bims-supasi 2026-01-11 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–01–11
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Chemical Strategies for Controlling Sulfation in Biomacromolecules.
The essential role of heparan sulfate in the entry of PDCoV and other porcine coronaviruses.
Anti-aging effects of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanisms of action and beneficial effects in older people.
Cationic Poly(glucosamine)-Based Polymers Bind to Glycans with Varying Affinity Facilitating Transport across the Glycocalyx of Endothelial Cells.
The Core Protein of the Syndecan-4 Ectodomain on Small Extracellular Vesicles Promotes Fusion with Endosomes.
Genome-Wide Comparative and Phylogenetic Analysis of Putative Algal Carbohydrate Sulfotransferases.
Targeting viral entry: Chemically engineered Gracilaria corticata galactan sulfates as multifunctional antivirals against respiratory syncytial and herpes simplex viruses.
A Novel Polyetheretherketone-Chondroitin Sulfate Zinc Composite: Enhancing Osseointegration through the Synergistic Effects of Chondroitin Sulfate and Zinc for Advanced Dental Implant Applications.
Plumericin Modulates the AhR-NFκB-Nrf2 Signaling Network to Counteract Indoxyl Sulfate-Induced Intestinal Epithelial Cells Impairment.
Essential Roles of Heparan Sulfate Endosulfatase Sulf1 in Reward and Aversion Learning Through Distinct Dopamine D1 and D2 Receptor Pathways in Male Mice.
Scube2 primes Dispatched and ADAM10-mediated Shh release by recruiting HDL acceptors to the plasma membrane.
Enzymatic basis of branching and extension of O-Man glycans for keratan sulfate biosynthesis.
Exploring Diffusion and Aggregation Behaviors in Carbohydrate Solutions.

ACS Chem Biol. 2026 Jan 09.

Chemical Strategies for Controlling Sulfation in Biomacromolecules.

Chao Liu, Xueyi Liu, Yu Deng, Jia Niu.

Sulfation is a fundamental post-translational modification that imparts negative charge and structural complexity to biomolecules, thereby regulating molecular recognition, signaling, and homeostasis across all domains of life. Yet, the ability to interrogate the biological functions of sulfation has long been hindered by the difficulty of constructing molecules with defined sulfation patterns. This Account summarizes our efforts to develop chemical strategies that enable precise control over sulfation in glycans and proteins. We describe an organobase-promoted sulfur(VI) fluoride exchange (SuFEx) chemistry that allows early stage, chemoselective O-sulfation across a broad substrate scope, providing a general solution to sulfate installation in complex settings. Building on this foundation, we introduce an iterative "clickable disaccharide" platform for the programmable assembly of sequence-defined heparan sulfate glycomimetics, enabling systematic dissection of sulfation-dependent glycan-protein interactions. Extending these concepts to the protein realm, we developed a fluorosulfate tyrosine strategy that installs latent sulfates into peptides and proteins, which can be unmasked under physiological conditions or light control via hydroxamic-acid-mediated Lossen rearrangement, offering spatiotemporal control of sulfation in living systems. Collectively, these approaches delineate a unified chemical framework for constructing and manipulating sulfated biomacromolecules with molecular precision, opening new opportunities to elucidate and engineer the biological roles of sulfation.

DOI: https://doi.org/10.1021/acschembio.5c00876
Virulence. 2026 Dec;17(1): 2614154

The essential role of heparan sulfate in the entry of PDCoV and other porcine coronaviruses.

Ningning Ma, Mengjia Zhang, Ahmed H Ghonaim, Pei Zhou, Chunyan Wang, Jiaru Zhou, Guanghao Guo, Robert Jan Lebbink, Berend Jan Bosch, Hongmei Zhu, Wentao Li, Qigai He.

  Porcine enteric coronaviruses, including porcine deltacoronavirus (PDCoV), porcine epidemic diarrhea virus (PEDV), swine acute diarrhea syndrome coronavirus (SADS-CoV), and transmissible gastroenteritis coronavirus (TGEV), can cause acute diarrhea, vomiting, dehydration, and high mortality in suckling piglets. Recent studies revealing human PDCoV infections and the potential of SADS-CoV to penetrate human cell lines have heightened apprehensions about the zoonotic transmission risks of these viruses. While heparan sulfate (HS) serves as a receptor in PDCoV binding, the key host genes involved in HS biogenesis and the specific molecular mechanisms underlying this process have not been fully examined. Enzymes involved in HS biosynthesis, including SLC35B2, EXT1, and NDST1, were identified as critical host factors via the use of CRISPR-Cas9 knockout cells. Moreover, inhibition assays using heparin sodium, a competitive HS mimic, demonstrated dose-dependent reductions in PDCoV infection in vitro. Additionally, mitoxantrone, an HS-binding drug, reduced PDCoV infection. Furthermore, HS was confirmed to facilitate the entry of other porcine enteric coronaviruses (SeCoVs), including PEDV, SADS-CoV, and TGEV, underscoring the conserved role of HS in CoV pathogenesis. These insights contribute to the understanding of porcine coronavirus-host interactions and support the development of innovative antiviral interventions.

Keywords:  EXT1; NDST1; SLC35B2; SeCoVs; heparan sulfate; mitoxantrone

DOI:  https://doi.org/10.1080/21505594.2026.2614154
Endocr J. 2025 Dec 26.

Anti-aging effects of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanisms of action and beneficial effects in older people.

Hajime Nawata, Toshihiko Yanase, Ken-Ichirou Morohashi, Masatoshi Nomura, Kazuo Muta.

  We review the recent remarkable progress of the molecular mechanisms of action of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) regarding their beneficial effects on older people and adrenal regenerative therapy by looking back on our research extending over 50 years since 1971. DHEAS is the most abundant circulating steroid hormone in humans and apes. DHEAS is essential for brain development in adrenarche and for anti-aging in adrenopause as shown by the evolutionary process in primates. The molecular mechanisms of action of DHEA and DHEAS have been clarified by the discovery of many membrane receptors and by the concept of intracrinological action, which is especially important in menopausal women. The genes associated with serum DHEAS concentrations were identified by genome-wide association study meta-analysis of cohort studies. Recent advances in aging research have shown that DHEA and DHEAS have anti-aging action via antioxidants, anti-inflammation, telomere protection, p38MAPK inhibition, anti-cortisol effects, and chaperone induction. DHEA has beneficial effects on the prevention of atherosclerosis based on visceral obesity-induced metabolic syndrome in middle-aged people. DHEA also prevents infection, frailty via reverse metabolism, sarcopenia, and osteoporosis in older people, with a marked decrease in serum DHEAS concentrations. This review discusses adrenal regenerative therapy using steroid-producing cell replacement by overexpressing Ad4BP/steroidogenic factor 1 in mouse or human bone marrow mesenchymal stem cells. This therapy replaces cortisol and DHEAS treatment for the prevention of sudden death by adrenal crisis and severe infection in primary adrenal insufficiency (Addison's disease).

Keywords:  Adrenal regenerative therapy; Adrenarche; Adrenopause; Anti-aging; Dehydroepiandrosterone sulfate

DOI:  https://doi.org/10.1507/endocrj.EJ25-0483
Biomacromolecules. 2026 Jan 05.

Cationic Poly(glucosamine)-Based Polymers Bind to Glycans with Varying Affinity Facilitating Transport across the Glycocalyx of Endothelial Cells.

Claire Bridges, Lu Fu, Dan Wang, James D Sterling, Susanna Liang, Shenda M Baker, Jonathan Yeow, Megan S Lord.

Natural polysaccharides, such as chitosan, offer promising avenues for drug delivery due to their cytocompatibility and ability to interact with cell surfaces. However, the endothelial glycocalyx, a glycan-rich extracellular matrix, presents a barrier that must be navigated for effective intracellular delivery. This study investigates how cationic poly(glucosamine)-based polymers, functionalized with guanidinium or ammonium groups, interact with key glycocalyx components including hyaluronan (HA) and heparan sulfate (HS). We demonstrate that these cationic polymers form tunable biomolecular condensates with glycans, with stronger binding observed for sulfated glycans, HS and heparin, than unsulfated HA. Derivatized chitosan polymers with varied cationic side chains exhibit differential binding affinities and cellular association, with guanidinium-containing polymers showing enhanced interaction with endothelial cells expressing a mature glycocalyx. Quartz crystal microbalance with dissipation monitoring revealed reversible binding profiles influenced by ionic strength, and competitive displacement assays using condensates confirmed preferential binding to heparin over HA. Enzymatic degradation of the glycocalyx reduced polymer-cell association, underscoring the role of the glycans in facilitating the cellular uptake of these polymers. These findings elucidate the mechanisms by which cationic polymers traverse the glycocalyx and highlight the potential of considering the glycocalyx in the design of polymer systems for targeted drug delivery applications.

DOI: https://doi.org/10.1021/acs.biomac.5c02490
Mol Pharm. 2026 Jan 08.

The Core Protein of the Syndecan-4 Ectodomain on Small Extracellular Vesicles Promotes Fusion with Endosomes.

Ryuta Yamanaka, Hiroki Nagumo, Rumina Ema, Mana Iwamoto, Toshihiko Sugiki, Yuki Takechi-Haraya, Norihito Shibata, Yasuomi Kiyota, Mayuko Takeda-Shitaka, Kumiko Sakai-Kato.

  Small extracellular vesicles (sEVs) can efficiently transfer payloads, such as nucleic acids, into the cytosol of cells. Endocytosis is a major pathway for the intracellular trafficking of sEVs, and some sEVs can fuse with late endosomes to release cargoes into the cytosol. Our understanding of the mechanisms regulating sEV composition heterogeneity and the molecular mechanism of the membrane fusion between sEVs and endosomes is limited. Here, we show that the core protein of the syndecan-4 ectodomain, the syndecan-4 ectodomain without heparan sulfate, on sEVs promoted this membrane fusion. In an in vitro lipid-mixing assay, the core protein of the syndecan-4 ectodomain was found to promote membrane fusion under the acidic conditions that are found in late endosomes. A recombinant core protein of the syndecan-4 ectodomain showed higher fusion activity than the domain with heparan sulfate. Conformational changes in the core protein were observed depending on the pH. The involvement of the core protein in membrane fusion was further investigated in a cell-based assay. Our results indicated that the conformation of the core protein was changed in late endosomes, which induced membrane fusion along with an increase in the membrane fluidity of the sEVs. This mechanism involving fusion proteins is similar to the mechanism of many virus infection systems. Syndecan-4, which is initially a glycoprotein containing heparan sulfate on the plasma membrane, has various functions, including cell adhesion and cell signaling, which are mainly thought to be facilitated through the heparan sulfate, and our results indicate the versatility of syndecan-4 actions in vivo.

Keywords:  core protein of syndecan-4; ectodomain; endosome; membrane fusion; small extracellular vesicles; virus infection system

DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01494
J Mol Evol. 2026 Jan 09.

Genome-Wide Comparative and Phylogenetic Analysis of Putative Algal Carbohydrate Sulfotransferases.

Chai-Ling Ho, Xuan-Zi Low, Wei-Kang Lee, John H Bothwell.

  Carbohydrate sulfotransferases (CHSTs) play a vital role in the production of sulfated polysaccharides (SPs) in algae by catalyzing the sulfation of carbohydrate moieties through the transfer of a sulfuryl group from the donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS). In the present study, putative algal CHSTs with a PF00685, PF03567. PF06990 and PF13469 domain were identified by HMMER search and Protein Basic Local Alignment Search Tool (BLAST) using the well-characterized human CHSTs as queries. Approximately half of the algal CHSTs that contained a PF00685 domain also possessed a PF13469 domain in an overlapping region. These CHSTs were structurally and phylogenetically distinct from algal CHSTs containing PF03567 or/and PF06990 domains. The PF00685/PF13469 domain is commonly found in Chlorophyta, while PF03567 and PF06990 domains are more prevalent in red algae and brown algae, respectively, reflecting the different types of SPs produced by these distinct phyla. Our phylogenetic analyses of algal CHSTs support the hypothesis of a polyphyletic origin, suggesting complex evolutionary histories involving both lineage-specific evolution and significant horizontal gene transfer (HGT) events between algae and organisms from other diverse taxa, including bacteria. In addition, the specificities of algal CHSTs for different carbohydrate moieties and site-specific sulfation patterns were inferred from the phylogenies of human CHSTs and the CHSTs from of algae with known SPs and chemical structures. This approach helps us to bridge the gap in knowledge, as a limited number of algal CHSTs have been biochemically characterized experimentally.

Keywords:  Algae; Evolution; Functions; Horizontal gene transfer; Phylogeny; Sulfated polysaccharides

DOI:  https://doi.org/10.1007/s00239-025-10299-9
Int J Biol Macromol. 2026 Jan 06. pii: S0141-8130(25)10598-9. [Epub ahead of print] 150041

Targeting viral entry: Chemically engineered Gracilaria corticata galactan sulfates as multifunctional antivirals against respiratory syncytial and herpes simplex viruses.

Saikat Pal, Andre Luiz Dyna, Shuvam Mukherjee, Mario Gabriel Lopes Barboza, Isabella Maria Tomaz Bissochi, Sueli Fumie Yamada-Ogatta, Maria Laura Goussain Darido, Danielle Bruna Leal Oliveira, Edison Luiz Durigon, Bimalendu Ray, Ligia Carla Faccin-Galhardi, Sayani Ray.

  Seaweed polysaccharides, particularly the sulfated varieties, have demonstrated potent activity against various enveloped viruses, including respiratory syncytial (RSV) and herpes simplex (HSV) viruses. Herein, we report the synthesis, structural characterization, and antiviral evaluation of two chemically engineered galactan sulfates-G-102 and G-103-from Gracilaria corticata via a novel one-step extraction-sulfation process using ClSO₃H·Pyr/DMF and SO₃·Pyr/DMF reagent systems, respectively. These compounds, which contained (1,3)-and (1,4)-linked galactan backbone, exhibited higher sulfate content (G-102: 11 %, G-103: 8 %) and distinct structural features compared to the water-extracted galactan (G-101). Structural analysis using FT-IR and 1H NMR revealed regioselective sulfation, predominantly at the C6 position of galactose residues in G-102, alongside altered 3,6-anhydrogalactose content. Among these compounds, G-102 demonstrated promising antiviral activity with low cytotoxicity (CC₅₀ >500 μg/mL) and potent inhibition against HSV-1 (IC₅₀ = 2.7 μg/mL, SI >185.18) and RSV (IC₅₀ = 18.03 μg/mL, SI >27.73). Notably, this is the first report of anti-RSV activity from galactans of G. corticata. Mechanistic studies revealed that G-102 exerted multi-stage inhibition of HSV-1, including virucidal effects, viral adsorption and penetration blockade, and prophylactic action, while anti-RSV effects were mainly due to virucidal and adsorption inhibition. These findings establish G-102 as a promising candidate for further development as a broad-spectrum antiviral agent targeting enveloped viruses.

Keywords:  Antiviral activity; Chemically engineered galactan sulfates; Gracilaria corticata; Mode of action

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.150041
ACS Biomater Sci Eng. 2026 Jan 08.

A Novel Polyetheretherketone-Chondroitin Sulfate Zinc Composite: Enhancing Osseointegration through the Synergistic Effects of Chondroitin Sulfate and Zinc for Advanced Dental Implant Applications.

Yansong Wang, Yichong He, Yuxun Wu, Enze Zhao, Hanwei Huang, Zhengbin Yan, Hainan Shen, Fenbo Ma, ShuaiShuai Cao, Bin Tang.

  Background: Polyetheretherketone (PEEK) is a promising alternative to titanium alloy for dental implants due to its bone-mimicking elastic modulus, which mitigates stress shielding. However, its bioinert nature limits osseointegration. Methods: We developed a novel PEEK variant, PEEK-chondroitin sulfate zinc (PEEK-CSZn), by chemically grafting zinc and chondroitin sulfate onto the PEEK surface. Material properties were characterized using SEM, FTIR, EDS, and ICP-MS. Anti-inflammatory, osteogenic, and angiogenic effects were evaluated in vitro using MC3T3-E1, HUVEC, and RAW264.7 cells and in vivo using a rabbit femur bone defect model. Results: Characterization confirmed successful CSZn integration. In vitro, PEEK-CSZn at 500 μg/mL enhanced the MC3T3-E1 cell proliferation. Osteogenic markers (OCN and Osterix) were upregulated by around 2.3- and 1.8-fold, respectively, in MC3T3-E1 cells (p < 0.05). Inflammatory markers (IL-6 and IL-12a) in RAW264.7 cells decreased by 23% and 49%, respectively (p < 0.05), while angiogenic markers (VEGF and CD31) in HUVECs increased by 2.2- and 2.8-fold (p < 0.05). In vivo, Micro-CT analysis revealed PEEK-CSZn increased bone volume fraction (BV/TV) and BMD compared to unmodified PEEK at 8 weeks postimplantation (p < 0.05). Conclusions: PEEK-CSZn exhibits trifunctional bioactivities, including anti-inflammatory, osteogenic, and angiogenic, and thus significantly enhances osseointegration, making it a promising material for advanced dental implant applications.

Keywords:  Polyetheretherketone; Zinc; chondroitin sulfate; dental implant; osseointegration

DOI:  https://doi.org/10.1021/acsbiomaterials.5c01189
Int J Mol Sci. 2025 Dec 27. pii: 293. [Epub ahead of print]27(1):

Plumericin Modulates the AhR-NFκB-Nrf2 Signaling Network to Counteract Indoxyl Sulfate-Induced Intestinal Epithelial Cells Impairment.

Rosaria Margherita Rispoli, Stefan Schwaiger, Ada Popolo, Giuseppina Autore, Marco Gargaro, Hermann Stuppner, Stefania Marzocco.

  Intestinal impairment plays a pivotal role in many chronic conditions, including chronic kidney disease (CKD), a progressive disorder affecting over 800 million people worldwide. CKD does not only affect the kidney, but it is recognized as a systemic condition characterized by chronic low-grade inflammation, that contributes to disease progression and associated complications. The intestine is one of the major sources of CKD-associated inflammation, also due to the production and accumulation of some uremic toxins, normally excreted by healthy kidneys, such as indoxyl sulfate (IS). IS is a pro-inflammatory and pro-oxidant protein-bound uremic toxin that increases intestinal epithelial permeability, promotes microbial translocation, and enhances inflammatory and oxidative responses. Although IS-induced intestinal damage has been documented, the underlying molecular mechanisms and effective therapeutic strategies to counteract its effects remain to be elucidated. Against this backdrop in the present study, we investigated the impact of plumericin, an iridoid spironolactone, on IS-induced intestinal impairment using IEC-6, an intestinal epithelial cells model. In IS-treated IEC-6, plumericin reduces apoptosis, inhibits inflammation and oxidative stress, and restores epithelial wound repair. In these conditions plumericin also promotes Nrf-2 and inhibits NF-kB and AhR activation induced by IS. Moreover, the same inhibitory effect of plumericin on inflammation and oxidative stress and in promoting wound repair is also observed in the presence of IS and pro-inflammatory stimuli, as occurs in CKD considering the associated systemic low-grade inflammation. These findings suggest that plumericin may represent a promising therapeutic candidate for intestinal impairment in CKD acting with an integrated mechanism.

Keywords:  apoptosis; chronic kidney disease; indoxyl sulfate; inflammation; oxidative stress; plumericin; wound repair

DOI:  https://doi.org/10.3390/ijms27010293
J Neurochem. 2026 Jan;170(1): e70338

Essential Roles of Heparan Sulfate Endosulfatase Sulf1 in Reward and Aversion Learning Through Distinct Dopamine D1 and D2 Receptor Pathways in Male Mice.

Ken Miya, Kent Ohta, Kazuko Keino-Masu, Takuya Okada, Seiya Mizuno, Satoru Takahashi, Tom Macpherson, Takatoshi Hikida, Masayuki Masu.

  Sulf1 and Sulf2 are extracellular sulfatases that remove 6-O-sulfate from heparan sulfate and thereby regulate cell signaling. Previous studies have revealed that Sulf1/Sulf2 double knockout (KO) mice had defects in differentiation and axon guidance during development, but their functional roles in the adult brain remain largely unknown. We recently found that Sulf1 mRNA is highly expressed in the nucleus accumbens (NAc) shell and that Sulf1 expression is detected in both types of medium spiny neurons expressing dopamine D1 or D2 receptors. Moreover, we found that Sulf1 KO led to changes in membrane excitability and excitatory synaptic transmission in medium spiny neurons of the NAc in adult mice. These findings suggest possible roles of Sulf1 in the functions of NAc circuitry. To address this question, we performed behavioral tests using Sulf1 KO mice. We found that constitutive Sulf1 KO mice showed impairment in both the cocaine-induced conditioned place preference (CPP) test and inhibitory avoidance (IA) test. Next, to examine which cell types the Sulf1 gene is required for, we generated Sulf1 floxed mice by means of CRISPR-Cas9-mediated genome editing and mated them with mice expressing Cre recombinase under a promoter for either the dopamine D1 or D2 receptor-encoding genes. Sulf1 conditional knockout (cKO) in cells expressing dopamine D1 receptors led to impairment only in the CPP test, whereas Sulf1 cKO in D2 receptor-expressing cells resulted in impairment only in the IA test. These results demonstrate that Sulf1 is required for both reward and aversion learning, and that the D1- and D2-pathways distinctly regulate these functions. The present study suggests that Sulf1 is essential for neuronal functions and behavioral control in the adult brain.

Keywords:  Sulf1; conditioned place preference test; heparan sulfate; inhibitory avoidance test; knockout mouse; medium spiny neuron; nucleus accumbens

DOI:  https://doi.org/10.1111/jnc.70338
Commun Biol. 2026 Jan 08.

Scube2 primes Dispatched and ADAM10-mediated Shh release by recruiting HDL acceptors to the plasma membrane.

J Puschmann, G Steffes, J Froese, D Manikowski, K Ehring, J Wittke, C Garbers, S V Wegner, K Grobe.

Sonic hedgehog (Shh) morphogens are lipidated proteins that firmly attach to the outer plasma membrane (PM) of the cells that produce them. The process by which Shh is solubilized requires the transmembrane protein Dispatched1 (Disp), the soluble glycoprotein Scube2, the proteolytic removal of lipidated peptide termini, and the use of soluble lipoproteins (LPPs) as Shh transporters. However, their molecular interplay remains controversial. Here, we demonstrate that A Disintegrin and Metalloproteinase 10, Scube2, and Disp act synergistically to remove Shh from the PM and transfer it to LPP acceptors. We also demonstrate physical Scube2 interactions with LPPs and that these interactions increase Shh release. Finally, we demonstrate that Scube2 strongly binds to heparan sulfate (HS) on cell surfaces. These findings reveal Scube2's previously unknown role in binding low-abundance, soluble LPP carriers for Shh and recruiting these carriers to HS-rich Shh release sites at the PM to enhance morphogen release.

DOI: https://doi.org/10.1038/s42003-025-09466-x
J Biol Chem. 2026 Jan 07. pii: S0021-9258(26)00010-4. [Epub ahead of print] 111140

Enzymatic basis of branching and extension of O-Man glycans for keratan sulfate biosynthesis.

Tomoya Itoh, Hide-Nori Tanaka, Mohit Pareek, Masamichi Nagae, Hiroshi Manya, Akemi Ido, Sushil K Mishra, Yasuhiko Kizuka.

  O-Mannose (Man) glycans are branched specifically in the brain by a dedicated glycosyltransferase, N-acetylglucosaminyltransferase IX (GnT-IX, also known as MGAT5B). Such branching of O-Man glycans was reported to be involved in diseases, including demyelination and glioma, but the enzymatic mechanisms by which O-Man glycan is specifically recognized by GnT-IX and how branched O-Man glycans are subsequently elongated by other enzymes in the brain have remained unclear. To shed light on these issues, we here first compared the structural model of GnT-IX complexed with its O-Man substrate with the crystal structure of the homologous N-glycan branching enzyme GnT-V (also known as MGAT5). Several residues in GnT-IX were predicted to be critical to recognition of the O-Man substrate, and an enzyme assay revealed that R304 in GnT-IX is crucial for the specificity toward O-Man glycans. We further investigated the role of O-Man branching for subsequent elongation in the brain and found that the level of keratan sulfate (KS) in O-Man glycans was significantly reduced in GnT-IX-knockout (KO) mouse brain, suggesting that O-Man branching promotes KS biosynthesis. Mechanistically, our enzymatic assays of the KS biosynthetic enzymes demonstrated that B4GALT1, B4GALT4, and CHST1 exhibited significantly higher activity toward branched O-Man glycans than toward their linear counterparts. These results imply that branching of O-Man glycans by GnT-IX provides the scaffold for efficient subsequent glycan elongation. Our findings deepen our understanding of the complex biosynthetic pathway of O-Man glycans in the brain.

Keywords:  MGAT5B (GnT-IX); O-mannose glycan; glycobiology; glycoprotein biosynthesis; glycosaminoglycan; glycosylation; glycosyltransferase; keratan sulfate

DOI:  https://doi.org/10.1016/j.jbc.2026.111140
J Phys Chem B. 2026 Jan 08.

Exploring Diffusion and Aggregation Behaviors in Carbohydrate Solutions.

Samuel G Holmes, Sawsan Mahmoud, Robert J Woods.

Engineered glycomaterials represent an exciting new field of biomaterials, owing to their vast structural diversity, yielding a myriad of potential properties and applications. Glycomaterials can be composed of naturally occurring polysaccharides (cellulose, hyaluronic acid, chondroitin sulfate, etc.), but these are also amenable to chemical derivatization, resulting in engineered glycomaterials with altered chemical and material properties. However, rules for predicting the properties of glycomaterials, based on their chemical structure, are not well established, hindering their rational design. Computational methods, such as molecular dynamics (MD) simulation, can accurately characterize the spatial and temporal properties, of glycomaterials; however, the application of MD simulations to predict material properties, such as diffusion, solubility, viscosity, and hydrogel formation, has received less attention. This work demonstrates that diffusion properties of well-known glycomaterial constituents, measured by DOSY NMR spectroscopy and calculated from explicit solvent MD simulations with the GLYCAM06 force field, generally agree well. However, the theoretical results are found to be heavily dependent on the water model, with the TIP5P and OPC models outperforming the widely used TIP3P model. Lastly, an empirical method for estimating the diffusion properties of carbohydrates, based on assessing the number of tightly bound waters, is proposed. Together, these results illustrate the potential of computational approaches to guide the rational design of engineered glycomaterials.

DOI: https://doi.org/10.1021/acs.jpcb.5c07628