bims-supasi 2026-06-28 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–06–28
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Glycosaminoglycans in axon growth and regeneration: molecular mechanisms and therapeutic implications.
Structural determinants of mucus barrier function: How chondroitin sulfate disaccharide composition modulates mucin binding and permeability.
An engineered aryl sulfotransferase for the biosynthesis of glycosaminoglycans.
Plasma heparan sulfate structural variation and phenotypic heterogeneity in pediatric Acute Respiratory Distress Syndrome.
Sulfation in the Biosynthesis of the Heptadecaglycoside Antibiotic Saccharomicin A.
Combined HS6ST1 and HS6ST2 loss disrupts the formation and migration of gonadotropin-releasing hormone neurons.
Sulfated Galactans From Red Algae: Cutting-Edge Extraction, Purification, Structural Characterization, Bioactivities, and Biomedical Applications: A Review.
Structurally distinct enzymatic depolymerization products of Fucus evanescens fucoidan exert cell line-specific anticancer effects in vitro.
Chemoenzymatic Synthesis of Asymmetric N-Glycans in Aqueous Solution via Sulfate and Phosphate Orthogonal Protection.
Chemoenzymatic Synthesis of 6-Sulfo Lewis X-Related Glycans for Probing Their Ligand-Binding Proteins.
Redox Network Failure in Chronic Kidney Disease: Hydrogen Sulfide Deficiency, Reactive Sulfur Species Dysregulation and the Uremic Toxin-AhR-Mitochondrial Axis.

Front Mol Biosci. 2026 ;13 1849064

Glycosaminoglycans in axon growth and regeneration: molecular mechanisms and therapeutic implications.

Kazuma Sakamoto, Yuko Nagai, Kenji Kadomatsu.

  Glycosaminoglycans (GAGs) are a structurally and chemically diverse family of sulfated polysaccharides that constitute a major component of the neural extracellular matrix and cell surface proteoglycans, where they exert pivotal regulatory functions in axon growth, guidance, synaptic organization, and regeneration. By forming highly specific and context-dependent interactions with axonal receptors, GAGs orchestrate the spatial patterning and temporal dynamics of signaling events after injury. Accumulating evidence indicates that the biological activities of GAGs are not dictated merely by their presence but are finely tuned by their sulfation codes, chain length, and domain organization. Recent mechanistic studies have revealed that distinct GAG species, particularly chondroitin sulfate (CS) and heparan sulfate (HS), exert opposing effects on axonal behavior through shared receptor systems. In the injured central nervous system (CNS), CS-rich extracellular matrices, prominently associated with reactive astrocytes and perineuronal nets, act as potent inhibitors of axon regeneration. These inhibitory effects are mediated through selective engagement of receptors such as protein tyrosine phosphatase sigma (PTPσ) leading to suppression of cytoskeletal dynamics and growth cone motility. In contrast, specific HS motifs promote axon elongation by inhibiting PTPσ. Based on these insights, therapeutic strategies targeting GAG biology have gained considerable attention. Approaches such as enzymatic digestion of inhibitory CS chains, development of synthetic or biomimetic GAGs, modulation of sulfation patterns, and gene editing of GAG-modifying enzymes have demonstrated encouraging efficacy in preclinical models of spinal cord injury, traumatic brain injury, and neurodegenerative disorders. Together, these findings indicate GAGs not only as passive structural components but as active, druggable regulators of axon growth and regeneration. This review integrates current advances in GAG structural biology, receptor interactions, and enzymatic regulation to provide a comprehensive framework for understanding how GAGs govern axonal behavior. We highlight unresolved questions and emerging opportunities for exploiting GAG-mediated mechanisms as actionable targets for next-generation neurorestorative therapies.

Keywords:  axon regeneration; chondroitin sulfate; glycosaminoglycan; heparan sulfate; protein tyrosine phosphatase sigma

DOI:  https://doi.org/10.3389/fmolb.2026.1849064
Int J Biol Macromol. 2026 Jun 24. pii: S0141-8130(26)03123-5. [Epub ahead of print]373 153196

Structural determinants of mucus barrier function: How chondroitin sulfate disaccharide composition modulates mucin binding and permeability.

Kangyu Wang, Ping Yang, Xiaojie Qin, Yujie Guo, Chunhui Zhang.

  Chondroitin sulfate (CS) is a bioactive polysaccharide derived from animal cartilage that must pass through the intestinal mucus layer before epithelial absorption. We investigated the penetration behavior and mucus permeability effects of CS samples with distinct disaccharide compositions from bovine (BCS), chicken (CCS), and shark (SCS) cartilage. Using a mucus layer model, mucin (MUC2) structure was observed to unfold and loosen upon binding with CS, accompanied by increased mucus viscoelasticity and reduced mucus permeability. Afterwards, binding affinity to MUC2 was found to be correlated positively with 4-chondroitin sulfate (CSA) content (BCS > CCS > SCS) and negatively with 6-chondroitin sulfate (CSC). Results of molecular dynamics suggested stronger CSA-MUC2 binding energy (-28.72 kcal/mol) than that of CSC (-20.8 kcal/mol), which was consistent with enhanced local MUC2 domain association and reduced pore like interfacial space. Overall, this study provides in vitro evidence that CS disaccharide composition may influence its interaction with MUC2 and the resulting changes in mucus permeability.

Keywords:  Chondroitin sulfate; Molecular dynamics simulation; Mucus permeability; Polysaccharide-mucin interaction

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153196
Int J Biol Macromol. 2026 Jun 24. pii: S0141-8130(26)03108-9. [Epub ahead of print] 153181

An engineered aryl sulfotransferase for the biosynthesis of glycosaminoglycans.

Yingying Zhou, Yanjie Gao, Zijian Tan, Na Shang, Junyue Li, Liang Yin, Lili Duan, Haifeng Liu, Jine Li, Jinshan Li, Leilei Zhu.

  3'-Phosphoadenosine-5'-phosphosulfate (PAPS) is an essential and expensive sulfonic acid donor, playing a central role in sulfonation modification for glycosaminoglycan biosynthesis. The aryl sulfotransferase (AST) is the primary enzyme responsible for catalyzing the regeneration of PAPS from 3'-phosphoadenosine-5'-phosphate (PAP). However, the application of AST in PAPS regeneration systems has been limited by its poor activity and stability. In this study, we identified a new AST from Hipposideros armiger, named as HaAST. Subsequent protein engineering of HaAST yielded variants exhibiting significantly enhanced catalytic activity and thermal stability. The variant HaAST M13 (D247G/V243E/Y186H/M24I/R187P/R285K/K122N/V25A) exhibiting a 9-fold enhancement in activity and showed 58-fold longer half-life than the reported AST IV at 50 °C. The HaAST M13-catalyzed PAPS regeneration system was successfully employed for the sulfation of glycosaminoglycans, including N- and 2-O-sulfated (NS2S) heparin and chondroitin sulfate (CS), with sulfation degree of 75.31% and 68.68%, respectively. Molecular dynamics (MD) simulations suggested that an enlarged entrance of the substrate pocket, together with increased rigidity in key regions including the substrate channel and binding sites, may contribute to the improvement of both catalytic activity and stability. This study offers an efficient PAPS regeneration system, providing a promising foundation for the enzymatic production of glycosaminoglycans.

Keywords:  Aryl sulfotransferase; Heparin; PAPS regeneration; Protein engineering

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153181
Sci Rep. 2026 Jun 26.

Plasma heparan sulfate structural variation and phenotypic heterogeneity in pediatric Acute Respiratory Distress Syndrome.

Colin J Sallee, Aline B Maddux, Joseph A Hippensteel, Daniela Markovic, Zhangjie Wang, Jian Liu, Kaori Oshima, Robert P Richter, Andreas Schwingshackl, Peter M Mourani, David Elashoff, Eric P Schmidt, Anil Sapru.

  Endothelial glycocalyx (eGCX) shedding contributes to microvascular endotheliopathy in Acute Respiratory Distress Syndrome (ARDS) and may represent an underrecognized source of phenotypic heterogeneity. We examined whether circulating heparan sulfate (HS) signatures, as readouts of eGCX shedding, capture patterns of inter-patient biological variation distinct from other eGCX components and conventional protein biomarkers, whether specific HS structural features are enriched, and whether these signatures are associated with heparanase-1 (HPSE) activity. We retrospectively analyzed prospectively collected plasma samples (2018-2020) from children with and without pediatric ARDS (PARDS). Plasma levels (ng/mL) of sulfated and non-sulfated HS disaccharides (following enzymatic digestion of total [unfractionated] HS), and HPSE activity (U/mL) were measured using mass spectrometry, while protein biomarkers were assessed by multiplex assay. Among 46 children (36 PARDS, 10 no PARDS), principal component analysis identified three components explaining > 60% of the variance. The primary component (PC1) was characterized by an HS-driven endothelial signature and was distinct from an inflammatory protein signature captured by PC2. In PARDS, children with higher PC1 scores had worse organ dysfunction and fewer ventilator-free days after adjustment for PC2 and PC3. Higher total HS levels were further associated with selective enrichment of sulfated HS motifs, whereas the opposite pattern was observed in non-PARDS. HPSE activity positively correlated with circulating HS levels. These preliminary findings suggest that circulating HS signatures capture a distinct and clinically meaningful dimension of PARDS heterogeneity.

Keywords:  Biological heterogeneity; Endothelial glycocalyx; Heparan sulfate; Heparanase; Mass spectrometry; Pediatric Acute Respiratory Distress Syndrome

DOI:  https://doi.org/10.1038/s41598-026-59291-3
JACS Au. 2026 Jun 22. 6(6): 3405-3413

Sulfation in the Biosynthesis of the Heptadecaglycoside Antibiotic Saccharomicin A.

Yang Cao, Sijia Guo, Yanyi Piao, Wei Zhang, Peng Sun, Li Cui, Zixin Deng, Qi Zhang, Wei Ding.

  Sulfation is a ubiquitous modification in glycobiology, yet its enzymology and biological significance in glycosylated natural products remain poorly understood. Saccharomicin A, a potent oligosaccharide antibiotic, carries 17 sugars including a unique sulfated fucose. Here, we report the identification of Sam10 as an unprecedented fucose-specific sulfotransferase through genetic studies, in vitro reconstitution, and structural analysis, establishing its role in saccharomicin sulfation. Comparative bioassays revealed that sulfation contributes to antibacterial potency, including activity against diverse multidrug-resistant pathogens. We also characterized Sam35 as an efficient adenylyl-sulfate kinase that boosts cellular 3'-phosphoadenosine-5'-phosphate sulfate (PAPS) supply. Our findings define the biochemical and structural basis of saccharomicin sulfation and provide enzymatic tools for engineering novel sulfated oligosaccharide antibiotics.

Keywords:  adenylyl-sulfate kinase; biosynthesis; oligosaccharide natural products; saccharomicins; sulfotransferase

DOI:  https://doi.org/10.1021/jacsau.6c00414
Development. 2026 Jun 26. pii: dev.204788. [Epub ahead of print]

Combined HS6ST1 and HS6ST2 loss disrupts the formation and migration of gonadotropin-releasing hormone neurons.

R Oleari, F Amoruso, A Lettieri, E Ioannou, A J J Paganoni, J Gimmelli, S Campinoti, S Manzini, C Ruhrberg, A Cariboni.

  6-O sulfotransferase (HS6ST) enzymes modify heparan sulfate proteoglycans (HSPGs) to promote growth factor binding to extracellular matrix or receptors. HS6ST1 variants are reported in patients with GnRH deficiency (GD), which is caused by the defective development of gonadotropin releasing hormone (GnRH) neurons. However, it is unknown whether and how HS6ST family members cooperate in GnRH neuron development. Here, we show that Hs6st1 and Hs6st2 are co-expressed in the nasal neurogenic epithelia, where GnRH neurons and their migratory substrate, the terminal nerve, originate. The combined but not individual disruption of Hs6st1 and Hs6st2 disrupted vomeronasal organ formation with incomplete penetrance and impaired brain entry of GnRH neurons, similar to mice with loss of the morphogen FGF8 or the axon guidance cue SEMA3A, respectively. In agreement with a role for HS6ST-modified HSPG in regulating SEMA3A signalling, SEMA3A binding to nasal tissues was impaired in the absence of HS6ST1 and HS6ST2. Our results establish a mechanistic role for HS6ST1 in GD and suggest HS6ST2 as an additional susceptibility locus for GD.

Keywords:  GnRH neuron; Heparan sulfate 6-O sulfotransferase; Heparan sulfate proteoglycan; Nasal axons; SEMA3A

DOI:  https://doi.org/10.1242/dev.204788
Chem Biodivers. 2026 Jun;23(6): e71449

Sulfated Galactans From Red Algae: Cutting-Edge Extraction, Purification, Structural Characterization, Bioactivities, and Biomedical Applications: A Review.

Divya Vijayakumar.

  The red algal sulfated galactans (SGs), which are primarily agarans and carrageenans are a structurally diverse group of marine polysaccharides with a remarkable biofunctional and physicochemical versatility. The review synthesizes the current developments in their extraction, purification, and structural clarification with the focus on the shift towards the advanced green procedures including enzyme-, ultrasound-, and microwave-assisted extraction. The unique sulfation patterns, molecular weight patterns and glycosidic linkages of the SGs are critically analyzed to determine their structure-function relationships and biological processes. The review also discusses the biomedical potential of SGs in tissue engineering, wound healing, drug delivery and regenerative medicine as well as its new use in environmental remediation, cosmeceuticals and smart medical materials. Specific focus is given to functional derivatization, multi-omics integration, and nanotechnological methods on the personalization of SG-based biomaterials. The translational issues, such as source variability, inconsistency in regulations, and scalability limits are also evaluated. In general, this article is an extensive interdisciplinary overview and suggests a road map to connect the molecular engineering, sustainability, and bioeconomy models to fulfill the therapeutic and industrial capacities of red algal SGs.

Keywords:  agarans; bioeconomy, biomedical applications; carrageenans; cosmeceuticals; drug delivery; environmental remediation; green extraction; nanotechnology; red algae; structure–function relationship; sulfated galactans; sustainability; tissue engineering

DOI:  https://doi.org/10.1002/cbdv.71449
Int J Biol Macromol. 2026 Jun 21. pii: S0141-8130(26)03067-9. [Epub ahead of print] 153140

Structurally distinct enzymatic depolymerization products of Fucus evanescens fucoidan exert cell line-specific anticancer effects in vitro.

Anastasiya O Zueva, Artem S Silchenko, Roman A Shkrabov, Stanislav D Anastyuk, Svetlana P Ermakova.

  Fucoidans are sulfated polysaccharides from brown algae with promising anticancer properties, but the specific structural determinants underlying their biological effects remain poorly defined. Here, four different GH107 family endo-fucanases were used to depolymerize Fucus evanescens fucoidan (FeF), yielding eight high- (HMP) and low-molecular weight (LMP) derivatives differing Mw and sulfation. Enzymatic depolymerization revealed the hidden structure regularity of FeF fucoidan, characterized by extended mostly regular sites of [→4)-α-L-Fucp2S-(1 → 3)-α-L-Fucp2S-(1→]n and [→4)-α-L-Fucp2S-(1 → 3)-α-L-Fucp2,4S-(1→]n linked by less regular sites rich in 2,3-di-sulfated L-fucose residues. The ability of FeF and its enzymatic derivatives to inhibit the colony growth of human cancer cell lines (MCF-7, MDA-MB-231, DLD-1, HuTu80, and SK-MEL-28) was further tested. Reduction in FeF molecular weight (Mw) proved critical for inhibiting colony growth of DLD-1 and MCF-7 cells, with native FeF most potent and LMP derivatives showing practically no effect. In contrast, certain HMP or LMP derivatives with reduced Mw and optimized sulfate content and/or sulfation pattern (especially 2,4-di-sulfated) exhibited enhanced activity against MDA-MB-231, SK-MEL-28, and HuTu 80 cell lines compared to native FeF. Additional EGF-treatment was found to alter the sensitivity of certain cancer cells to specific structural motifs of fucoidans. Certain HMP and LMP derivatives also demonstrated enhanced chemopreventive effects against EGF-induced JB6 Cl41 transformation. These findings reveal that structural determinants of fucoidan anticancer effects differ not only by cancer cell type but also by exogenous or endogenous factors modulating cellular responses. These data further demonstrate the efficacy of specific endo-fucanases in tailoring native fucoidan structure to modulate its biological activity.

Keywords:  Anticancer activity; Chemopreventive activity; Fucoidan degradation; GH107 family endo-fucanases; Structure-activity relationship

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153140
J Am Chem Soc. 2026 Jun 22.

Chemoenzymatic Synthesis of Asymmetric N-Glycans in Aqueous Solution via Sulfate and Phosphate Orthogonal Protection.

Pengxi Chen, Ruofan Li, Yi-Fang Zeng, Tzu-Hao Tseng, Larissa Krasnova, Chi-Huey Wong.

Glycoproteins often exist in nature as heterogeneous glycoforms, making it difficult to obtain pure homogeneous samples for studying the roles of specific N-glycans within a glycoprotein. Despite various chemical and enzymatic methods developed for the synthesis of N-glycans, access to highly diverse N-glycans remains a challenge. Herein, we report a concise strategy for the synthesis of multiantennary N-glycans from designed common core structures with phosphate and sulfate protecting groups, which can be selectively deprotected by respective phosphatase and sulfatase, thereby enabling enzymatic elongation to install a desired glycan chain at a specific antenna. We also explored the directing effect of galactose sulfation for enzymatic fucosylation of the neighboring GlcNAc, further expanding the structural diversity of multiantennary N-glycans. Starting from sulfate and phosphate-terminated core structures, this synthetic strategy in aqueous solution provides an efficient and practical route for the enzymatic assembly of a diverse array of complex N-glycans for biological study.

DOI: https://doi.org/10.1021/jacs.6c06320
J Am Chem Soc. 2026 Jun 23.

Chemoenzymatic Synthesis of 6-Sulfo Lewis X-Related Glycans for Probing Their Ligand-Binding Proteins.

Fangyu Wei, Shengzhou Ma, Xiao Tian, Jiabin Zhang, Liuqing Wen.

6-sulfo Lewis x-related glycan epitopes, including 6-sulfo Lewis x and its sialylated form, sialyl 6-sulfo Lewis x, constitute an important class of carbohydrate determinants that are widely expressed in human cells. Elucidating the biological roles and structure-function relationships of these glycans has attracted considerable attention, as a substantial body of literatures suggest that 6-sulfo Lewis x-related glycans regulate numerous physiological and pathological processes through interactions with their glycan-binding proteins. However, the synthesis of intact complex glycans processing 6-sulfo Lewis x or sialyl 6-sulfo Lewis x glycan epitopes is much more difficult, as the incorporation of the sulfate group and sialic acid residue introduces additional complexity to the oligosaccharide synthesis. Here, we present a chemoenzymatic synthetic strategy for the efficient synthesis of complex N-glycans and O-glycans bearing 6-sulfo Lewis x-related epitopes. By screening a microarray prepared with this glycan library, we systematically probed their binding specificities with many important human glycan-binding proteins. The results provide an insightful understanding of the structure-function relationships of this important class of glycan structures.

DOI: https://doi.org/10.1021/jacs.6c06355
Antioxidants (Basel). 2026 Jun 12. pii: 746. [Epub ahead of print]15(6):

Redox Network Failure in Chronic Kidney Disease: Hydrogen Sulfide Deficiency, Reactive Sulfur Species Dysregulation and the Uremic Toxin-AhR-Mitochondrial Axis.

Kuo-Cheng Lu, Chia-Chao Wu, Te-Chao Fang, Yi-Chou Hou, Cai-Mei Zheng, Chien-Lin Lu.

  Chronic kidney disease (CKD) affects approximately 700 million people worldwide and is a major contributor to end-stage renal disease (ESRD), cardiovascular morbidity, and premature mortality. Although oxidative stress has long been considered central to CKD progression, conventional antioxidant strategies have not consistently improved clinical outcomes, suggesting that excess reactive oxygen species (ROS) alone cannot fully account for the underlying disease pathophysiology. Emerging evidence supports a broader paradigm of redox network failure, characterized by the disruption of coordinated signaling among ROS, nitric oxide (NO), and reactive sulfur species (RSS). Within this framework, hydrogen sulfide (H2S), a major endogenous RSS, functions as a key regulator of renal redox homeostasis. CKD is consistently associated with systemic and renal H2S deficiency, accompanied by downregulation of cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), as well as impaired transsulfuration and disrupted mitochondrial sulfide oxidation. Importantly, this deficiency cannot be explained solely by reduced renal function but instead reflects active suppression of H2S biosynthesis. Uremic toxins, particularly indoxyl sulfate (IS), contribute to this process through activation of the aryl hydrocarbon receptor (AhR), which inhibits specificity protein 1 (Sp1)-dependent transcription of H2S-producing enzymes. This IS-AhR-Sp1 axis provides a mechanistic link between toxin accumulation and disruption of the sulfur arm of the redox network, amplifying oxidative stress, endothelial dysfunction, mitochondrial impairment, ferroptotic vulnerability, and fibrotic remodeling. Beyond H2S itself, downstream RSS, including persulfides, polysulfides, and thiosulfate, may represent the principal bioactive mediators of sulfur-dependent redox signaling, and their coordinated depletion in CKD may impair redox buffering capacity beyond what H2S measurement alone reflects. This review integrates current evidence to propose a conceptual model in which CKD progression involves failure of coordinated redox signaling-characterized by feed-forward network collapse and threshold-dependent transition to a self-sustaining high-ROS state-with H2S deficiency representing one mechanistically supported component of this broader network disruption. This framework highlights the therapeutic potential of targeting redox network restoration rather than isolated oxidative pathways in CKD.

Keywords:  aryl hydrocarbon receptor; chronic kidney disease; hydrogen sulfide; indoxyl sulfate; redox signaling

DOI:  https://doi.org/10.3390/antiox15060746