bims-supasi 2025-07-13 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–07–13
ten papers selected by
Jonathan Wolf Mueller, University of Birmingham

Developing FGF2 Mutants with Selectively Reduced Heparan Sulfate Affinity to Explore Their Impact on FGFR1 Signaling.
DNA Aptamer-Guided Glycomimetics for Developmental Stage-Specific Glycocalyx Engineering to Control Stem Cell Differentiation.
Ultra-Sensitive Quantification of Indoxyl Sulfate and 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid in Plasma Using Ultra-Performance Liquid Chromatography Coupled to Quadrupole Time-of-Flight Mass Spectrometry.
Fucosylated chondroitin sulfate exerts in vitro anti-tumor property through manipulating the metabolism related polarization of macrophages.
Controlling the Sulfation Density of Glycosaminoglycan Glycopolymer Mimetics Enables High Antiviral Activity against SARS-CoV-2 and Reduces Anticoagulant Activity.
Dual effects of indoxyl sulfate on modulation of human hepatic CYP3A activity, with individual differences.
Sialic Acid-Containing Glycolipids Extend the Receptor Repertoire of Enterovirus-D68.
Structural insights into human polyspecific organic anion transporters OAT1 and OAT4.
Arylsulfamates inhibit colonic Bacteroidota growth through a sulfatase-independent mechanism.
Blockade of Aryl Hydrocarbon Receptor Ameliorates Functional Insufficiency in 5/6 Nephrectomized Rat Kidneys by Restoring Hydrogen Sulfide Formation.

Chembiochem. 2025 Jul 08. e202500353

Developing FGF2 Mutants with Selectively Reduced Heparan Sulfate Affinity to Explore Their Impact on FGFR1 Signaling.

Yuga Okada, Akihiro Eguchi, Daisuke Kuroda, Kouhei Tsumoto, Ryosuke Ueki, Shinsuke Sando.

  Fibroblast growth factor 2 (FGF2) regulates signal transduction by forming complexes with its receptors, FGF receptors (FGFRs), and heparan sulfate (HS), playing a crucial role in biological systems. Although HS has been suggested to modulate FGF/FGFR signaling as a co-receptor, multiple hypotheses exist regarding how HS affects FGF/FGFR signaling, and the mechanism remains unclear. In this study, to highlight the role of FGF2/HS interaction in FGF2/FGFR1 signaling, FGF2 mutants with reduced HS-binding affinity were rationally designed through in silico analysis. These FGF2 mutants exhibited reduced HS affinity by more than two orders of magnitude while maintaining binding affinity to FGFR1. In addition, these mutants retained their thermal stability. Cellular assays using the FGF2 mutant suggested that, contrary to previous reports, the contribution of the FGF2/HS interaction in FGF2/FGFR1 signaling may be limited. The mutant FGFs that specifically alter the interaction with HS, achieved in this study, would contribute to an understanding of the role of FGF/HS interaction in FGF/FGFR signaling.

Keywords:  growth factors * receptors * protein design * signal transduction * heparan sulfate

DOI:  https://doi.org/10.1002/cbic.202500353
J Am Chem Soc. 2025 Jul 08.

DNA Aptamer-Guided Glycomimetics for Developmental Stage-Specific Glycocalyx Engineering to Control Stem Cell Differentiation.

Sean C Purcell, Matthew R Naticchia, Julianna L Follmar, Nathaniel Marroquin, Hans Jefferson C Ng, Kamil Godula.

Heparan sulfate glycosaminoglycans in the stem cell glycocalyx are crucial in controlling growth factor activity during development. Augmenting the surface of stem cells with synthetic heparan sulfate mimetics with defined compositions and growth factor binding profiles has emerged as a promising strategy to fine-tune cellular signaling responses and differentiation. However, current glycocalyx engineering methods lack specificity for stem cells or require prior genetic manipulation, limiting their applicability in a therapeutic context. Here, we report a heparan sulfate mimetic containing a DNA aptamer with affinity for the membrane-associated pluripotency marker, alkaline phosphatase, that can be selectively targeted to the surface of embryonic stem cells. The glycomimetic-enhanced fibroblast growth factor 2 recruitment to the stem cell surface activated signaling through the mitogen-activated protein kinase pathway and promoted neural differentiation. While the present work targets pluripotent cells specifically, it can be more broadly applicable to progenitor cells at other developmental stages to better control their differentiation and enhance their therapeutic potential.

DOI: https://doi.org/10.1021/jacs.5c07724
J Clin Lab Anal. 2025 Jul 11. e70077

Ultra-Sensitive Quantification of Indoxyl Sulfate and 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid in Plasma Using Ultra-Performance Liquid Chromatography Coupled to Quadrupole Time-of-Flight Mass Spectrometry.

Jun Negami, Yosuke Suzuki, Haruki Sato, Daiki Toyama, Ayako Oda, Ryota Tanaka, Hiroyuki Ono, Tadasuke Ando, Toshitaka Shin, Hiroki Itoh, Keiko Ohno.

   BACKGROUND: Uremic toxins such as indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) are accumulated in patients with chronic kidney disease (CKD). Recent studies have shown that the accumulation of indoxyl sulfate and CMPF alters the activity of organic anion transporting polypeptide (OATP) 1B and cytochrome P450 (CYP) 3A, respectively. We established and validated a novel ultra-sensitive method for simultaneous quantification of indoxyl sulfate and CMPF using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS).
METHOD: In this method, plasma samples were prepared by solid phase extraction, then analyzed by UPLC-QTOF/MS to measure concentrations of analytes. Using only 5 μL of human plasma per assay, the calibration range was 0.05-200 μg/mL and the lower limit of quantification was 0.05 μg/mL for both indoxyl sulfate and CMPF.
RESULTS: This assay met the acceptance criteria of the U.S. Food and Drug Administration bioanalytical method validation guidance. The clinical applicability of this assay was evaluated by measuring plasma concentrations in healthy volunteers and CKD patients. All measured concentrations were within the calibration range.
CONCLUSION: Our novel assay may contribute to the estimation of variation of OATP1B and CYP3A activities in patients, including those with CKD.

Keywords:  3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid; chronic kidney disease; indoxyl sulfate; plasma; quadrupole time‐of‐flight mass spectrometry; uremic toxin

DOI:  https://doi.org/10.1002/jcla.70077
Int J Biol Macromol. 2025 Jul 07. pii: S0141-8130(25)06385-8. [Epub ahead of print]320(Pt 2): 145830

Fucosylated chondroitin sulfate exerts in vitro anti-tumor property through manipulating the metabolism related polarization of macrophages.

Jing Liu, Mengqiu Hu, Yanying Sun, Lei Zhao, Bin Wang, Xiaohui Qi, Jiaojiao Mou, Jie Yang.

  Tumor associated macrophages (TAMs) participate in the development of tumor, which was reported to dominantly be alternatively activated M2 subtype. Metabolic reprogramming of TAMs into tumor-inhibiting M1 type has shown to be a promising treatment strategy. In this study, we firstly demonstrated fucosylated chondroitin sulfate isolated from sea cucumber Stichopus chloronotus (fCS-Sc) exerted anti-tumor effects. fCS-Sc intervened the metabolism-polarization crosstalk of macrophages and reprogrammed M2 RAW264.7 cells to M1 subtype. fCS-Sc converted IL-4 and IL-13 mediated M2-like RAW264.7 cells to M1 subtype and enhanced the M1-like anti-tumor immunity via suppressing STAT6 signaling and promoting TLRs-NF-κB pathway. The reprogramming effect of fCS-Sc on M2 subtype macrophages were closely related to its metabolism. fCS-Sc markedly elevated the glycolytic pathway and down-regulated fatty acid oxidation pathway. Furthermore, the co-culture assay of M2 subtype RAW264.7 cells and 4 T1 cells demonstrated that fCS-Sc reprogrammed the M2 macrophages to M1 subtype and facilitated its tumor-killing ability. This study will contribute to the application of fCS-Sc as an ancillary drug in anti-tumor treatments.

Keywords:  Anti-tumor property; Cell metabolism; Fucosylated chondroitin sulfate; Polarization of macrophages

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145830
Biomacromolecules. 2025 Jul 06.

Controlling the Sulfation Density of Glycosaminoglycan Glycopolymer Mimetics Enables High Antiviral Activity against SARS-CoV-2 and Reduces Anticoagulant Activity.

Miriam Hoffmann, Lorand Bonda, Ines Fels, Darisuran Anhlan, Eike Hrincius, Derik Hermsen, Stephan Ludwig, Mario Schelhaas, Nicole L Snyder, Laura Hartmann.

Sulfated glycosaminoglycans (sGAGs) make up a class of cell-surface glycans known to mediate pathogen engagement. Glycopolymers mimicking sGAGs can reduce or prevent pathogen attachment. However, their high anticoagulant activity limits their biomedical applications. Here, we report the synthesis and evaluation of synthetic glycopolymers mimicking sGAGs with high antiviral activity but low anticoagulant activity. The key lies in the control of the density of carbohydrates presented along the polymeric backbone. This was accomplished via copolymerization of carbohydrate with noncarbohydrate monomers. We reveal that the polymer chain length affects inhibition of SARS-CoV-2 pseudovirus (PsV) and authentic virus infections, and that above a critical chain length, density of carbohydrate and sulfate groups can be reduced, maintaining high antiviral activity while minimizing anticoagulant activity. This demonstrates, for the first time, how specific structural parameters of glycopolymers can be used to maximize inhibition while minimizing anticoagulative properties unlocking the full potential of sGAG mimetics in fighting infections.

DOI: https://doi.org/10.1021/acs.biomac.5c00576
PLoS One. 2025 ;20(7): e0328182

Dual effects of indoxyl sulfate on modulation of human hepatic CYP3A activity, with individual differences.

Masao Togao, Naoyuki Asakawa, Gaku Wagai, Yuki Ohta-Takada, Jun Otsuka, Minoru Ando, Akinobu Kurita, Koji Kawakami.

This study aimed to identify gut microbiota-derived metabolites governing the activity of hepatic CYP3A in blood level. Indole propionic acid (IPA) and lithocholic acid, ligands of the pregnane X receptor, a transcriptional regulator of CYP3A, and various gut microbiota-derived metabolites in blood level were analyzed. Results revealed that IPA and lithocholic acid did not affect CYP3A activity, while indoxyl sulfate (IS), a uremic toxin, affected CYP3A across different cell lines. The effects of IS on primary hepatocytes from three donors were analyzed, and a concentration-dependent impact was observed, as the CYP3A activity decreased in one donor and increased in another. These findings offer initial insights into blood-level gut microbiota-derived metabolites influencing hepatic CYP3A. Furthermore, the study demonstrates that the response to IS, beyond its concentration, can cause variations in hepatic CYP3A activity among individuals. This study advocates accounting for the dual effects of IS and the benefits of personalized medicine.

DOI: https://doi.org/10.1371/journal.pone.0328182
ACS Infect Dis. 2025 Jul 09.

Sialic Acid-Containing Glycolipids Extend the Receptor Repertoire of Enterovirus-D68.

Ashley K Pereirinha da Silva, Jacobus P van Trijp, Anouk Montenarie, Jelle A Fok, Syriam Sooksawasdi Na Ayudhya, Roland J Pieters, Geert-Jan Boons, Debby van Riel, Robert P de Vries, Lisa Bauer.

  Enterovirus D68 (EV-D68) emerged as a pathogen of increasing health concern globally, particularly due to its association with outbreaks of severe respiratory diseases and acute flaccid myelitis (AFM) in children. Knowledge regarding the tissue tropism and pathogenesis of EV-D68 within the respiratory tract and central nervous system remains limited, primarily due to an incomplete understanding of the host factors that facilitate the entry of EV-D68 into host cells. Several cellular receptors involved in EV-D68 infections have been identified, including ICAM-5, sialylated glycoproteins, and heparan sulfate (HS). Here, we investigate the receptor requirement of a panel of EV-D68 strains covering all clades, focusing on HS and sialosides utilizing glycan arrays. We found that all EV-D68 strains binding to HS harbor a cell culture adaptive substitution in the structural protein VP1 at position 271, which changes the amino acid into a positively charged one. Glycan array analyses revealed that EV-D68 strains prefer α2,6-linked sialic acids presented on N-glycans, α2,8-linked sialic acids on gangliosides, or both. Inhibition of glycolipid biosynthesis or multivalent glycolipid mimics confirmed that ganglioside structures serve as entry receptors for certain EV-D68 strains. Lastly, we examined whether EV-D68 strains that bind to HS or glycolipids require different uncoating mechanisms. Bafilomycin A1 minimally affected the cell entry of HS-binding EV-D68 strains B2/039 and B2/947, and the ganglioside preferring B1/2013 and other viruses were strongly inhibited. Together, we identified that EV-D68 strains can use disialoglycolipids as novel receptors and that different EV-D68 strains show a promiscuous sialic acid binding repertoire.

Keywords:  enterovirus-D68; glycolipids; heparan sulfate; receptors; sialic acid

DOI:  https://doi.org/10.1021/acsinfecdis.5c00063
Cell Rep. 2025 Jul 09. pii: S2211-1247(25)00746-6. [Epub ahead of print]44(7): 115975

Structural insights into human polyspecific organic anion transporters OAT1 and OAT4.

Wei Zhang, Youfu Chu, Ziyang Shan, Huihui Liu, Xuemei Yang, Jing Nan, Feiwen Wei, Yanqing Zhang.

  Organic anion transporters (OATs) play a critical role in the transport of organic anions. OAT1, located in the kidney, is essential for the transport of organic anion drugs and metabolites, while OAT4 facilitates absorption processes in the kidney and placenta. Here, we resolved the cryo-electron microscopy structures of human OAT1 in its apo form and bound to probenecid, adefovir, cefazolin, and para-aminohippuric acid (PAH), as well as human OAT4 in its apo form and in complex with dehydroepiandrosterone sulfate (DHEAS). We observed a shared ligand-binding mode in OAT1 that appears to be common within the SLC22 family, characterized by two aromatic residues clamping the ligand and a pair of opposing charged residues that determine ligand orientation. DHEAS in OAT4 exhibits a different binding mode, illustrating the multispecific ligand-binding characteristics of OATs. Our findings provide a framework for drug design and management of drug-drug interactions involving OAT1.

Keywords:  CP: Molecular biology; OAT1; OAT4; cryo-EM; organic anion transporter

DOI:  https://doi.org/10.1016/j.celrep.2025.115975
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2414331122

Arylsulfamates inhibit colonic Bacteroidota growth through a sulfatase-independent mechanism.

Conor J Crawford, Charles W E Tomlinson, Christian Gunawan, Zongjia Chen, Dominic P Byrne, Cosette Darby, Martina L G Conti, Tony Larson, Ana S Luis, Stefano Elli, Edwin A Yates, David N Bolam, Sjoerd van der Post, Spencer J Williams, Alan Cartmell.

  Excessive degradation of the colonic mucin layer by Bacteroides within the human gut microbiota drives inflammatory bowel disease (IBD) in mice. Bacterial carbohydrate sulfatases are key enzymes in gut colonization, and they are elevated in human IBD and correlate with disease severity. Selective inhibitors of carbohydrate sulfatases could function as sulfatase-selective drugs, allowing precise control of sulfatase activity while preserving these otherwise beneficial bacteria. Arylsulfamates are covalent inhibitors that target a catalytic formylglycine residue of steroid sulfatases, a residue that is also conserved in carbohydrate sulfatases. Here, we find that a library of aryl- and carbohydrate sulfamates is ineffective against carbohydrate sulfatases, yet can inhibit human gut microbiota (HGM) species grown on sulfated glycans. Leveraging thermal proteome profiling (TPP), we identify a lipid kinase as the target responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and reveals the adverse effects that arylsulfamates have on Bacteroides species of the HGM.

Keywords:  arylsulfamates; complex glycans; drug discovery; gut microbiota; sulfatases

DOI:  https://doi.org/10.1073/pnas.2414331122
Antioxid Redox Signal. 2025 Jul 08.

Blockade of Aryl Hydrocarbon Receptor Ameliorates Functional Insufficiency in 5/6 Nephrectomized Rat Kidneys by Restoring Hydrogen Sulfide Formation.

Chien-Lin Lu, Yi-Shiou Tseng, Wen-Bin Wu, Chun-Hou Liao, Ming-Chieh Ma.

  Aims: We previously demonstrated that aryl hydrocarbon receptor (AhR) activation attenuates the cytoprotective effect of hydrogen sulfide (H2S), leading to indoxyl sulfate (IS)-mediated renal tubular damage. However, it is unclear whether this pathway would be present in an in vivo uremic model. Results: In a rat chronic kidney disease (CKD) model with 5/6 nephrectomized (Nx), we found that poor renal filtration is associated with accumulation of IS and homocysteine (Hcy), an H2S precursor. Compared with controls, the protein and mRNA levels of H2S-producing enzymes, including cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase, were attenuated in Nx kidneys. Since the transcription factor, specificity protein 1 (Sp1), acts as an upstream regulator of these enzyme expressions, we found that the protein level and activity of Sp1 were significantly decreased in Nx kidneys. Interestingly, employing the blocker of the AhR CH-223191 not only reverses the decrease in H2S-producing enzymes and Sp1, but it also reverses H2S reduction in Nx rats. These are associated with the mitigation of plasma Hcy accumulation, renal excretion, perfusion insufficiency, and tubular damage. Moreover, the oxidative stress in Nx kidneys due to increased superoxide formation and decreased glutathione contents was also attenuated by AhR inhibition. Innovation: Our findings highlight the deleterious effect of AhR activation on renal H2S formation may be due to IS accumulation and underline AhR blockade as a novel therapy for CKD. Conclusion: AhR is detrimental to Sp1 function in vivo, leading to impeding renal H2S generation and exacerbating oxidative stress during CKD progression. Antioxid. Redox Signal. 00, 000-000.

Keywords:  aryl hydrocarbon receptor; chronic kidney disease; hydrogen sulfide; oxidative stress; specificity protein 1; uremic toxin

DOI:  https://doi.org/10.1089/ars.2024.0833