bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2026–05–03
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Establishing Komagataella phaffii as a cell factory for efficient production of chondroitin sulfate.
  2. Coordinated optimization of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) supply and sulfotransferase expression in Escherichia coli for production of chondroitin sulfate A with high sulfation degree.
  3. Sulfated polysaccharides from Laminaria japonica and Porphyra inhibit SARS-CoV-2 main protease: mechanistic insights into molecular interactions.
  4. Intestinal epithelial Syndecan-1 maintains mucosal homeostasis in inflammatory bowel disease by enhancing Faecalibacterium prausnitzii biofilm formation.
  5. Synthesis, characterization and antibacterial activity of sulfate-modified β-glucan.
  6. Highly specific ID-UHPLC-MS/MS method for analyzing polar and non-polar steroid hormones.
  7. Longitudinal analysis of human milk oligosaccharides (HMOs) and Mucin-2-glycans in infants reveals enrichment of sulfated and glucuronic acid-bearing HMOs.
  8. Immune checkpoint blockade as an accelerator of adrenal aging: a testable model linking low-grade cortical inflammation to proteostasis failure, LDLR/SULT2A1 suppression, and reduced DHEA output.
  9. The Structure-Activity Relationship and Anticoagulation Mechanism of Polyglycerol Sulfates of Different Architectures.
  10. Sulfated Polysaccharides in Cancer Therapy: A Focus on Algal-Derived Bioactive.
  11. High-throughput UHPLC-MS/MS method for 15 protein-bound uremic toxins in human serum.
  1. Biodes Res. 2026 Mar;8(1): 100062
    Establishing Komagataella phaffii as a cell factory for efficient production of chondroitin sulfate.
    Binying Lv, Feng Xiao, Yingjia Pan, Dongfang Li, Jine Li, Chang Dong, Lei Huang, Zhinan Xu, Jiazhang Lian.
      Chondroitin sulfate (CS) is a vital sulfated glycosaminoglycan with essential physiological functions and broad applications in pharmaceuticals and nutraceuticals. Commercial CS production currently relies on extraction from animal tissues, which suffers from raw material scarcity, long production cycles, and safety concerns. Here, an efficient microbial platform for de novo biosynthesis of chondroitin sulfate A (CSA) was established in Komagataella phaffii. The chondroitin biosynthetic pathway was first reconstructed and optimized through rearrangement of three heterologous genes and promoter selection, achieving 927 mg/L unsulfated chondroitin. Functional expression of a chondroitin-4-O-sulfotransferase (CHST11) enabled the biosynthesis of 750.5 mg/L CSA with a sulfation degree of 2.6 %. Replacement of wild-type CHST11 with its engineered mutant (SMp) significantly enhanced sulfation to 12.1 %. Subsequent multi-copy genomic integration of the SMp expression cassette further increased the sulfation degree to 45.0 % while maintaining a high CSA titer of 1.10 g/L in shake flasks. Enhancement of the 3'-phosphoadenosine-5'-phosphosulfate (PAPS) supply, the key cofactor for sulfation, further improved sulfation to 48.0 %. Finally, the optimized strain PM06 achieved a CSA titer of 7.13 g/L with a sulfation degree of 48.4 % in a 5-L fed-batch fermentation, representing the highest microbial CSA production reported to date. This study demonstrates the successful establishment of K. phaffii as a robust cell factory for high-level and high-sulfation production of CSA. The modular engineering strategy described here provides a generalizable framework for balancing multi-enzyme pathways and offers an efficient, non-animal-derived route for the sustainable industrial production of CS.
    Keywords:  3′-phosphoadenosine-5′-phosphosulfate; Chondroitin sulfate A; Chondroitin-4-O-Sulfotransferase; Komagataella phaffii; Synthetic biology
    DOI:  https://doi.org/10.1016/j.bidere.2025.100062
  2. Carbohydr Polym. 2026 Jul 01. pii: S0144-8617(26)00397-8. [Epub ahead of print]383 125280
    Coordinated optimization of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) supply and sulfotransferase expression in Escherichia coli for production of chondroitin sulfate A with high sulfation degree.
    Hejia Qi, Lei Shi, Lingxin Huang, Xiangting Song, Linhao Zhang, Weiwei Meng, Cong Gao, Guipeng Hu, Jia Liu, Zhimeng Wu, Jing Wu, Xiaomin Li.
      Chondroitin sulfate A (CS-A) is a sulfated glycosaminoglycan with broad biomedical applications, yet its sustainable and controllable production remains challenging due to inefficient sulfation. Here, we developed a modularly engineered Escherichia coli platform for the de novo biosynthesis of CS-A from renewable carbon sources. Introduction of an engineered chondroitin-4-O-sulfotransferase into a plasmid-free chondroitin-producing chassis revealed intracellular 3'-phosphoadenosine-5'-phosphosulfate (PAPS) availability as the primary bottleneck for sulfation. This limitation was addressed by enhancing sulfate assimilation and uptake, implementing an artificial PAPS regeneration pathway, and systematically amplifying and spatially assembling key PAPS biosynthetic enzymes. In parallel, pathway flux imbalance was alleviated through PAP-PAPS recycling and fine-tuning of sulfotransferase expression to coordinate backbone synthesis, cofactor supply, and sulfation capacity. The final engineered strain GZ32 achieved de novo production of 8.56 g/L CS-A with a sulfation degree of 90% in a 5 L fed-batch bioreactor using glycerol as the carbon source. This work establishes a scalable microbial platform for CS-A biosynthesis and provides a generalizable framework for sustainable production of well-characterized sulfated glycosaminoglycans.
    Keywords:  CS-A; E. coli cell factory; Enzyme scaffolding; Fed-batch fermentation; Metabolic engineering; PAPS supply
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125280
  3. Bioorg Chem. 2026 Apr 23. pii: S0045-2068(26)00434-7. [Epub ahead of print]177 109898
    Sulfated polysaccharides from Laminaria japonica and Porphyra inhibit SARS-CoV-2 main protease: mechanistic insights into molecular interactions.
    Jinwen Li, Shu Jie Li.
      The replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in host cells relies on its non-structural protein, the main protease (Mpro), a cysteine protease that serves as a primary target for antiviral drug design. Here, the inhibitory effects of sulfated polysaccharides from Laminaria japonica (IJSPS) and Porphyra (PSPS) on Mpro activity were investigated. IJSPS displayed a marked inhibitory effect on Mpro activity, whereas PSPS showed no effect. The half maximal inhibitory concentration (IC50) and inhibition constant (Ki) of the IJSPS for Mpro activity are 1.17 ± 0.34 nM and 1.05 nM, respectively, which is significantly stronger than that of chondroitin sulfate and heparin. Fluorescence quenching experiments indicated that both sulfated polysaccharides interact with Mpro via hydrogen bonds and van der Waals forces. At 25 °C and 0.15 M salt concentration, the dissociation constants (KD) for the interactions of IJSPS and PSPS with Mpro are 7.82 and 8.33 μM, respectively. Furthermore, molecular docking and molecular dynamics (MD) simulations suggested that IJSPS may bind to the active site region of Mpro and form a stable complex with it, providing supportive theoretical evidence for the experimental findings. Our findings indicate that sulfated polysaccharides from Laminaria japonica exhibit strong inhibitory activity against SARS-CoV-2 Mpro, highlighting their potential as functional food components that may contribute to antiviral defense and support host health.
    Keywords:  Activity; Inhibition; Interaction; Main protease; SARS-CoV-2; Sulfated polysaccharides
    DOI:  https://doi.org/10.1016/j.bioorg.2026.109898
  4. Gut Microbes. 2026 Dec 31. 18(1): 2665870
    Intestinal epithelial Syndecan-1 maintains mucosal homeostasis in inflammatory bowel disease by enhancing Faecalibacterium prausnitzii biofilm formation.
    Shuze Chen, Hanxiao Feng, Ying Wang, Jun Huang, Senbao Xu, Yunying Gong, Xiuying Liu, Ye Ouyang, Qiujuan Ye, Dekai Zheng, Kai Sun, Anjiang Wang, Ye Chen.
      Despite the rising global incidence of inflammatory bowel disease (IBD), curative therapies remain unavailable. While our previous work implicated the intestinal proteoglycan Syndecan-1 (SDC1) in IBD-associated barrier dysfunction and inflammation, the underlying mechanism was unclear. This study aimed to elucidate how SDC1 maintains intestinal barrier integrity through interactions with the gut microbiome. In DSS-induced colitis, global knockout of Sdc1 (Sdc1-/-) exhibited exacerbated inflammatory infiltration and greater impairment of barrier structure and function than wild-type (WT). Formation of intestinal organoids was independent of genotype, indicating that Sdc1-/- does not impair barrier function via disrupting epithelial development. The heightened colitis susceptibility in Sdc1-/- mice was abolished in the antibiotic-treated pseudo-germ-free models, and transmissible to WT mice via fecal microbiota transplantation. Similar results were reproduced in a germ-free mouse model. Metagenomic sequencing identified Faecalibacterium prausnitzii as the most significantly depleted species upon Sdc1 knockout. In vitro, SDC1-attached glycosaminoglycans (heparan sulfate (HS) and chondroitin sulfate (CS)) but not the SDC1 core protein promoted F. prausnitzii growth. Prokaryotic transcriptome profiling indicated that HS/CS induces cobalamin biosynthesis in F. prausnitzii. The critical role of cobalamin as a mediator was confirmed, as its synthetic inhibition significantly diminished the growth-promoting effect of HS/CS. Mechanism studies showed that HS/CS enhanced biofilm formation in F. prausnitzii, thereby facilitating cobalamin biosynthesis. Oral administration of HS ameliorated DSS-induced colitis and promoted mucosal colonization of F. prausnitzii, independent of the host genotype. Finally, human IBD biopsies revealed a positive correlation between epithelial SDC1 and mucosal F. prausnitzii, as well as an inverse correlation with bacterial translocation and the number of LPS‑positive cells. Our study elucidates a novel mechanism in which the glycosaminoglycan chains of SDC1 promote F. prausnitzii colonization and growth through enhanced biofilm formation and cobalamin synthesis, thereby highlighting the therapeutic potential of HS for IBD and offering a new basis for host-directed microbiota regulation.
    Keywords:  Faecalibacterium prausnitzii; Syndecan-1; biofilm; cobalamin biosynthesis; heparan sulfate; inflammatory bowel disease
    DOI:  https://doi.org/10.1080/19490976.2026.2665870
  5. Food Chem. 2026 Apr 23. pii: S0308-8146(26)01549-9. [Epub ahead of print]516 149391
    Synthesis, characterization and antibacterial activity of sulfate-modified β-glucan.
    Jingyi Zheng, Fangjun Wang, Zhengyu Jin, Tao Zhang, Ming Miao.
      Natural oat β-glucan (βG) exhibits potential biological activity but is constrained by structural limitations. This study extracted βG from oats and synthesized sulfated derivatives SβG1 and SβG2 with degrees of substitution (DS) of 0.62 and 1.07 by controlling pyridine‑sulfur trioxide complex (SO₃·Pyr) proportions. Techniques including gel permeation chromatography (GPC), Fourier transform infrared (FT-IR), and nuclear magnetic resonance (NMR) spectroscopy confirmed sulfation introduced sulfate groups primarily at the C6 hydroxyl. SβG1 demonstrated greater pH stability than SβG2 over pH 3-10. Antibacterial tests revealed SβG1's concentration-dependent inhibition against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), with stronger effects on S. aureus (60% inhibition at 1.5 mg/mL after 12 h). Molecular dynamics simulation indicated SβG1 binds DOPC/DOPG bacterial membranes via van der Waals forces, increasing the solvent-accessible surface area, reducing membrane rigidity, enhancing fluidity, and disrupting its integrity through widening bilayer spacing and inducing local bending.
    Keywords:  Antibacterial activity; Antibacterial mechanism; Molecular dynamics simulation; Oat β-glucan; Sulfation modification
    DOI:  https://doi.org/10.1016/j.foodchem.2026.149391
  6. Anal Bioanal Chem. 2026 Apr 29.
    Highly specific ID-UHPLC-MS/MS method for analyzing polar and non-polar steroid hormones.
    Lumi Duke, Paul H Kim, Alicia N Lyle, Julianne C Botelho, Natalie D Shaw, Hubert W Vesper.
      The accurate and precise measurement of endogenous steroid hormone levels in serum is essential for their use as biomarkers of endocrine and metabolic diseases in patient care and translational science. Herein, we describe a newly developed, highly accurate, and precise isotope-dilution liquid chromatography-mass spectrometry (LC-MS/MS) method capable of simultaneously measuring eight clinically relevant polar and non-polar steroid hormones in 200 µL of serum. This steroid hormone panel method uses sequential liquid-liquid extractions for the isolation of total testosterone (TT), estradiol (E2), progesterone (P4), 17-hydroxyprogesterone (17-OHP), androstenedione (AD), estrone (E1), estrone sulfate (E1S), and dehydroepiandrosterone sulfate (DHEAS) without derivatization or hydrolysis. The method demonstrated a broad analytical measurement range for all eight hormones as a result of improved selectivity and sensitivity, making it suitable for the analysis of general population serum samples, including postmenopausal women and children. The total imprecision, expressed as coefficients of variation, was evaluated at three levels for each analyte and ranged from 3.5 to 10.7%. The mean bias to well-established secondary reference materials was -1.00% for TT and 1.91% for E2. When applied to 268 commercially sourced serum samples from men, women, and children, only 2% of measurement results were below the limits of detection; therefore, this method was deemed suitable for measurement of eight steroid hormones across the general population. The establishment of this new steroid hormone panel LC-MS/MS method will facilitate investigations of associations between health disorders and individualized steroid profiles, which can be utilized for evaluations at the individual or population levels.
    Keywords:  Androgens; Estrogens; LC-MS/MS; Liquid-liquid extraction; Progestogens; Steroid hormones
    DOI:  https://doi.org/10.1007/s00216-026-06504-3
  7. J Biol Chem. 2026 Apr 27. pii: S0021-9258(26)01971-X. [Epub ahead of print] 113099
    Longitudinal analysis of human milk oligosaccharides (HMOs) and Mucin-2-glycans in infants reveals enrichment of sulfated and glucuronic acid-bearing HMOs.
    Nitin Nitin, Parandis Daneshgar, Darrek Kniffen, Sara D Vicaretti, Brandon Whitmore, Linus Kipchumba, Candice Quin, Deanna L Gibson, Kirk S B Bergstrom, Wesley F Zandberg.
      In infants, the acquisition of an adult-like gastrointestinal (GI) microbiome begins at birth, fully developing by toddlerhood. This colonization is influenced by the diet which, in breast-fed infants, contains high concentrations of soluble human milk oligosaccharides (HMOs), prebiotics bearing structural-resemblance to the glycans that decorate Mucin-2 (MUC2). MUC2 is the first line of defense between the microbiota and the underlying mucosal tissues; it also provides a nutrient-rich habitat for GI commensal microbes. The research described herein builds on two earlier findings: the ability to sample MUC2 adhering to the surface of stool samples and the discovery of a class of sulfated HMOs within human milk. Studies have shown that de-sulfation of MUC2-borne glycans is a key for their metabolism by GI microbes in vitro and, if sulfated glycans are otherwise metabolically-resistant, two hypotheses follow. First, in contrast with major prebiotic HMOs, sulfated HMOs will be enriched in the infant GI tract; second, high abundances of glyco-epitopes like sulfation in HMOs will deflect the microbiome's metabolic activity away from MUC2 leading to detectible changes in the host glycome. We show that both HMOs and MUC2 could be non-invasively sampled from the same infant stool samples. Capillary electrophoresis analyses of paired milk/stool samples demonstrated significant enrichment of sulfate-containing HMOs in stool. High-resolution mass spectrometry (HRMS) was used to detect numerous sulfated HMOs, including a new class concurrently containing glucuronic acid (GlcA) residues. Infant MUC2-derived glycans were also analyzed by HRMS; this is the first reported semi-quantitative longitudinal study and provides a benchmark for future research.
    Keywords:  Human milk oligosaccharides (HMOs); O-glycans; capillary electrophoresis; glucuronic acid; glycomics; mass spectrometry; metabolism; mucus; stool; sulfate
    DOI:  https://doi.org/10.1016/j.jbc.2026.113099
  8. J Immunother Cancer. 2026 Apr 27. pii: e014454. [Epub ahead of print]14(4):
    Immune checkpoint blockade as an accelerator of adrenal aging: a testable model linking low-grade cortical inflammation to proteostasis failure, LDLR/SULT2A1 suppression, and reduced DHEA output.
    Guanxiong Ding, Yangyang Xu, Ting Guo, Chenchen Feng.
      Immune checkpoint blockade (ICB) unleashes antitumor immunity but frequently provokes enduring endocrine toxicities. We hypothesize that ICB accelerates adrenal aging by establishing chronic low-level inflammation within the adrenal cortex, with targeting vulnerability of the zona reticularis. Integrating a recently published human multiorgan aging proteome atlas and primate adrenal aging study with survivorship data after ICB therapy, we propose a testable signaling cascade: ICB-amplified interferon gamma (IFNγ)/ tumor necrosis factor (TNF)/ interleukin-1 signaling activates nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 1 (STAT1), suppressing sterol regulatory element-binding protein 2 (SREBP2)-low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake; concurrent mitochondrial/endoplasmic reticulum stress drives proteome-transcriptome decoupling, loss of cytochrome b5 type A (CYB5A), and impaired cytochrome P450 family 17 subfamily A member 1 (CYP17A1) 17,20-lyase activity; inflammatory transcriptional repression of sulfotransferase family 2A member 1 (SULT2A1) with proteostasis decay reduces dehydroepiandrosterone (DHEA) sulfation. The net result is a persistent fall in DHEA/DHEA sulfate (DHEAS) with comparatively preserved cortisol-mirroring natural adrenal aging. We advocate prospective measurement of DHEAS, DHEA, adrenocorticotropic hormone (ACTH), and cortisol at baseline, during therapy, end of therapy, and 6-24 months post-therapy; if early DHEAS decline is confirmed, targeted interventions including DHEA replacement or glucocorticoid receptor antagonism warrant evaluation. This framework reframes certain endocrine immune-related adverse events as "accelerated organ aging," with implications for risk stratification, toxicity prevention, and survivorship care.
    Keywords:  Immune Checkpoint Inhibitor; Immune related adverse event - irAE
    DOI:  https://doi.org/10.1136/jitc-2025-014454
  9. Biomacromolecules. 2026 Apr 29.
    The Structure-Activity Relationship and Anticoagulation Mechanism of Polyglycerol Sulfates of Different Architectures.
    Clemens Krage, Marie Weinhart, Benjamin F L Lai, Anja Stöshel, Katharina Achazi, Jayachandran N Kizhakkedathu, Rainer Haag.
      Although unfractionated heparin (UFH) remains a vital agent for rapid anticoagulation, its reliance on animal-derived sources results in batch-to-batch variability and contamination risks, and its clinical application is further restricted by the possibility of heparin-induced thrombocytopenia. Dendritic polyglycerol sulfates were investigated as heparin analogues in 2004 due to their ability to mimic its charge, which is essential for its acting mechanism, and revealed an anticoagulant activity of 15-35% compared to UFH. In the current study, we found that the anticoagulant effect of polyglycerol sulfates further increases with their flexibility, resulting in a comparable activity of linear polyglycerol sulfate to UFH. Furthermore, we comprehensively analyzed the mechanism of action and discovered an antithrombin-independent, thrombin-selective mechanism. Moreover, we confirmed that FDA-approved protamine sulfate is a viable reversal agent for polyglycerol sulfate.
    DOI:  https://doi.org/10.1021/acs.biomac.6c00308
  10. Mar Drugs. 2026 Mar 31. pii: 131. [Epub ahead of print]24(4):
    Sulfated Polysaccharides in Cancer Therapy: A Focus on Algal-Derived Bioactive.
    N M Liyanage, D S Dissanayake, Yiqiao Li, Kyung Yuk Ko, D P Nagahawatta, You-Jin Jeon.
      Sulfated polysaccharides (SPs), biologically active macromolecules from marine and terrestrial organisms, hold significant potential in revolutionizing cancer therapy. Characterized by their unique sulfate ester groups and structural diversity, SPs exhibit a broad spectrum of bioactivities, including immunomodulation, apoptosis induction, metastasis suppression, and angiogenesis inhibition. Prominent SPs, such as fucoidan from brown algae and carrageenan from red algae, have shown remarkable anticancer properties, either as standalone agents or in synergy with conventional therapies like chemotherapy and radiotherapy. Their mechanisms of action involve targeting critical pathways such as NF-kB, VEGF, and PI3K/Akt, disrupting cancer cell proliferation, invasion, and tumor microenvironment dynamics. SPs also enhance immune system responses, reduce chemotherapy-induced side effects, and exhibit antioxidant properties, making them versatile candidates in cancer treatment. Innovations like SP-based nanoparticles are addressing bioavailability and drug delivery challenges, providing targeted and sustained therapeutic effects while minimizing off-target toxicity. Despite their promise, challenges such as structural complexity, scalability, and clinical validation hinder their widespread adoption. This review provides a comprehensive analysis of SPs' therapeutic potential, mechanisms, and emerging applications in oncology. It emphasizes the need for advanced extraction, characterization techniques, and clinical research to unlock their full potential, paving the way for novel, efficient, and safer cancer therapies.
    Keywords:  anticancer; apoptosis; fucoidan; invasion; metastasis; nanoparticles; sulfated polysaccharides
    DOI:  https://doi.org/10.3390/md24040131
  11. Clin Chim Acta. 2026 Apr 25. pii: S0009-8981(26)00208-1. [Epub ahead of print]589 121026
    High-throughput UHPLC-MS/MS method for 15 protein-bound uremic toxins in human serum.
    Qiong Wu, Zhipeng Wan, Jinhua Lan, Xiuxiu Zhang, Linlang Huang, Bo Ji, Longhao Chen, Yang Sha, Zhiguo Pan, Yu Shao.
      Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a severe complication of chronic kidney disease (CKD), linked to the systemic accumulation of protein-bound uremic toxins (PBUTs). Current methods for PBUT analysis are often constrained by limited analyte coverage and lack of integrated high-throughput quantification of multiple toxins. A high-throughput targeted Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) method was developed and validated for the quantitative determination of PBUTs in human serum, including Nδ-(carboxymethyl)lysine (CML) and pentosidine (PE). Reproducible sample preparation and reliable quantification were achieved using 96-well protein/phospholipid removal plates for sample preparation and optimizing chromatographic and mass spectrometric conditions. The method was validated, demonstrating acceptable linearity over the concentration range of 10-2000 ng/mL for all 15 analytes (R2 > 0.99), with lower limits of quantification (LLOQ) of 10-20 ng/mL. The limits of detection (LOD) ranged from 5 to 10 ng/mL, and the precision expressed as relative standard deviation (RSD) was below 15%. Application to serum samples from 40 uremic patients and 20 healthy controls revealed significantly elevated levels of 10 PBUTs, with p-cresyl sulfate (PCS) concentrations approximately 400-fold higher in patients. Five PBUTs were undetectable in healthy individuals. This study provides a reliable and accurate method for PBUTs quantification, offering valuable insights into the critical role of PBUTs in the pathogenesis of CKD-MBD, and advancing PBUT-related metabolomic research.
    Keywords:  Biomarkers; Bone disorder; Chronic kidney disease; Protein-bound uremic toxins; Ultra high-performance liquid chromatography-tandem mass spectrometry; Vascular calcification
    DOI:  https://doi.org/10.1016/j.cca.2026.121026
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