bims-supasi 2026-03-08 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–03–08
eight papers selected by
Jonathan Wolf Mueller, University of Birmingham

PA14 domain of glycosyltransferase B4GALNT3 is a lectin that binds to sulfated glycan ligands.
Comprehensively investigating pharmacokinetics and metabolic fate of andrographolide in rats by liquid chromatography/mass spectrometry-based approach.
Comparative Study of Sulfated Polysaccharides From Ulva Lactuca Grown in Tunisia and Morocco: in Vitro Antioxidant Activity and in Vivo Anti-Inflammatory and Anti-Ulcer Effects.
Optimization of extraction, structural modification, and bioactivity of polysaccharides from Euphorbia trigona Mill. and their derivatives.
An Automation Platform for the Chemoenzymatic Synthesis of Complex Sulfated and Branched Glycans.
Novel roles of sulfur metabolism in stress-controlled stomata aperture regulation.
Challenges in developing broad-spectrum viral attachment inhibitors targeting heparan sulfates and sialic acids.
Time-dependent adaptations of damaged neurons and their microenvironment in the regenerating adult zebrafish spinal cord.

J Biol Chem. 2026 Feb 26. pii: S0021-9258(26)00198-5. [Epub ahead of print] 111328

PA14 domain of glycosyltransferase B4GALNT3 is a lectin that binds to sulfated glycan ligands.

Yuko Tokoro, Takahiro Yamasaki, Hiroaki Tateno, Yuji O Kamatari, Bakhtyar Sepehri, Tomohiro Sensui, Hiroto Kawashima, Robert J Doerksen, Yasuhiko Kizuka.

  Mammalian proteins are decorated with a variety of glycans, providing proteins with enormous functional diversity. GalNAcβ1-4GlcNAc (LacdiNAc or LDN), a unique sub-terminal glycan structure regulating the half-life of circulating glycoproteins, is biosynthesized by the dedicated glycosyltransferases, B4GALNT3 and B4GALNT4. We recently reported that B4GALNT3 contains a unique non-catalytic PA14 domain that is necessary for the enzyme activity, while the precise function of PA14 is unclear. Here we show that PA14 in B4GALNT3 is a lectin domain required for the activity of B4GALNT3 toward glycoprotein substrates. Glycan microarray experiments, together with surface plasmon resonance and molecular dynamics simulations, demonstrated the specific binding between the PA14 domain of B4GALNT3 and sulfated glycan ligands, such as Gal[6S]β1-4GlcNAc[6S]. Both addition of the sulfated disaccharide ligands and point-mutation at the putative sugar binding site in the PA14 domain inhibited the in vitro activity of B4GALNT3 particularly toward glycoprotein substrates. These data suggest that sulfated glycans negatively regulate the PA14-dependent catalytic activity of B4GALNT3 toward glycoproteins. Suppression of cellular glycan sulfation by knocking out the Golgi transporters for sulfation donor PAPS, SLC35B2 and SLC35B3, likely resulted in the enhanced biosynthesis of LDN by B4GALNT3 in cells. Moreover, overexpression of CHST8, which catalyzes sulfation of LDN, seemed to reduce B4GALNT3 activity in cells, suggesting negative feedback regulation of B4GALNT3 by the sulfated product. These findings indicate that recognition of sulfated glycan ligands by its PA14 domain negatively regulates B4GALNT3 activity, highlighting a novel regulation mechanism for LDN synthesis mediated by a lectin domain.

Keywords:  B4GALNT3; LacdiNAc; N-linked glycosylation; PA14; glycobiology; glycoprotein biosynthesis; glycosylation; glycosyltransferase; lectin

DOI:  https://doi.org/10.1016/j.jbc.2026.111328
RSC Adv. 2026 Feb 26. 16(13): 11348-11360

Comprehensively investigating pharmacokinetics and metabolic fate of andrographolide in rats by liquid chromatography/mass spectrometry-based approach.

Xuelin Sun, Yatong Zhang, Zhanpeng Shang, Lin Dou, Tianying Wang, Jiantao Qiu, Shuang Chen.

Andrographolide, a natural labdane diterpenoid lactone isolated from Andrographis paniculata, possesses diverse pharmacological properties such as anti-tumor, anti-inflammatory, antiviral, and immunomodulatory activities, rendering it a promising candidate for therapeutic development. In this study, pharmacokinetic profiles, excretion features, and metabolism of andrographolide were systematically investigated in rats using a liquid chromatography/mass spectrometry (LC/MS)-based approach. Following intravenous and oral administration, andrographolide exhibited high elimination and moderate bioavailability. Excretion study revealed that less than 5% of the administered dose was eliminated in its parent form in urine and feces. Metabolic profiling identified a total of 39 analytes, among which 34 were sulfated conjugates-establishing sulfation as the most structurally diverse metabolic pathway of andrographolide in rats. A novel MS/MS fragmentation workflow was established, which enabled the unambiguous discrimination of four sulfation modification sites: O-sulfation at the C3 and C19 positions, and C-sulfation at the C12 and C14 positions. Collectively, this comprehensive study delineates the complete in vivo disposition of andrographolide in rats and clarifies the site-specific sulfation rules of its metabolites.

DOI: https://doi.org/10.1039/d5ra08654j
Chem Biodivers. 2026 Mar;23(3): e02636

Comparative Study of Sulfated Polysaccharides From Ulva Lactuca Grown in Tunisia and Morocco: in Vitro Antioxidant Activity and in Vivo Anti-Inflammatory and Anti-Ulcer Effects.

Nourhene Kharrat, Yasmine Touhamia, Rihab Ben Abdallah Kolsi, Khaled Hamden, Rafik Ben Said, Touria Ould Bel Lahcen, Hichem Ben Salah, Noureddine Allouche.

  This study presents a comparative analysis of sulfated polysaccharides extracted from Ulva lactuca collected in Tunisia (PSUT) and Morocco (PSUM). FTIR confirmed the presence of sulfate groups, while GC-MS identified diverse sugar components. Both polysaccharides showed strong antioxidant activity, with DPPH and ABTS radical scavenging rates exceeding 50% at the highest concentrations. In a rat model of gastric ulceration, PSUT and PSUM significantly reduced inflammation and lymphocytic infiltration and lowered the activities of 5-lipoxygenase and myeloperoxidase. Treatment also produced clear antioxidant effects, decreasing hydrogen peroxide by 48% and 61% and reducing TBARS by 65% and 71%, respectively. In addition, both polysaccharides inhibited gastric H+/K+-ATPase and pepsin, contributing to notable anti-acidic effects and improved protection of the gastric mucosa. Mucin levels increased by 82% and 100%, while gastric mucus content rose by 32% and 71% for PSUT and PSUM. Overall, PSUM displayed stronger in vivo anti-inflammatory and gastroprotective activities, whereas PSUT showed slightly higher in vitro antioxidant capacity. These findings confirm that the geographic origin of U. lactuca influences the structural features of its polysaccharides and their biological effects. Although based on a single animal model and dose, this work offers a solid basis for future mechanistic and clinical investigations.

Keywords:  Antioxidant activity; Anti‐inflammatory activity; Gastric ulcers; Sulfated polysaccharides; Ulva lactuca

DOI:  https://doi.org/10.1002/cbdv.202502636
Prep Biochem Biotechnol. 2026 Mar 02. 1-19

Optimization of extraction, structural modification, and bioactivity of polysaccharides from Euphorbia trigona Mill. and their derivatives.

Xiaoliang Zhao, Yuanyuan Ma, Haidong Wen, Lixia Xiong, Cunjin Wang, Jing Zhang, Pengcheng Shao, Yuhui Zhao, Ji Zhang, Weijie Zhang.

  The optimal hot water extraction process for a polysaccharide from Euphorbia trigona Mill. was established using single-factor and orthogonal experiments, yielding the best conditions of a 1:30 (g/mL) solid-to-liquid ratio at 90 °C for 3.5 h, with a polysaccharide yield of 5.89%. Sulfated (ETM-S) and phosphorylated (ETM-P) derivatives were successfully prepared, with degree of substitution of 0.32 and 0.48, respectively. Structural analysis confirmed the polysaccharides were acidic with complex monosaccharide compositions. Bioactivity assessments revealed that both modifications markedly improved functional properties. ETM-P exhibited significantly enhanced antioxidant activity, with IC50 values of 2.16, 1.57, and 1.79 mg/mL against DPPH, ·OH, and O2·-, respectively. Sulfation boosted inhibitory effects on α-amylase and α-glucosidase, suggesting hypoglycemic potential, and also increased pancreatic lipase inhibition, indicating a synergistic role in regulating glucose and lipid metabolism. Furthermore, ETM-S showed the strongest in vitro cytotoxicity against HepG2 cells, achieving an inhibition rate of 45.00% at 800 μg/mL, outperforming ETM-P (33.37% at 400 μg/mL) and the native polysaccharide (27.92% at 800 μg/mL). Both modified polysaccharides promoted RAW264.7 macrophage proliferation, enhanced phagocytosis, and stimulated NO release, demonstrating immunomodulatory capacity. In summary, chemical modification, especially sulfation, effectively enhances the bioactivities of polysaccharides, showing promise for regulating glycolipid metabolism and immune modulation.

Keywords:  Bioactivity evaluation; Euphorbia trigona Mill; phosphorylation; polysaccharides; structural characterization; sulfation

DOI:  https://doi.org/10.1080/10826068.2026.2636920
J Am Chem Soc. 2026 Mar 06.

An Automation Platform for the Chemoenzymatic Synthesis of Complex Sulfated and Branched Glycans.

Saptashwa Chakraborty, Kyle Minder, Anthony Robert Prudden, Geert-Jan Boons.

Diverse collections of well-defined glycans are needed to investigate the molecular mechanisms by which these biomolecules mediate biological and disease processes. Several automation approaches have been introduced to accelerate the enzymatic synthesis of complex glycans. These methodologies have, however, provided only relatively simple oligosaccharides due to limitations of glycosyl transferase selectivity. Here, we describe an automation platform that makes it possible, for the first time, to prepare in an automated fashion sulfated polylactosamines and asymmetric multiantennary complex N-glycans via sequential enzymatic and chemical reaction cycles. It integrates glycosyltransferase catalyzed glycosylations, the use of the unnatural sugar nucleotide donor 5'-diphosphate-2-deoxy-2-trifluoro-N-acetamido-glucose (UDP-GlcNHTFA), and chemical manipulations including base-mediated trifluoroacetamido (TFA) removal, azido transfer and azido reduction, tert-butyloxycarbonyl (Boc) protection, acid mediated deprotection, and amine acylation. The latter transformations are important for stop-and-go chemoenzymatic synthetic strategies in which unnatural monosaccharides are introduced to temporarily disable specific sites from enzymatic modification. It is shown that, due to the modular architecture of glycans, a limited number of glycosyl transferases can provide access to large numbers of structurally diverse glycans. In this study, only 11 recombinant human glycosyl- and sulfo transferases were employed to prepare highly complex glycans. Removal of the Nap tag can be performed by hydrogenation to give oligosaccharides that are ready for microarray printing or bioconjugation.

DOI: https://doi.org/10.1021/jacs.5c22181
New Phytol. 2026 Mar 02.

Novel roles of sulfur metabolism in stress-controlled stomata aperture regulation.

Sheng-Kai Sun, Rüdiger Hell, Markus Wirtz.

  Stomatal closure allows plants to conserve water by reducing transpiration during drought. Surprisingly, the assimilation of the macronutrient sulfur is intimately connected to the drought stress response. This Tansley insight will only briefly touch on the general impact of sulfate assimilation on the production of drought-response metabolites. Instead, the emphasis will be on the unexpected role of cysteine in triggering guard cell-autonomous abscisic acid biosynthesis in response to diverse drought-associated stresses. A particular focus will be on identifying the chloroplast-localized cysteine synthase complex as a sensor hub that integrates long-distance soil-drying signals and local high-light signals to mediate stress-induced stomatal closure. Furthermore, we will discuss the emerging role of cysteine-derived sulfide as a signal in stomatal closure.

Keywords:  3′‐phosphoadenosine 5′‐phosphate; ABA biosynthesis; cysteine biosynthesis; cysteine synthase complex; guard cells; stomata closure; sulfate; sulfide; sulfur

DOI:  https://doi.org/10.1111/nph.71048
J Virol. 2026 Mar 02. e0013926

Challenges in developing broad-spectrum viral attachment inhibitors targeting heparan sulfates and sialic acids.

Valeria Cagno.

  Many distinct viruses exploit cell surface glycans, particularly heparan sulfates and sialic acids, as initial attachment factors to facilitate entry into host cells. Because these interactions are highly conserved across diverse viral families, they have long been viewed as attractive targets for the development of broad-spectrum antiviral strategies. Over the past decades, numerous approaches have attempted to block these early binding events, including genetic or enzymatic removal of glycans from the cell surface, masking of cell surface glycans, the use of engineered decoy receptors, and the development of multivalent inhibitors. Despite promising in vitro results, no antiviral therapy based on this mechanism has yet advanced to routine clinical use. Here, the biological roles of heparan sulfates and sialic acids in viral entry are examined, and the range of antiviral strategies designed to interfere with these interactions is discussed. The major challenges that have limited clinical translation are highlighted, including insufficient potency, potential off-target effects, the risk of resistance, and challenges related to routes of administration. Finally, recent technological advances that may help overcome these barriers and enable the development of clinically viable viral attachment inhibitors are proposed.

Keywords:  antiviral; broad spectrum; entry; glycomimetic; heparan sulfates; receptor; sialic acid

DOI:  https://doi.org/10.1128/jvi.00139-26
Sci Adv. 2026 Mar 06. 12(10): eaea2882

Time-dependent adaptations of damaged neurons and their microenvironment in the regenerating adult zebrafish spinal cord.

Leslie Lafouasse, Konstantinos Koutsogiannis, Yu-Wen E Dai, Lisa Del Vecchio, Andrea Pedroni, Dimitrios Tsagkogiannis, Judith Habicher, Konstantinos Ampatzis.

Spinal cord injury (SCI) triggers complex cellular and extracellular responses that disrupt neuronal connectivity and hinder repair. While mammals have limited regenerative abilities, zebrafish achieve functional recovery through coordinated neuroprotection and plasticity. Here, we examined how structural and functional adaptations of damaged spinal neurons interact with extracellular matrix (ECM) dynamics during regeneration in adult zebrafish. We found that injured neurons undergo reversible changes in cellular properties and synaptic input, mediated mainly by glutamatergic signaling. These modifications coincide with a transient ECM reorganization marked by increased deposition of chondroitin sulfate proteoglycans (CSPGs). Enzymatic CSPG degradation paradoxically partially impaired long-term axonal regrowth and locomotor recovery. Thus, CSPG-rich ECM exerts a dual role: initially restricting plasticity but subsequently supporting structural stabilization and regeneration. Our findings highlight a temporally coordinated interplay between neuronal excitability, synaptic remodeling, and ECM reorganization as key determinants of spinal cord repair, offering mechanistic insights for enhancing nervous system regeneration.

DOI: https://doi.org/10.1126/sciadv.aea2882