bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2024‒04‒21
sixteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

  1. Proteoglycan Res. 2024 Jan 01. pii: e17. [Epub ahead of print]2(1):
      Heparan sulfate proteoglycans (HSPGs) serve as co-receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HS N-deacetylase/N-sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock-in (KI) Drosophila strains with the insertion of mouse Ndst1 (mNdst1) or Ndst2 (mNdst2) in the locus of sulfateless (sfl), the only Drosophila NDST. In these KI lines, mNDSTs are expressed from the sfl locus, in the level and patterns identical to the endogenous sfl gene. Thus, phenotypes of Ndst1 KI and Ndst2KI animals reflect the ability of HS structures made by these enzymes to rescue sfl mutation. Remarkably, we found that mNdst1 completely rescued the loss of sfl. mNdst2 showed a limited rescue ability, despite a higher level of HS sulfation compared to HS in mNdst1 KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.
    Keywords:  Drosophila; N-deacetylase/N-sulfotransferase (NDST); development; heparan sulfate; morphogenesis
  2. Curr Opin Chem Biol. 2024 Apr 17. pii: S1367-5931(24)00031-0. [Epub ahead of print]80 102455
      Heparan sulfate (HS) is a linear, sulfated and highly negatively-charged polysaccharide that plays important roles in many biological events. As a member of the glycosaminoglycan (GAG) family, HS is commonly found on mammalian cell surfaces and within the extracellular matrix. The structural complexities of natural HS polysaccharides have hampered the comprehension of their biological functions and structure-activity relationships (SARs). Although the sulfation patterns and backbone structures of HS can be major determinants of their biological activities, obtaining significant amounts of pure HS from natural sources for comprehensive SAR studies is challenging. Chemical and enzyme-based synthesis can aid in the production of structurally well-defined HS oligosaccharides. In this review, we discuss recent innovations enabling the syntheses of large libraries of HS and how these libraries can provide insights into the structural preferences of various HS binding proteins.
    Keywords:  Automation; Heparan sulfate; Library synthesis; Solid phase; Structure activity relationship
  3. Blood. 2024 Mar 22. pii: blood.2023022736. [Epub ahead of print]
      From signaling mediators in stem cells, to markers of differentiation and lineage commitment, to facilitators for the entry of viruses like HIV-1, cell surface heparan sulfate (HS) glycans with their distinct modification patterns play important roles in hematopoietic biology. In this review, we provide an overview of the importance of HS and the proteoglycans (HSPGs) to which they are attached, within the major cellular subtypes of the hematopoietic system. We summarize the roles of HSPGs, HS, and HS modifications within each main hematopoietic cell lineage of both myeloid and lymphoid arms. Lastly, we discuss the biological advances of the detection of HS modifications, and their potential to further discriminate cell types within hematopoietic tissue.
  4. J Pharm Sci. 2024 Apr 17. pii: S0022-3549(24)00142-4. [Epub ahead of print]
      Sodium-phosphate transporter NPT4 (SLC17A3) is a membrane transporter for organic anionic compounds localized on the apical membranes of kidney proximal tubular epithelial cells and plays a role in the urinary excretion of organic anionic compounds. However, its physiological role has not been sufficiently elucidated because its substrate specificity is yet to be determined. The present study aimed to comprehensively explore the physiological substrates of NPT4 in newly developed Slc17a3-/- mice using a metabolomic approach. Metabolomic analysis showed that the plasma concentrations of 11 biological substances, including 3-indoxyl sulfate, were more than two-fold higher in Slc17a3-/- mice than in wild-type mice. Moreover, urinary excretion of 3-indoxyl sulfate was reduced in Slc17a3-/- mice compared to that in wild-type mice. The uptake of 3-indoxyl sulfate by NPT4-expressing Xenopus oocytes was significantly higher than that by water-injected oocytes. The calculated Km and Vmax values for NPT4-mediated 3-indoxyl sulfate uptake were 4.52 ± 1.18 mM and 1.45 ± 0.14 nmol/oocyte/90 min, respectively. In conclusion, the present study revealed that 3-indoxyl sulfate is a novel substrate of NPT4 based on the metabolomic analysis of Slc17a3-/- mice, suggesting that NPT4 regulates systemic exposure to 3-indoxyl sulfate by regulating its urinary excretion.
    Keywords:  NPT4; Organic anion transporter; kidney proximal tubules; metabolome analysis; secretion; uremic toxin
  5. Essays Biochem. 2024 Apr 19. pii: EBC20230097. [Epub ahead of print]
      Sulfate is an important anion as sulfonation is essential in modulation of several compounds, such as exogens, polysaccharide chains of proteoglycans, cholesterol or cholesterol derivatives and tyrosine residues of several proteins. Sulfonation requires the presence of both the sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) and a sulfotransferase. Genetic disorders affecting sulfonation, associated with skeletal abnormalities, impaired neurological development and endocrinopathies, demonstrate the importance of sulfate. Yet sulfate is not measured in clinical practice. This review addresses sulfate metabolism and consequences of sulfonation defects, how to measure sulfate and why we should measure sulfate more often.
    Keywords:  Endocrinopathy; Skeletal dysplasias; neurological development; sulfate
  6. Biochem Biophys Res Commun. 2024 Apr 06. pii: S0006-291X(24)00427-3. [Epub ahead of print]711 149891
      Microorganisms synthesize a plethora of complex secondary metabolites, many of which are beneficial to human health, such as anticancer agents and antibiotics. Among these, the Sungeidines are a distinct class of secondary metabolites known for their bulky and intricate structures. They are produced by a specific biosynthetic gene cluster within the genome of the soil-dwelling actinomycete Micromonospora sp. MD118. A notable enzyme in the Sungeidine biosynthetic pathway is the activating sulfotransferase SgdX2. In this pathway, SgdX2 mediates a key sulfation step, after which the product undergoes spontaneous dehydration to yield a Sungeidine compound. To delineate the structural basis for SgdX2's substrate recognition and catalytic action, we have determined the crystal structure of SgdX2 in complex with its sulfate donor product, 3'-phosphoadenosine 5'-phosphate (PAP), at a resolution of 1.6 Å. Although SgdX2 presents a compact overall structure, its core elements are conserved among other activating sulfotransferases. Our structural analysis reveals a unique substrate-binding pocket that accommodates bulky, complex substrates, suggesting a specialized adaptation for Sungeidine synthesis. Moreover, we have constructed a substrate docking model that provides insights into the molecular interactions between SgdX2 and Sungeidine F, enhancing our understanding of the enzyme's specificity and catalytic mechanism. The model supports a general acid-base catalysis mechanism, akin to other sulfotransferases, and underscores the minor role of disordered regions in substrate recognition. This integrative study of crystallography and computational modeling advances our knowledge of microbial secondary metabolite biosynthesis and may facilitate the development of novel biotechnological applications.
    Keywords:  Cytosolic sulfotransferase; Enzymology; Secondary metabolites; Sulfation; Sungeidine biosynthesis; X-ray crystallography
  7. Int Immunopharmacol. 2024 Apr 12. pii: S1567-5769(24)00575-7. [Epub ahead of print]133 112057
      BACKGROUND: Dehydroepiandrosterone sulfate (DHEA-S) has been associated with an immunomodulatory function. This study aims to explore the relationship between serum levels of DHEA-S and the immune responses triggered by the Oxford-AstraZeneca COVID-19 vaccine in individuals candidate for vaccination.METHODS: Serum levels of DHEA-S, cytokine release, antibody production and virus neutralization potential were assessed in 50 male and 50 female subjects before and 2 weeks after vaccination with Oxford-AstraZeneca COVID-19 vaccine.
    RESULTS: Level of DHEA-S before and 2 weeks after first and second dose of vaccination was not different significantly. Levels of Interleukin (IL)-2 and Interferon (IFN)-γ were significantly higher in the supernatant of peripheral blood mononuclear cells (PBMCs) obtained from subjects 2 weeks after both first and second dose of vaccination compared to before vaccination. Serum levels of IgM 2 weeks after first dose of vaccination was significantly higher compared to before first dose of vaccination. However, serum levels of IgG 2 weeks after first and second dose of vaccination were significantly higher compared to before first and second dose of vaccination. The 50 % focus reduction neutralization test (FRNT50) titer was significantly higher 2 weeks after both first and second dose of vaccination compared to before vaccination. Levels of DHEA-S did not have significant correlation with levels of IL-2, IFN-γ, IgM and IgG, and FRNT50 before and after first and second dose of vaccination. Vaccination did not result in intense unwanted clinical presentations.
    CONCLUSION: DHEA-S is not involved in the quality of protective immune response during Oxford-AstraZeneca COVID-19 vaccination.
    Keywords:  COVID-19; DHEA-S; Protective antibody; SARS-CoV-2
  8. BMC Cancer. 2024 Apr 15. 24(1): 476
      OBJECTIVE: Anxiety is a prevalent comorbidity in lung cancer (LC) patients associated with a decline in quality of life. Dehydroepiandrosterone (DHEA), a neuroactive steroid, levels rise in response to stress. Prior research on the association between DHEA and anxiety has yielded contradictory results and no study has investigated this association in LC patients.METHODS: A total of 213 patients with LC were recruited from a general hospital. Data on demographic and cancer-related variables were collected. Using the Chinese version of the Hospital Anxiety and Depression Scale (HADS), the degree of anxiety was determined. Cortisol, DHEA, and Dehydroepiandrosterone sulfate (DHEA-S) levels in saliva were measured. Adjusting for confounding variables, a multivariate regression analysis was conducted.
    RESULTS: 147 men and 66 women comprised our group with an average age of 63.75 years. After accounting for demographic and treatment-related factors, anxiety levels were significantly correlated with, post-traumatic stress symptoms (PTSSs) (β = 0.332, p < 0.001) and fatigue (β = 0.247, p = 0.02). Association between anxiety and three factors, including DHEA, PTSSs, and fatigue, was observed in patients with advanced cancer stages (III and IV) (DHEA β = 0.319, p = 0.004; PTSS β = 0.396, p = 0.001; fatigue β = 0.289, p = 0.027) and those undergoing chemotherapy (DHEA β = 0.346, p = 0.001; PTSS β = 0.407, p = 0.001; fatigue β = 0.326, p = 0.011).
    CONCLUSIONS: The association between anxiety and DHEA remained positive in advanced cancer stages and chemotherapy patients. Further study is necessary to determine whether DHEA is a potential biomarker of anxiety in LC patients.
    Keywords:  Anxiety; Chemotherapy; Dehydroepiandrosterone (DHEA); Lung cancer (LC)
  9. J Chem Neuroanat. 2024 Apr 13. pii: S0891-0618(24)00031-0. [Epub ahead of print] 102418
      Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. From minutes to months following damage, injury can result in a complex pathophysiology that can lead to temporary or permanent deficits including an array of neurodegenerative symptoms. These changes can include behavioral dysregulation, memory dysfunctions, and mood changes including depression. The nature and severity of impairments resulting from TBIs vary widely given the range of injury type, location, and extent of brain tissue involved. In response to the injury, the brain induces structural and functional changes to promote repair and minimize injury size. Despite its high prevalence, effective treatment strategies for TBI are limited. PNNs are part of the neuronal extracellular matrix (ECM) that mediate synaptic stabilization in the adult brain and thus neuroplasticity. They are associated mostly with inhibitory GABAergic interneurons and are thought to be responsible for maintaining the excitatory/inhibitory balance of the brain. The major structural components of PNNs include multiple chondroitin sulfate proteoglycans (CSPGs) as well as other structural proteins. Here we examine the effects of injury on CSPG expression, specifically around the changes in the side change moieties. To investigate CSPG expression following injury, adult male and female zebra finches received either a bilateral penetrating, or no injury and qPCR analysis and immunohistochemistry for components of the CSPGs were examined at 1- or 7-days post-injury. Next, to determine if CSPGs and thus PNNs should be a target for therapeutic intervention, CSPG side chains were degraded at the time of injury with chondroitinase ABC (ChABC) CSPGs moieties were examined. Additionally, GABA receptor mRNA and aromatase mRNA expression was quantified following CSPG degradation as they have been implicated in neuronal survival and neurogenesis. Our data indicate the CSPG moieties change following injury, potentially allowing for a brief period of synaptic reorganization, and that treatments that target CSPG side chains are successful in further targeting this brief critical period by decreasing GABA mRNA receptor expression, but also decreasing aromatase expression.
    Keywords:  avian; chondroitin sulfate; injury; neuroprotection; perineuronal nets
  10. ACS Biomater Sci Eng. 2024 Apr 17.
      Osteoarthritis is characterized by enzymatic breakdown of the articular cartilage via the disruption of chondrocyte homeostasis, ultimately resulting in the destruction of the articular surface. Decades of research have highlighted the importance of inflammation in osteoarthritis progression, with inflammatory cytokines shifting resident chondrocytes into a pro-catabolic state. Inflammation can result in poor outcomes for cells implanted for cartilage regeneration. Therefore, a method to promote the growth of new cartilage and protect the implanted cells from the pro-inflammatory cytokines found in the joint space is required. In this study, we fabricate two gel types: polymer network hydrogels composed of chondroitin sulfate and hyaluronic acid, glycosaminoglycans (GAGs) known for their anti-inflammatory and prochondrogenic activity, and interpenetrating networks of GAGs and collagen I. Compared to a collagen-only hydrogel, which does not provide an anti-inflammatory stimulus, chondrocytes in GAG hydrogels result in reduced production of pro-inflammatory cytokines and enzymes as well as preservation of collagen II and aggrecan expression. Overall, GAG-based hydrogels have the potential to promote cartilage regeneration under pro-inflammatory conditions. Further, the data have implications for the use of GAGs to generally support tissue engineering in pro-inflammatory environments.
    Keywords:  cartilage; collagen; glycosaminoglycan; osteoarthritis; tissue engineering
  11. Reprod Biol Endocrinol. 2024 Apr 16. 22(1): 43
      BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with infertility and pregnancy complications. The pathogenesis of PCOS and its impact on reproductive function may be influenced by the source of androgens, including testosterone, free androgen, dehydroepiandrosterone sulfate (DHEAS). However, the differential effects of these androgen on pregnancy and neonatal outcomes and the cut-off value of East Asian population with PCOS remain unclear.METHODS: A retrospective cohort study was conducted at the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University from January 2015 to November 2022, involving 636 cycles of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Subgroup analyses were performed using cut-off values of 6.4 for free androgen index (FAI), 9.5 µmol/L for DHEAS. Pregnancy and neonatal outcomes were compared between groups. Restricted cubic spline (RCS) was used to identify significant cut-off values affecting pregnancy.
    RESULTS: Higher FAI levels (> 6.4) were associated with decrease in clinical pregnancy rate (PR) (50.61% vs. 41.66%, p = 0.024), live birth rate (LBR) (42.42% vs. 32.35%, p = 0.011). When DHEAS levels exceeded 9.5 µmol/L, there was a significant decrease in clinical PR (51.27% vs. 42.73%, P = 0.039), LBR (42.73% vs. 32.73%, P = 0.012). Negative correlations were also observed between DHEAS levels and cumulative pregnancy rate (70.57% vs 56.62% p = 0.002) and cumulative live birth rate (CLBR) (59.35% vs 43.37%, p = 0.0007). Both FAI and DHEAS elevated is associated with the lowest clinical pregnancy rate (37.84%). Conversely, when solely FAI is elevated, the pregnancy rate increases to 52.38%, while an elevation in DHEAS alone is associated with a pregnancy rate of, both of which are lower than when neither FAI nor DHEAS are elevated (60.68%). The live birth rates exhibit a similar trend (30.00% vs 40.00% vs 41.83% vs 44.48%). RCS revealed a significant decrease in CPR and CLBR when DHEA levels exceeded 7.69 umol/L, while the cut-off value of FAI was 6.36 for CPR and CLBR.
    CONCLUSION: In conclusion, PCOS patients with biochemical hyperandrogenism show unsatisfactory clinical PR and CLBR when undergoing assisted reproductive technology (ART). This may be attributed to the influence of both adrenal-derived DHEAS and ovarian-derived FAI on the unfavorable pregnancy outcomes.
    Keywords:  Androgens; Cumulative live birth rates (CLBR); Cumulative pregnancy rates (CPR); Dehydroepiandrosterone sulfate (DHEAS); Free androgen index (FAI); Polycystic ovary syndrome (PCOS)
  12. Ann Hum Biol. 2024 Feb;51(1): 2337731
      BACKGROUND: The causal association between particulate matter 2.5 (PM2.5) and Alzheimer's disease (AD) remains inconclusive, and the mediators of the association have yet to be explored.AIMS: We aimed to assess the potential causal relationship between PM2.5 and AD, and to investigate the mediating role of dehydroepiandrosterone sulphate (DHEAS).
    SUBJECTS AND METHODS: We implemented a two-sample Mendelian randomisation (MR) study to examine the genetic predisposition to PM2.5 exposure and its association with AD. The inverse-variance weighted (IVW) method served as the primary analytical tool to estimate the odds ratio (OR) and 95% confidence interval (95% CI).
    RESULTS: There were 6 and 4 genetic variants associated with DHEAS and PM2.5, respectively. Based on the multivariable MR analysis, we found that after adjusting for DHEAS, each standard deviation increase in PM2.5 was associated with the risk of AD (OR: 2.96, 95% CI: 1.33, 6.58, p = 0.00769). The MR Egger intercept test did not detect horizontal pleiotropy for PM2.5 (P-pleiotropy = 0.879) and DHEAS(P-pleiotropy = 0.941). According to the results of the mediation analysis, DHEAS accounted for 18.3% of the association between PM2.5 and AD.
    CONCLUSION: Our findings affirm a significant causal association between PM2.5 exposure and AD, with DHEAS playing a mediating role in this relationship.
    Keywords:  Alzheimer’s disease; Mendelian randomisation; ambient particulate matter 2.5; dehydroepiandrosterone sulphate; mediation analysis
  13. Front Med (Lausanne). 2024 ;11 1364657
      The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an urgent need for effective therapeutic options. SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic that has resulted in significant morbidity and mortality worldwide. The virus is known to enter host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, and emerging evidence suggests that heparan sulfate proteoglycans (HSPGs) play a crucial role in facilitating this process. HSPGs are abundant cell surface proteoglycan present in many tissues, including the lung, and have been shown to interact directly with the spike protein of SARS-CoV-2. This review aims to summarize the current understanding of the role of HSPGs in SARS-CoV-2 infection and the potential of developing new therapies targeting HSPGs.
    Keywords:  COVID-19; HSPG; drug development; viral entry; viral entry and infection
  14. Chemistry. 2024 Apr 17. e202400783
      Glycosaminoglycans (GAGs) are linear and acidic polysaccharides. They are ubiquitous molecules, which are involved in a wide range of biological processes. Despite being structurally simple at first glance, with a repeating backbone of alternating hexuronic acid and hexosamine dimers, GAGs display a highly complex structure, which predominantly results from their heterogeneous sulfation patterns. The commonly applied method for compositional analysis of all GAGs is "disaccharide analysis." In this process, GAGs are enzymatically depolymerized into disaccharides, derivatized with a fluorescent label, and then analysed through liquid chromatography. The limiting factor in the high throughput analysis of GAG disaccharides is the time-consuming liquid chromatography. To address this limitation, we here utilized trapped ion mobility-mass spectrometry (TIM-MS) for the separation of isomeric GAG disaccharides, which reduces the measurement time from hours to a few minutes. A full set of disaccharides comprises twelve structures, with eight possessing isomers. Most disaccharides cannot be differentiated by TIM-MS in underivatized form. Therefore, we developed chemical modifications to reduce sample complexity and enhance differentiability. Quantification is performed using stable isotope labelled standards, which are easily available due to the nature of the performed modifications.
    Keywords:  disaccharide analysis; glycosaminoglycans; heparin; quantification; trapped ion mobility spectrometry
  15. Bioorg Med Chem Lett. 2024 Apr 17. pii: S0960-894X(24)00162-8. [Epub ahead of print] 129760
      The naturally occurring bile acid lithocholic acid (LCA) has been a crucial core structure for many non-sugar-containing sialyltranferase (ST) inhibitors documented in literature. With the aim of elucidating the impact of the terminal carboxyl acid substituent of LCA on its ST inhibition, in this present study, we report the (bio)isosteric replacement-based design and synthesis of sulfonate and sulfate analogues of LCA. Among these compounds, the sulfate analogue SPP-002 was found to selectively inhibit N-glycan sialylation by at least an order of magnitude, indicating a substantial improvement in both potency and selectivity when compared to the unmodified parent bile acid. Molecular docking analysis supported the stronger binding of the synthetic analogue in the enzyme active site. Treatment with SPP-002 also hampered the migration, adhesion, and invasion of MDA-MB-231 cells in vitro by suppressing the expression of signaling proteins involved in the cancer metastasis-associated integrin/FAK/paxillin pathway. In totality, these findings offer not only a novel structural scaffold but also valuable insights for the future development of more potent and selective ST inhibitors with potential therapeutic effects against tumor cancer metastasis.
    Keywords:  Cancer metastasis; Integrin-FAK-paxillin signaling pathway; Lithocholic acid; Sialyltransferase inhibitor
  16. Int J Biol Macromol. 2024 Apr 12. pii: S0141-8130(24)02382-1. [Epub ahead of print]267(Pt 2): 131577
      Chondroitin sulphates (CSs) are the most well-known glycosaminoglycans (GAGs) found in any living organism, from microorganisms to invertebrates and vertebrates (including humans), and provide several health benefits. The applications of CSs are numerous including tissue engineering, osteoarthritis treatment, antiviral, cosmetics, and skincare applications. The current commercial production of CSs mostly uses animal, bovine, porcine, and avian tissues as well as marine organisms, marine mammals, sharks, and other fish. The production process consists of tissue hydrolysis, protein removal, and purification using various methods. Mostly, these are chemical-dependent and are complex, multi-step processes. There is a developing trend for abandonment of harsh extraction chemicals and their substitution with different green-extraction technologies, however, these are still in their infancy. The quality of CSs is the first and foremost requirement for end-applications and is dependent on the extraction and purification methodologies used. The final products will show different bio-functional properties, depending on their origin and production methodology. This is a comprehensive review of the characteristics, properties, uses, sources, and extraction methods of CSs. This review emphasises the need for extraction and purification processes to be environmentally friendly and gentle, followed by product analysis and quality control to ensure the expected bioactivity of CSs.
    Keywords:  Chemical extraction; Chondroitin sulphate (CS); Glycosaminoglycans (GAGs); Green extraction and purification; Osteoarthritis; Polysaccharides; Tissue engineering; Ultrafiltration and diafiltration; Wound healing