = 36), adult donors (n = 9), and MLD patients (n = 11) at different timepoints [pre-gene therapy (GT), post-GT + 1 Year, post-GT + 2 Years, post-GT + 3 Years]. We have used our fluorometric assay for the determination of ARSA activity. The total protein content in the samples was also evaluated. Results: We discovered that ARSA activity was higher in pediatric donors (geometric mean: 1.039 nmol/mg/h; 95% range: 0.859–1.258 nmol/mg/h) compared to adults (geometric mean: 0.305 nmol/mg/h; 95% range: 0.214–0.435 nmol/mg/h). No ARSA activity was detected in the CSF of MLD patients pre-GT, whereas ARSA activity was stably expressed and almost restored to range of values of pediatric donors in MLD patients post-GT + 3 Years with a geometric mean of 0.822 nmol/mg/h (95% range: 0.580–1.165 nmol/mg/h). Conclusions: This study establishes range of values of ARSA activity in the CSF for MLD clinical practice. The observed ranges of ARSA activities in CSF exhibited an unpredicted age dependence and, in turn, revealed the need of using pediatric ARSA activity for evaluating the restoration of the enzyme activity during the therapy of MLD. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is an autosomal recessive hereditary disorder characterized by the accumulation of sulfatide in the central and peripheral nervous systems. Herein, we present the case of an adult patient with MLD who had mild cognitive and psychiatric dysfunctions and severe vision disturbance, who was initially misdiagnosed as multiple sclerosis. Through genetic screening, this patient was later identified to have a full deletion of exon 4 and the novel p.P220L mutation in the arylsulfatase A (ARSA) gene. These mutations are reported for the first time in MLD. These data will help to update the mutation profiles of patients with MLD. [ABSTRACT FROM AUTHOR]

Objective: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA), resulting in severe motor and cognitive dysfunction. This phase 1/2 study evaluated the safety and efficacy of intravenous (IV) recombinant human ASA (rhASA; HGT‐1111, previously known as Metazym) in children with MLD. Methods: Thirteen children with MLD (symptom onset < 4 years of age) were enrolled in an open‐label, nonrandomized, dose‐escalation trial and received IV rhASA at 50, 100, or 200 U/kg body weight every 14 (± 4) days for 52 weeks (NCT00418561; NCT00633139). Eleven children continued to receive rhASA at 100 or 200 U/kg during a 24‐month extension period (NCT00681811). Outcome measures included safety observations, changes in motor and cognitive function, and changes in nerve conduction and morphometry. Results: There were no serious adverse events considered related to IV rhASA. Motor function and developmental testing scores declined during the study in all dose groups; no significant differences were observed between groups. Nerve conduction studies and morphometric analysis indicated that peripheral nerve pathology did not worsen during the study in any dose group. Interpretation: IV rhASA was generally well tolerated. There was no evidence of efficacy in preventing motor and cognitive deterioration, suggesting that IV rhASA may not cross the blood–brain barrier in therapeutic quantities. The relative stability of peripheral nerve function during the study indicates that rhASA may be beneficial if delivered to the appropriate target site and supports the development of rhASA for intrathecal administration in MLD. [ABSTRACT FROM AUTHOR]

Natural estrogen conjugates play important roles in municipal wastewater treatment plant (WWTP), but their deconjugation potentials are poorly understood. This work is the first to investigate the relationships between the enzyme activities of arylsulfatase/β-glucuronidase and deconjugation potentials of natural estrogen conjugates. This work led to three important findings. First, the enzyme activity of β-glucuronidase in sewage is far higher than that of arylsulfatase, while their corresponding activities in activated sludge were similar. Second, a model based on β-glucuronidase could successfully predict the deconjugation potentials of natural estrogen glucuronide conjugates in sewage. Third, the enzyme activity of arylsulfatase in sewage was too low to lead to evident deconjugation of sulfate conjugates, which means that the deconjugation rate of estrogen sulfates can be regarded as zero. By comparing their theoretical removal based on enzyme activity and on-site investigation, it is reasonable to conclude that reverse deconjugation of estrogen conjugates (i.e., conjugation of natural estrogens to form conjugated estrogens) likely exist in WWTP, which explains well why natural estrogen conjugates cannot be effectively removed in WWTP. Meanwhile, this work provides new insights how to improve the removal performance of WWTP on natural estrogen conjugates. SYNOPSIS: This work is the first to show how arylsulfatase/β-glucuronidase could affect deconjugation of natural estrogen conjugates and possible way to enhance their removal in wastewater treatment plant., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metachromatic leukodystrophy (MLD) is a rare genetic disease characterised by a dysfunction of the enzyme arylsulphatase A leading to the lysosomal accumulation of cerebroside sulphate (sulphatide) causing subsequent demyelination in patients. The enzyme galactosylceramide (cerebroside) sulphotransferase (CST) catalyses the transfer of a sulphate group from 3′-phosphoadenosine-5'-phosphosulphate (PAPS) to cerebrosides producing sulphatides. Substrate reduction therapy for arylsulphatase A by inhibition of CST was proposed as a promising therapeutic approach. To identify competitive CST inhibitors, we synthesised and investigated analogues of the substrate galactosylceramide with variations at the anomeric position, the acyl substituent and the carbohydrate moiety, and investigated their structure–activity relationships. While most of the compounds behaved as substrates, α-galactosylceramide 16 was identified as the first competitive CST inhibitor. Compound 16 can serve as a new lead structure for the development of drugs for the treatment of this devastating disease, MLD, for which small molecule therapeutics are currently not available. [ABSTRACT FROM AUTHOR]

Recent recurrent outbreaks of Gram-negative bacteria show the critical need to target essential bacterial mechanisms to fight the increase of antibiotic resistance. Pathogenic Gram-negative bacteria have developed several strategies to protect themselves against the host immune response and antibiotics. One such strategy is to remodel the outer membrane where several genes are involved. yejM was discovered as an essential gene in E. coli and S. typhimurium that plays a critical role in their virulence by changing the outer membrane permeability. How the inner membrane protein YejM with its periplasmic domain changes membrane properties remains unknown. Despite overwhelming structural similarity between the periplasmic domains of two YejM homologues with hydrolases like arylsulfatases, no enzymatic activity has been previously reported for YejM. Our studies reveal an intact active site with bound metal ions in the structure of YejM periplasmic domain. Furthermore, we show that YejM has a phosphatase activity that is dependent on the presence of magnesium ions and is linked to its function of regulating outer membrane properties. Understanding the molecular mechanism by which YejM is involved in outer membrane remodeling will help to identify a new drug target in the fight against the increased antibiotic resistance. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficient arylsulfatase A (ASA) activity and characterized by neurological involvement that results in severe disability and premature death. We examined the safety and tolerability of intrathecally delivered recombinant human ASA (rhASA; SHP611, now TAK-611) in children with MLD (NCT01510028). Secondary endpoints included change in cerebrospinal fluid (CSF) sulfatide and lysosulfatide levels, and motor function (assessed by Gross Motor Function Measure-88 total score). Twenty-four children with MLD who experienced symptom onset aged ≤ 30 months were enrolled. Patients received rhASA every other week (EOW) for 38 weeks at 10, 30, or 100 mg (cohorts 1–3; n = 6 per cohort), or 100 mg manufactured using a revised process (cohort 4; n = 6). No rhASA-related serious adverse events (SAEs) were observed; 25% of patients experienced an SAE related to the intrathecal device or drug delivery method. Mean CSF sulfatide and lysosulfatide levels fell to within normal ranges in both 100 mg cohorts following treatment. Although there was a general decline in motor function over time, there was a tendency towards a less pronounced decline in patients receiving 100 mg. Intrathecal rhASA was generally well tolerated at doses up to 100 mg EOW. These preliminary data support further development of rhASA as a therapy for patients with MLD. [ABSTRACT FROM AUTHOR]