bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2026–08–16
ten papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Recent advances in the chemical synthesis of Glycosaminoglycans.
  2. The relationship between the mechanisms of animal polysaccharides and their structural and conformational features.
  3. Chemoenzymatic assembly of structurally defined heparan sulfate oligosaccharides reveals heparanase substrate plasticity and enables inhibitor design.
  4. Chemical Synthesis and Biological Evaluation of Sulfated DK4 Derivatives from Escherichia coli K4 Polysaccharide.
  5. Keratan sulfate proteoglycans in pancreatic cancer: From stromal architects to potential therapeutic targets.
  6. Pleiotrophin regulates presynaptic assembly and function through heparan sulfate-dependent binding to neurexin1.
  7. Development and validation of a sex- and age-adjusted dehydroepiandrosterone sulfate index for suspected adrenal insufficiency.
  8. Chondroitin Sulfate-Based Self-Assembling Nanoprodrug for Controlled Methotrexate Delivery in Cancer Therapy.
  9. 4-Ethyl phenyl sulfate binding to human serum albumin.
  10. Golgi enzymes are retrieved from the plasma membrane to the trans-Golgi network.
  1. Curr Opin Chem Biol. 2026 Aug 14. pii: S1367-5931(26)00090-6. [Epub ahead of print]94 102741
    Recent advances in the chemical synthesis of Glycosaminoglycans.
    Jasper S Dumalaog, Shang-Cheng Hung.
      Glycosaminoglycans (GAGs) are complex carbohydrates ubiquitously expressed on cell surfaces and within the extracellular matrix, where they regulate essential biological processes through sequence- and sulfation-dependent interactions. Major GAG classes, including heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), and hyaluronic acid (HA), exhibit diverse sulfation patterns that encode specific molecular recognition events. Deciphering their structure-activity relationships has been hindered by intrinsic heterogeneity and limited access to well-defined materials. This review focuses on the recent advances in the chemical synthesis of GAGs, highlighting strategies that enable precise control over GAG structure and sulfation patterns. Recent innovations in protecting group design, stereoselective glycosylation, and automated assembly have significantly improved synthetic efficiency, facilitating the construction of increasingly complex and biologically relevant structures and advancing the rational design of GAG-based tools and therapeutics.
    DOI:  https://doi.org/10.1016/j.cbpa.2026.102741
  2. Carbohydr Res. 2026 Aug 06. pii: S0008-6215(26)00249-1. [Epub ahead of print]569 110060
    The relationship between the mechanisms of animal polysaccharides and their structural and conformational features.
    Oksana Zaitseva, Marta Sergushkina, Tatyana Polezhaeva, Olga Solomina, Andrey Khudyakov.
      This review characterizes the mechanisms of action of animal polysaccharides (chitin, chitosan, hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin/heparan sulfate) based on their structural and conformational features. A systematic search was conducted in PubMed, Scopus, Web of Science, and the Russian Citation Index (2015-2026). The review organizes polysaccharides according to three structure-dependent targeting paradigms: (1) charge-mediated targeting (chitosan, dermatan sulfate), where cationic or anionic density determines electrostatic interactions; (2) molecular weight-dependent receptor selection (hyaluronan, chitosan), where chain length dictates receptor engagement and signaling outcomes; and (3) sulfation pattern-directed protein recognition (heparin/heparan sulfate, chondroitin sulfate, keratan sulfate), where specific O- and N-sulfation codes enable selective protein binding. Key findings reveal that biological activity depends largely on molecular weight, sulfation pattern, and charge density, with concentration-dependent reversal of immunomodulatory effects - low doses elicit anti-inflammatory while high doses induce pro-inflammatory activation - representing a critical consideration for therapeutic design. Recent methodological advances (UPLC-MS/MS, chemical synthesis, chemoenzymatic synthesis) now enable detailed structure-activity studies, particularly for keratan sulfate, though knowledge gaps remain. The convergence of mechanisms across polysaccharide classes - particularly NF-κB pathway modulation - suggests common principles underlying bioactivity. The review also addresses major obstacles to clinical translation, including polydispersity, batch variability, and characterization challenges, and proposes future research directions to overcome these limitations.
    Keywords:  Animal polysaccharides; Functional activity; Mechanisms; Structural characteristics; Structure-activity relationships; Therapeutic effect
    DOI:  https://doi.org/10.1016/j.carres.2026.110060
  3. Bioorg Chem. 2026 Aug 10. pii: S0045-2068(26)00894-1. [Epub ahead of print]181 110358
    Chemoenzymatic assembly of structurally defined heparan sulfate oligosaccharides reveals heparanase substrate plasticity and enables inhibitor design.
    Xiao Wang, Qinyu Liu, Guijiao Zhang, Aohui Liu, Yanzhen Cheng, Qiuhan Xu, Jiukun Liu, Chunhui Liu.
      Heparanase (HPSE) is a promising therapeutic target, yet current heparin-derived inhibitors are limited by structural heterogeneity, poor selectivity, and off-target anticoagulant effects. Here, we synthesized a library of structurally defined heparan sulfate (HS) oligosaccharides via a robust chemoenzymatic strategy, enabling a systematic investigation of HPSE cleavage specificity. Our data confirm the minimal cleavable tetrasaccharide motif for HPSE and the preference for the endolytic site proximal to the nonreducing end in HS hexasaccharides. We demonstrate that a 2-O-sulfated iduronic acid (IdoA2S) residue confers susceptibility to HPSE cleavage on 6-O-nonsulfated HS oligosaccharides through compensatory interactions with the enzyme's heparin-binding domain (HBDs), and acts synergistically with 6-O-sulfated GlcNS residues to promote catalytic efficiency. HPSE exhibits an atypical exo-type cleavage at the nonreducing-terminal GlcA residue, dependent on sulfation patterns and chain length, challenging the traditional classification of HPSE as a strictly endo-acting β-glucuronidase. Leveraging insights into substrate plasticity, we rationally designed highly sulfated HS oligosaccharides, each featuring a disfavored terminal GlcA motif linked to an IdoA2S-enriched sequence. A 3-O-sulfated HS nonasaccharide 28 exhibited sub-micromolar HPSE inhibitory potency (IC50 = 0.761 μM) and is expected to minimize anticoagulant liabilities by lacking the canonical antithrombin-binding sequence. Collectively, this work elucidates the molecular determinants of HPSE substrate plasticity and provides a structure-based foundation for the rational design of next-generation anti-metastatic agents with improved selectivity and safety profiles.
    Keywords:  Chemoenzymatic synthesis; Exo-type cleavage; Heparan sulfate oligosaccharides; Heparanase; O-sulfation; Rational inhibitor design; Substrate plasticity
    DOI:  https://doi.org/10.1016/j.bioorg.2026.110358
  4. Molecules. 2026 Aug 05. pii: 2721. [Epub ahead of print]31(15):
    Chemical Synthesis and Biological Evaluation of Sulfated DK4 Derivatives from Escherichia coli K4 Polysaccharide.
    Yajia Wang, Yue Chen, Meiling Qiu, Shuqin Xu.
      Three sulfated derivatives were synthesized using microbially derived defructosylated K4 (DK4) polysaccharide as a chondroitin-like polysaccharide backbone. The obtained derivatives were structurally characterized by nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, elemental analysis, and disaccharide composition analysis. The results demonstrated that sulfate groups were successfully introduced into the DK4 structure, while the main chondroitin-like polysaccharide backbone of DK4 was largely preserved after sulfation. Further biological evaluation indicated that the sulfated DK4 derivatives differentially altered the expression levels of Ras homolog family member A/Rho-associated coiled-coil-containing protein kinase 1 (RhoA/ROCK1) and myelin basic protein (MBP). This work provides an experimental basis for further elucidating the structure-activity relationship between sulfation patterns and glial cell functions.
    Keywords:  NMR; bioactivity; defructosylated K4; sulfation
    DOI:  https://doi.org/10.3390/molecules31152721
  5. Biochim Biophys Acta Rev Cancer. 2026 Aug 11. pii: S0304-419X(26)00154-X. [Epub ahead of print] 189682
    Keratan sulfate proteoglycans in pancreatic cancer: From stromal architects to potential therapeutic targets.
    Wenjing Liang, Dongyi Lyu, Kunzheng Fan, Chao Liu, Qiang Ren, Huijie Gao, Yuntao Zhang.
      Pancreatic cancer features a dense desmoplastic stroma driving therapeutic resistance and immune evasion. Traditionally viewed as inert scaffolds, keratan sulfate proteoglycans (KSPGs) now emerge as active signaling modulators within this tumor microenvironment. This review elucidates the multifaceted roles of KSPGs and their specific sulfation patterns in pancreatic ductal adenocarcinoma (PDAC). We detail how KSPG core proteins orchestrate collagen fibrillogenesis and tissue biomechanics, while highly sulfated keratan sulfate (KS) chains act as biochemical traps sequestering oncogenic ligands and chemokines. This biochemical interplay synergistically reprograms signaling cascades to govern tumor plasticity and metastasis. Crucially, KSPGs mediate immune exclusion by impeding CD8+ T cell infiltration and sustaining chronic inflammation via damage-associated molecular patterns (DAMPs). Finally, we highlight the translational potential of targeting KS sulfation via carbohydrate sulfotransferases (CHSTs) as a promising strategy for stromal normalization to overcome current therapeutic bottlenecks in PDAC.
    Keywords:  Carbohydrate sulfotransferases; Desmoplastic stroma; Keratan sulfate proteoglycans; Pancreatic ductal adenocarcinoma; Stromal normalization
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189682
  6. Cell Rep. 2026 Aug 12. pii: S2211-1247(26)00905-8. [Epub ahead of print]45(8): 117827
    Pleiotrophin regulates presynaptic assembly and function through heparan sulfate-dependent binding to neurexin1.
    Qin Xu, Andrew W Schilling, Alexander W Sorum, Peipei Zhang, Destini C Weller, Donovan Whitfield, Gokul Velayoudame, Allison J Wu, Qian Sun, Linda C Hsieh-Wilson, Peng Zhang.
      Synapses are the fundamental units of neural circuits, and their dysfunction contributes to numerous neuropsychiatric disorders. Although synaptic adhesion proteins have been well studied, how extracellular cues and matrix glycans specify synaptic properties remains much less well understood. Here, we identify pleiotrophin (Ptn) as a regulator of presynaptic development. Affinity purification-based proteomics shows that Ptn associates with heparan sulfate (HS)-modified neurexin1 (HS-Nrxn1) in the brain through an HS-glycan-dependent mechanism. Glycan microarray analyses further reveal that Ptn selectively recognizes defined HS sulfation motifs. Functionally, Ptn requires both HS glycans and Nrxns to induce presynaptic assembly in cultured neurons. In vivo, Ptn deletion disrupts presynaptic protein clustering, reduces neurotransmitter release probability at CA3-CA1 synapses, and impairs contextual fear discrimination. Together, these findings establish Ptn as an extracellular organizer of presynaptic development and support a model in which Nrxn1's HS glycan provides a platform for extracellular ligand recruitment.
    Keywords:  CP: molecular biology; CP: neuroscience; extracellular glycan; extracellular matrix; presynaptic assembly; proteoglycan; synaptic organizer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117827
  7. Eur J Endocrinol. 2026 Aug 03. 195(2): 281-292
    Development and validation of a sex- and age-adjusted dehydroepiandrosterone sulfate index for suspected adrenal insufficiency.
    Arturo Vega-Beyhart, David Salas Bravo, Mireia Mora, Aida Orois, Manuel Morales, Clara Sola, Karen Castillo, Qiang Zhao, Marta Araujo-Castro, Gregori Casals, Felicia Alexandra Hanzu.
       IMPORTANCE: Adrenal insufficiency (AI) diagnosis is challenging, particularly with indeterminate morning cortisol levels (5-11 µg/dL). This study aimed to develop and validate a sex- and age-adjusted dehydroepiandrosterone sulfate (DHEAS)-index to improve AI diagnosis and reduce the need for ACTH stimulation tests.
    DESIGN: A 2-phase study was conducted. First, a retrospective training cohort of 3.307 DHEAS and morning cortisol measurements from 1.720 adult patients was analyzed to develop sex- and age-specific DHEAS cutoffs. Subsequently, these cutoffs were used to calculate a DHEAS-Index, which was then validated in a prospective external cohort of 71 patients undergoing ACTH stimulation testing for suspected AI.
    RESULTS: In the training cohort, DHEAS levels were significantly lower in patients with morning cortisol <5 µg/dL (0.10 [0.10-0.22] µg/mL) compared to those with cortisol >5 µg/dL (P = .000). Linear regression showed higher morning cortisol, male sex, and younger age were independently associated with higher DHEAS, while older age predicted lower levels (all P = .000). Optimal DHEAS cutoffs, determined by ROC analysis, demonstrated high discriminatory capacity (AUC ranging from 75.2% to 90.5%) for AI across all age and sex subgroups, with men aged 18-29 showing the highest AUC (90.5%). In the validation cohort, the DHEAS-Index achieved a sensitivity of 93% and specificity of 79% for classifying AI (cortisol 60' < 18 µg/dL), with a negative predictive value of 98%. The DHEAS-Index also correlated with the delta increase of cortisol during the ACTH test (rho=0.571, P < .001). Among patients with cortisol values 5-11 µg/dL, a DHEAS-Index >1 was associated with a very low probability of AI (5%), whereas a DHEAS-Index <1 increased the likelihood of AI (40%). Finally, a universal DHEAS threshold of <0.2 µg/mL yielded 80% sensitivity and 89% specificity, with a 94% negative predictive value, demonstrating the superior performance of the DHEAS-Index.
    CONCLUSIONS AND RELEVANCE: Age- and sex-adjusted DHEAS thresholds improve screening for adrenal insufficiency diagnosis, reducing unnecessary ACTH testing and enhancing clinical decision-making, particularly in patients with borderline baseline cortisol.
    Keywords:  DHEAS index; adrenal insufficiency; diagnosis
    DOI:  https://doi.org/10.1093/ejendo/lvag120
  8. Molecules. 2026 Jul 24. pii: 2578. [Epub ahead of print]31(15):
    Chondroitin Sulfate-Based Self-Assembling Nanoprodrug for Controlled Methotrexate Delivery in Cancer Therapy.
    Ludovica Scorzafave, Michele Pellegrino, Giuseppe Cirillo, Marco Fiore, Roberta Pino, Diana Amantea, Antonella Leggio, Fiore Pasquale Nicoletta, Francesca Iemma, Manuela Curcio.
      In this study, a pH-responsive chondroitin sulfate-methotrexate (MTX) polymeric prodrug was synthesized through Schiff base formation between oxidized chondroitin sulfate and MTX. The resulting amphiphilic conjugate exhibited a conjugation degree of 184 mg MTX per g conjugate and spontaneously self-assembled into stable nanoparticles (CSMXPs) with a mean diameter of 120 ± 10 nm, a polydispersity index of 0.24, and a critical aggregation concentration of 4.7 × 10-4 mg mL-1. Drug release studies demonstrated a marked pH-dependent behavior, with complete MTX release after 24 h at pH 5.0 and a sustained release profile under physiological conditions. The release mechanism followed reversible first-order kinetics and was accelerated by acid-catalyzed hydrolysis of the imine linkage. Biological evaluation revealed enhanced therapeutic selectivity of CSMXPs compared with free MTX. At 36 μM MTX-equivalent concentration, CSMXPs reduced HeLa cell viability to 37%, while maintaining MCF-10A viability above 88%, whereas free MTX decreased viability in both cell lines (51% and 65%, respectively). Fluorescence confocal microscopy confirmed efficient nanoparticle uptake by cancer cells. These findings demonstrate that CSMXPs represent a promising self-assembling nanoprodrug platform for selective and targeted cancer therapy.
    Keywords:  cancer therapy; chondroitin sulfate; methotrexate; pH-responsive polymeric prodrug; self-assembling nanoparticles
    DOI:  https://doi.org/10.3390/molecules31152578
  9. Protein Sci. 2026 Sep;35(9): e70755
    4-Ethyl phenyl sulfate binding to human serum albumin.
    Vida Dehghan Niestanak, Jacopo Zattoni, Ryan T McKay, Marcello Tonelli, Maral Aminpour, Larry D Unsworth.
      Protein-bound uremic toxins (PBUTs) such as 4-ethylphenyl sulfate (4-EPS) challenge kidney failure management due to strong binding to human serum albumin (HSA), thus limiting dialysis clearance. This study examined 4-EPS-HSA interactions using saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), isothermal titration calorimetry (ITC), in silico analysis via molecular docking, molecular dynamics (MD), and molecular mechanics Generalized Born surface area (MM/GBSA) simulations. STD-NMR qualitatively showed competitive binding with the site-specific ligands, warfarin and ibuprofen, indicating interaction with both Sudlow Sites I and II; competitive ITC results also showed competition between these molecules. ITC analysis using a two-component model indicated two distinct binding interactions with association constants Ka1 = 6.62 × 105 M-1 (entropically unfavorable) and Ka2 = 2.71 × 104 M-1 (enthalpically favorable), respectively. Docking models were used to analyze representative binding poses at Sudlow Sites I and II, while MD revealed hydrophobic stabilization at Site I and polar interactions at Site II. MM/GBSA per-residue decomposition identified key stabilizing residues. Circular dichroism measurements showed that the observed binding effects are not accompanied by gross protein unfolding. Comparisons with other PBUTs, including indoxyl sulfate and p-cresyl sulfate, indicated the role of electrostatic and hydrophobic forces involved in binding. These findings advance understanding of PBUT-HSA interactions and inform strategies for improved toxin removal in kidney failure treatments.
    Keywords:  4‐ethylphenyl sulfate; isothermal titration calorimetry; molecular docking; molecular dynamics; nuclear magnetic resonance spectroscopy; saturation transfer difference
    DOI:  https://doi.org/10.1002/pro.70755
  10. FEBS Lett. 2026 Aug 15.
    Golgi enzymes are retrieved from the plasma membrane to the trans-Golgi network.
    Dominik P Buser, Tina Junne.
      The Golgi complex is not only a central hub for bidirectional protein trafficking, but also a key site for post-translational modifications; the enzymes responsible are trafficked to the Golgi. To determine whether Golgi-resident enzymes can be recaptured from distal sites, we employed a nanobody-based transport assay. While most enzymes studied localized predominantly to the Golgi complex, some were also observed at the plasma membrane. Using sulfation-competent and fluorescently marked nanobody, we observed that certain enzymes are capable of retrograde transport to the trans-Golgi network. In contrast, classical and abundant recycling receptors readily internalized the nanobody but did not undergo retrograde transport. Our findings provide evidence that select Golgi enzymes can be retrieved from the cell surface to the sulfation compartment.
    Keywords:  Golgi enzymes; Golgi‐IP; endosome; microscopy; nanobodies; retrograde transport; sulfation; trans‐Golgi network
    DOI:  https://doi.org/10.1002/1873-3468.70438
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒16 at 10:15.