bims-supasi 2024-06-09 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–06–09
sixteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Study on the interaction between agglutinin and chondroitin sulfate and dermatan sulfate using multiple methods.
Galectin-3-binding protein inhibits extracellular heparan 6-O-endosulfatase Sulf-2.
Modeling interactions between Heparan Sulfate and proteins based on the Heparan Sulfate microarray analysis.
Intervention effects of low-molecular-weight chondroitin sulfate from the nasal cartilage of yellow cattle on lipopolysaccharide-induced behavioral disorders: regulation of the microbiome-gut-brain axis.
Regulatory Effects of Antioxidants on Indoxyl Sulfate-Enhanced Intracellular Oxidation and Impaired Phagocytic Activity in Differentiated U937 Human Macrophage Cells.
A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage by Candida albicans.
Chondroitin sulfate-functionalized selenium nanoparticle-induced S-phase cell cycle arrest and apoptosis in HeLa Cells.
A Unique Enoxaparin Derived from Bovine Intestinal Heparin: A Single Purification Step of the Starting Material Assures a Bovine Enoxaparin Like the Standard from Porcine Origin.
Photocrosslinked gelatin/chondroitin sulfate/chitosan-based composites with tunable multifunctionality for bone tissue regeneration.
Integrated chemoenzymatic synthesis of a comprehensive sulfated ganglioside glycan library to decipher functional sulfoglycomics and sialoglycomics.
Quality control, safety assessment and preparation approaches of low molecular weight heparin.
Oat Dietary Fiber Delays the Progression of Chronic Kidney Disease in Mice by Modulating the Gut Microbiota and Reducing Uremic Toxin Levels.
Extracellular Matrix Mimicking Wound Microenvironment Responsive Amyloid-Heparin@TAAgNP Co-Assembled Hydrogel: An Effective Conductive Antibacterial Wound Healing Material.
Overview of the current procedures in synthesis of heparin saccharides.
Adaptive Modifications in Plant Sulfur Metabolism over Evolutionary Time.
Genome mining of sulfonated lanthipeptides reveals unique cyclic peptide sulfotransferases.

Int J Biol Macromol. 2024 Jun 04. pii: S0141-8130(24)03429-9. [Epub ahead of print]272(Pt 1): 132624

Study on the interaction between agglutinin and chondroitin sulfate and dermatan sulfate using multiple methods.

Shuxian Liu, Xiao Zhang, Ying Chen, Yitong Li, Xiumei Liu.

  In this work, the interaction of chondroitin sulfate (CS) and dermatan sulfate (DS) with plant lectins was studied by affinity capillary electrophoresis (ACE), surface plasmon resonance (SPR) technology, molecular docking simulation, and circular dichroism spectroscopy. The ACE method was used for the first time to study the interaction of Ricinus Communis Agglutinin I (RCA I), Wisteria Floribunda Lectin (WFA), and Soybean Agglutinin (SBA) with CS and DS, and the results were in good agreement with those of the SPR method. The results of experiments indicate that RCA I has a strong binding affinity with CS, and the sulfated position does not affect the relationship, but the degree of sulfation can affect the combination of RCA I with CS to some extent. However, the binding affinity with DS is very weak. This study lays the foundation for developing more specialized analysis methods for CS and DS based on RCA I.

Keywords:  Chondroitin sulfate; Dermatan sulfate; Interaction; Multiple methods; Plant lectins

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.132624
Mol Cell Proteomics. 2024 May 31. pii: S1535-9476(24)00083-5. [Epub ahead of print] 100793

Galectin-3-binding protein inhibits extracellular heparan 6-O-endosulfatase Sulf-2.

Aswini Panigrahi, Julius Benicky, Reem Aljuhani, Pritha Mukherjee, Zora Nováková, Cyril Bařinka, Radoslav Goldman.

Human extracellular 6-O-endosulfatases Sulf-1 and Sulf-2 are the only enzymes that post-synthetically alter the 6-O sulfation of heparan sulfate proteoglycans (HSPG), which regulates interactions of HSPG with many proteins. Oncogenicity of Sulf-2 in different cancers has been documented and we have shown that Sulf-2 is associated with poor survival outcomes in head and neck squamous cell carcinoma (HNSCC). In spite of its importance, limited information is available on direct protein-protein interactions of the Sulf-2 protein in the tumor microenvironment. In this study, we used monoclonal antibody (mAb) affinity purification and mass spectrometry to identify galectin-3-binding protein (LG3BP) as a highly specific binding partner of Sulf-2 in the conditioned media of HNSCC cell lines. We validated their direct interaction in vitro using recombinant proteins and have shown that the chondroitin sulfate (CS) covalently bound to the Sulf-2 influences the binding to LG3BP. We confirmed importance of the CS chain for the interaction by generating a mutant Sulf-2 protein that lacks the CS. Importantly, we have shown that the LG3BP inhibits Sulf-2 activity in vitro in a concentration dependent manner. As a consequence, the addition of LG3BP to a spheroid cell culture inhibited invasion of the HNSCC cells into Matrigel. Thus, Sulf-2 interaction with LG3BP may regulate physiological activity of the Sulf-2 enzyme as well as its activity in the tumor microenvironment.

DOI: https://doi.org/10.1016/j.mcpro.2024.100793
Glycobiology. 2024 Jun 05. pii: cwae039. [Epub ahead of print]

Modeling interactions between Heparan Sulfate and proteins based on the Heparan Sulfate microarray analysis.

Cleber C Melo-Filho, Guowei Su, Kevin Liu, Eugene N Muratov, Alexander Tropsha, Jian Liu.

  Heparan sulfate (HS), a sulfated polysaccharide abundant in the extracellular matrix, plays pivotal roles in various physiological and pathological processes by interacting with proteins. Investigating the binding selectivity of HS oligosaccharides to target proteins is essential, but the exhaustive inclusion of all possible oligosaccharides in microarray experiments is impractical. To address this challenge, we present a hybrid pipeline that integrates microarray and in silico techniques to design oligosaccharides with desired protein affinity. Using fibroblast growth factor 2 (FGF2) as a model protein, we assembled an in-house dataset of HS oligosaccharides on microarrays and developed two structural representations: a standard representation with all atoms explicit and a simplified representation with disaccharide units as "quasi-atoms." Predictive Quantitative Structure-Activity Relationship (QSAR) models for FGF2 affinity were developed using the Random Forest (RF) algorithm. The resulting models, considering the applicability domain, demonstrated high predictivity, with a correct classification rate of 0.81-0.80 and improved positive predictive values (PPV) up to 0.95. Virtual screening of 40 new oligosaccharides using the simplified model identified 15 computational hits, 11 of which were experimentally validated for high FGF2 affinity. This hybrid approach marks a significant step toward the targeted design of oligosaccharides with desired protein interactions, providing a foundation for broader applications in glycobiology.

Keywords:  Chemoenzymatic synthesis; Glycan microarray; Heparin; Oligosaccharides

DOI:  https://doi.org/10.1093/glycob/cwae039
Front Nutr. 2024 ;11 1371691

Intervention effects of low-molecular-weight chondroitin sulfate from the nasal cartilage of yellow cattle on lipopolysaccharide-induced behavioral disorders: regulation of the microbiome-gut-brain axis.

Yuxuan Deng, Qingyuan Li, Junxian Song, Rui Guo, Tianchen Ma, Zhigang Liu, Qian Liu.

  Chondroitin sulfate (CS) is a sulfated linear polysaccharide with different functional activities, including antioxidant, anti-inflammatory, lipid-lowering, and immune regulation. As natural sulfated polysaccharides have high molecular weight, high apparent viscosity, low water solubility, complex structure, and high negative charge, they have difficulty binding to receptors within cells across tissue barriers, resulting in low bioavailability and unclear structure-activity relationships. In this study, an H2O2-Vc oxidative degradation system was employed to perform environmentally friendly and controllable degradation of CS extracted from the nasal cartilage of Shaanxi Yellow cattle. Two low-molecular-weight chondroitin sulfates (LMWCSs), CS-1 (14.8 kDa) and CS-2 (50.9 kDa), that exhibit strong in vitro free radical scavenging ability were obtained, and their structures were characterized. Mice intraperitoneally administered lipopolysaccharide (LPS) were used to explore the cognitive intervention effects of LMWCS. Supplementing CS-1 and CS-2 significantly downregulated the levels of the serum inflammatory factors, TNF-α and IL-1β, promoted the expression of GSH in the brain, and inhibited the production of the lipid peroxidation product, malondialdehyde (MDA), ultimately inhibiting LPS-induced cognitive impairment in mice. Surprisingly, compared to the LPS model group, the abundances of Streptococcus, Eisenbergiella, Vampirovibrio, Coprococcus, Enterococcus and Lachnoanaerobaculum were significantly increased in the intestines of mice in the CS-1 and CS-2 group, whereas those of Parabacteroides and Mycoplasma were significantly decreased. Altogether, this study provides a theoretical basis for the comprehensive utilization of agricultural and animal resources and the application of brain nutrition, anti-inflammatory, and LMWCS health products.

Keywords:  anti-inflammatory; chondroitin sulfate; cognitive function; intestinal microbiota; oxidation degradation

DOI:  https://doi.org/10.3389/fnut.2024.1371691
Biosci Biotechnol Biochem. 2024 Jun 07. pii: zbae077. [Epub ahead of print]

Regulatory Effects of Antioxidants on Indoxyl Sulfate-Enhanced Intracellular Oxidation and Impaired Phagocytic Activity in Differentiated U937 Human Macrophage Cells.

Wakana Iwamoto, Tomohiro Ikeda, Hirotaka Nishikawa, Masashi Hirano, Hideki Kinoshita, Masateru Ono, Katsuhisa Kurogi, Yoichi Sakakibara, Masahito Suiko, Shin Yasuda.

  Indoxyl sulfate (IS), a uremic toxin, is a physiologically active sulfated metabolite, specifically in kidney failure patients. Our previous studies have shown that IS downregulates phagocytic immune function in a differentiated HL-60 human macrophage cell model. However, it remains unclear whether IS exerts similar effects on macrophage function in other cell types or in lipopolysaccharide (LPS)-sensitive immune cell models. Therefore, this study aimed to investigate the effects of IS on intracellular oxidation levels and phagocytic activity in a differentiated U937 human macrophage cell model, both in the absence and presence of LPS. Our results demonstrated that IS significantly increases intracellular oxidation levels and decreases phagocytic activity, particularly in cells activated by LPS. Furthermore, we found that 2-acetylphenothiazine, an NADH oxidase inhibitor, attenuates the effects of IS in LPS-activated macrophage cells. Representative antioxidants, trolox, α-tocopherol, and ascorbic acid, significantly mitigated the effects of IS on the macrophages responding to LPS.

Keywords:  Indoxyl sulfate; U937; antioxidant; lipopolysaccharide; macrophage

DOI:  https://doi.org/10.1093/bbb/zbae077
bioRxiv. 2024 May 23. pii: 2024.05.23.595417. [Epub ahead of print]

A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage by Candida albicans.

Jianfeng Lin, Jian Miao, Katherine G Schaefer, Charles M Russell, Robert J Pyron, Fuming Zhang, Quynh T Phan, Norma V Solis-Swidergall, Hong Liu, Masato Tashiro, Jonathan S Dordick, Robert J Linhardt, Michael R Yeaman, Gavin M King, Francisco N Barrera, Brian M Peters, Scott G Filler.

Candidalysin is a cytolytic peptide produced by the opportunistic fungal pathogen Candida albicans. This peptide is a key virulence factor in mouse models of mucosal and hematogenously disseminated candidiasis. Despite intense interest in the role of candidalysin in C. albicans pathogenicity, its host cell targets have remained elusive. To fill this knowledge gap, we performed a genome-wide loss-of-function CRISPR screen in a human oral epithelial cell line to identify specific host factors required for susceptibility to candidalysin-induced cellular damage. Among the top hits were XYLT2 , B3GALT6 and B3GAT3 , genes that function in glycosaminoglycan (GAG) biosynthesis. Deletion of these genes led to the absence of GAGs such as heparan sulfate on the epithelial cell surface and increased resistance to damage induced by both candidalysin and live C. albicans. Biophysical analyses including surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin physically binds to sulfated GAGs, facilitating its oligomerization or enrichment on the host cell surface. The addition of exogenous sulfated GAGs or the GAG analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate, but not non-sulfated dextran, also inhibited epithelial cell endocytosis of C. albicans and fungal-induced epithelial cell cytokine and chemokine production. In a murine model of vulvovaginal candidiasis, topical dextran sulfate administration reduced host tissue damage and decreased intravaginal IL-1β and neutrophil levels. Collectively, these data indicate that GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage.

DOI: https://doi.org/10.1101/2024.05.23.595417
J Food Sci. 2024 Jun 05.

Chondroitin sulfate-functionalized selenium nanoparticle-induced S-phase cell cycle arrest and apoptosis in HeLa Cells.

Jianping Chen, Xuehua Chen, Anqi Tang, Zhuo Wang, Kit-Leong Cheong, Xiaofei Liu, Saiyi Zhong.

  This study aimed to evaluate the anti-cervical cancer activity of chondroitin sulfate-functionalized selenium nanoparticles (SeCS) and to elucidate their action mechanism. Cytotoxic effect of SeCS on HeLa cells was assessed by MTT assay. Further molecular mechanism of SeCS was analyzed by flow cytometric assay and western blotting. The results showed that treatment with SeCS resulted in a dose- and time-dependent inhibition in the proliferation of HeLa cells. The data obtained from flow cytometry demonstrated that SeCS inhibited HeLa cell growth via the induction of S-phase arrest and cell apoptosis. Further mechanism analysis found that SeCS down-regulated expression levels of cyclin A and CDK2 and up-regulated p21 expression, which contributed to S arrest. Moreover, SeCS increased the level of Bax and decreased the expression of Bcl-2, resulting in the release of cytochrome C from mitochondria and activating caspase-3/8/9 for caspase-dependent apoptosis. Meanwhile, intracellular reactive oxygen species (ROS) levels were elevated after SeCS treatment, suggesting that ROS might be upstream of SeCS-induced S-phase arrest and cell apoptosis. These data show that SeCS has anti-tumor effects and possesses the potential to become a new therapeutic agent or adjuvant therapy for cancer patients. PRACTICAL APPLICATION: In our previous study, we used chondroitin sulfate to stabilize nano-selenium to obtain SeCS to improve the bioactivity and stability of nano-selenium. We found that it possessed an inhibitory effect on HeLa cells. However, the molecular mechanism remains unclear. This study elucidated the mechanism of SeCS damage to HeLa cells. SeCS has the potential to become a new therapeutic agent or adjuvant therapy for cancer patients.

Keywords:  cell apoptosis; chondroitin sulfate; hela cells; selenium nanoparticles; s‐phase arrest

DOI:  https://doi.org/10.1111/1750-3841.17137
ACS Omega. 2024 May 28. 9(21): 23111-23120

A Unique Enoxaparin Derived from Bovine Intestinal Heparin: A Single Purification Step of the Starting Material Assures a Bovine Enoxaparin Like the Standard from Porcine Origin.

Stephan N M C G Oliveira, Francisco F Bezerra, Adriana A Piquet, Rodrigo A Sales, Gabrielly C T Valle, Nina V Capillé, Ana M F Tovar, Paulo A S Mourão.

Low-molecular-weight heparin represent a significant advancement in anticoagulant therapy with enoxaparin being a prominent example obtained exclusively through the fragmentation of porcine intestinal heparin. However, escalating demand and limited resources have raised concerns about enoxaparin supplementation. The current challenge involves exploring alternative heparin sources for large-scale enoxaparin production with bovine intestinal heparin emerging as a promising option. Our study demonstrates that enoxaparin derived from the available bovine heparin preparation differs significantly from the reference compound. Yet, the implementation of a straightforward purification step yields a preparation termed "high-anticoagulant bovine heparin". Fragmentation of this purified product through β-elimination produces enoxaparin akin to the standard from a porcine origin. To ensure physicochemical similarity, we employed various spectroscopic, enzymatic, and chromatographic tests to compare the new bovine-derived enoxaparin with the original porcine compound. Biological activity was confirmed through in vitro coagulation assays and assessments using an animal model of venous thrombosis. Our study affirms that the β-elimination reaction cleaves the bovine heparin chain without preferential breaks in regions with different sulfation patterns. Additionally, we scrutinized decasaccharides purified from enoxaparin preparations, providing a comprehensive demonstration of the similarity between products obtained from porcine and bovine heparin. In summary, our findings indicate that an enoxaparin equivalent to the original porcine-derived product can be derived from bovine heparin, given that the starting material undergoes a simple purification step.

DOI: https://doi.org/10.1021/acsomega.4c02128
Int J Biol Macromol. 2024 May 28. pii: S0141-8130(24)03480-9. [Epub ahead of print] 132675

Photocrosslinked gelatin/chondroitin sulfate/chitosan-based composites with tunable multifunctionality for bone tissue regeneration.

Joanna Klara, Sylwia Onak, Andrzej Kowalczyk, Kinga Wójcik, Joanna Lewandowska-Łańcucka.

  Novel hydrogel-based multifunctional systems prepared utilizing photocrosslinking and freeze-drying processes (PhotoCross/Freeze-dried) dedicated for bone tissue regeneration are presented. Fabricated materials, composed of methacrylated gelatin, chitosan, and chondroitin sulfate, possess interesting features including bioactivity, biocompatibility, as well as antibacterial activity. Importantly, their degradation and swellability might be easily tuned by playing with the biopolymeric content in the photocrosllinked systems. To broaden the potential application and deliver the therapeutic features, mesoporous silica particles functionalized with methacrylate moieties decorated with hydroxyapatite and loaded with the antiosteoporotic drug, alendronate, (MSP-MA-HAp-ALN) were dispersed within the biopolymeric sol and photocrosslinked. It was demonstrated that the obtained composites are characterized by a significantly extended degradation time, ensuring optimal conditions for balancing hybrids removal with the deposition of fresh bone. We have shown that attachment of MSP-MA-HAp-ALN to the polymeric matrix minimizes the initial burst effect and provides a prolonged release of ALN (up to 22 days). Moreover, the biological evaluation in vitro suggested the capability of the resulted systems to promote bone remodeling. Developed materials might potentially serve as scaffolds that after implantation will fill up bone defects of various origin (osteoporosis, tumour resection, accidents) providing the favourable conditions for bone regeneration and supporting the infections' treatment.

Keywords:  Biopolymers; Functionalized mesoporous silica particles; Photocrosslinking

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.132675
Nat Chem. 2024 Jun 06.

Integrated chemoenzymatic synthesis of a comprehensive sulfated ganglioside glycan library to decipher functional sulfoglycomics and sialoglycomics.

Zhuojia Xu, Yating Liu, Jialin Liu, Wenjing Ma, Zhumin Zhang, Digantkumar G Chapla, Liuqing Wen, Kelley W Moremen, Wen Yi, Tiehai Li.

Ganglioside glycans are ubiquitous and complex biomolecules that are involved in a wide range of biological functions and disease processes. Variations in sialylation and sulfation render the structural complexity and diversity of ganglioside glycans, and influence protein-carbohydrate interactions. Structural and functional insights into the biological roles of these glycans are impeded due to the limited accessibility of well-defined structures. Here we report an integrated chemoenzymatic strategy for expeditious and systematic synthesis of a comprehensive 65-membered ganglioside glycan library covering all possible patterns of sulfation and sialylation. This strategy relies on the streamlined modular assembly of three common sialylated precursors by highly stereoselective iterative sialylation, modular site-specific sulfation through flexible orthogonal protecting-group manipulations and enzymatic-catalysed diversification using three sialyltransferase modules and a galactosidase module. These diverse ganglioside glycans enable exploration into their structure-function relationships using high-throughput glycan microarray technology, which reveals that different patterns of sulfation and sialylation on these glycans mediate their unique binding specificities.

DOI: https://doi.org/10.1038/s41557-024-01540-x
Carbohydr Polym. 2024 Sep 01. pii: S0144-8617(24)00442-9. [Epub ahead of print]339 122216

Quality control, safety assessment and preparation approaches of low molecular weight heparin.

Yanlei Yu, Yue Song, Yunjie Zhao, Ningning Wang, Bin Wei, Robert J Linhardt, Jonathan S Dordick, Fuming Zhang, Hong Wang.

  Low Molecular Weight Heparins (LMWHs) are well-established for use in the prevention and treatment of thrombotic diseases, and as a substitute for unfractionated heparin (UFH) due to their predictable pharmacokinetics and subcutaneous bioavailability. LMWHs are produced by various depolymerization methods from UFH, resulting in heterogeneous compounds with similar biochemical and pharmacological properties. However, the delicate supply chain of UFH and potential contamination from animal sources require new manufacturing approaches for LMWHs. Various LMWH preparation methods are emerging, such as chemical synthesis, enzymatic or chemical depolymerization and chemoenzymatic synthesis. To establish the sameness of active ingredients in both innovator and generic LMWH products, the Food and Drug Administration has implemented a stringent scientific method of equivalence based on physicochemical properties, heparin source material and depolymerization techniques, disaccharide composition and oligosaccharide mapping, biological and biochemical properties, and in vivo pharmacodynamic profiles. In this review, we discuss currently available LMWHs, potential manufacturing methods, and recent progress for manufacturing quality control of these LMWHs.

Keywords:  Chemical synthesis; Chemoenzymatic synthesis; Depolymerization methods; Low molecular weight heparin; Quality control

DOI:  https://doi.org/10.1016/j.carbpol.2024.122216
J Agric Food Chem. 2024 Jun 05.

Oat Dietary Fiber Delays the Progression of Chronic Kidney Disease in Mice by Modulating the Gut Microbiota and Reducing Uremic Toxin Levels.

Ji'an Xia, Yu Zhang, Suhua Zhang, Chunlai Lu, Hongdi Huan, Xiao Guan.

  Chronic kidney disease (CKD) has emerged as a significant public health concern. In this article, we investigated the mechanism of oat dietary fiber in regulating CKD. Our findings indicated that the gut microbiota of CKD patients promoted gut microbiota dysbiosis and kidney injury in CKD mice. Intervention with oat-resistant starch prepared by ultrasonic combined enzymatic hydrolysis (ORSU) and oat β-glucan with a molecular weight of 5 × 104 Da (OBGM) elevated the levels of short-chain fatty acids (SCFAs) and regulated gut dysbiosis in the gut-humanized CKD mice. ORSU and OBGM also reduced CKD-related uremic toxins such as creatinine, indoxyl sulfate (IS), and p-cresol sulfate (PCS) levels; reinforced the intestinal barrier function of the gut-humanized CKD mice; and mitigated renal inflammation and fibrosis via the NF-κB/TGF-β pathway. Therefore, ORSU and OBGM might delay the progression of CKD by modulating the gut microbiota to reduce uremic toxins levels. Our results explain the mechanism of oat dietary fiber aimed at mitigating CKD.

Keywords:  chronic kidney disease; gut microbiota; oat β-glucan; oat-resistant starch; uremic toxins

DOI:  https://doi.org/10.1021/acs.jafc.4c02591
ACS Appl Mater Interfaces. 2024 Jun 04.

Extracellular Matrix Mimicking Wound Microenvironment Responsive Amyloid-Heparin@TAAgNP Co-Assembled Hydrogel: An Effective Conductive Antibacterial Wound Healing Material.

Nabanita Mukherjee, Satyajit Ghosh, Rajsekhar Roy, Dipro Mukherjee, Samya Sen, Debasmita Nandi, Jayita Sarkar, Surajit Ghosh.

  Bioengineered composite hydrogel platforms made of a supramolecular coassembly have recently garnered significant attention as promising biomaterial-based healthcare therapeutics. The mechanical durability of amyloids, in conjunction with the structured charged framework rendered by biologically abundant key ECM component glycosaminoglycan, enables us to design minimalistic customized biomaterial suited for stimuli responsive therapy. In this study, by harnessing the heparin sulfate-binding aptitude of amyloid fibrils, we have constructed a pH-responsive extracellular matrix (ECM) mimicking hydrogel matrix. This effective biocompatible platform comprising heparin sulfate-amyloid coassembled hydrogel embedded with polyphenol functionalized silver nanoparticles not only provide a native skin ECM-like conductive environment but also provide wound-microenvironment responsive on-demand superior antibacterial efficacy for effective diabetic wound healing. Interestingly, both the cytocompatibility and antibacterial properties of this bioinspired matrix can be fine-tuned by controlling the mutual ratio of heparin sulfate-amyloid and incubated silver nanoparticle components, respectively. The designed biomaterial platform exhibits notable effectiveness in the treatment of chronic hyperglycemic wounds infected with multidrug-resistant bacteria, because of the integration of pH-responsive release characteristics of the incubated functionalized AgNP and the antibacterial amyloid fibrils. In addition to this, the aforementioned assemblage shows exceptional hemocompatibility with significant antibiofilm and antioxidant characteristics. Histological evidence of the incised skin tissue sections indicates that the fabricated composite hydrogel is also effective in controlling pro-inflammatory cytokines such as IL6 and TNFα expressions at the wound vicinity with significant upregulation of angiogenesis markers like CD31 and α-SMA.

Keywords:  amyloids; heparin sulfate; polyphenol; silver nanoparticle; wound healing

DOI:  https://doi.org/10.1021/acsami.4c05559
Carbohydr Polym. 2024 Sep 01. pii: S0144-8617(24)00446-6. [Epub ahead of print]339 122220

Overview of the current procedures in synthesis of heparin saccharides.

Siran Zhao, Tianji Zhang, Ying Kan, Hongmei Li, Jin-Ping Li.

Natural heparin, a glycosaminoglycan consisting of repeating hexuronic acid and glucosamine linked by 1 → 4 glycosidic bonds, is the most widely used anticoagulant. To subvert the dependence on animal sourced heparin, alternative methods to produce heparin saccharides, i.e., either heterogenous sugar chains similar to natural heparin, or structurally defined oligosaccharides, are becoming hot subjects. Although the success by chemical synthesis of the pentasaccharide, fondaparinux, encourages to proceed through a chemical approach generating homogenous product, synthesizing larger oligos is still cumbersome and beyond reach so far. Alternatively, the chemoenzymatic pathway exhibited exquisite stereoselectivity of glycosylation and regioselectivity of modification, with the advantage to skip the tedious protection steps unavoidable in chemical synthesis. However, to a scale of drug production needed today is still not in sight. In comparison, a procedure of de novo biosynthesis in an organism could be an ultimate goal. The main purpose of this review is to summarize the current available/developing strategies and techniques, which is expected to provide a comprehensive picture for production of heparin saccharides to replenish or eventually to replace the animal derived products. In chemical and chemoenzymatic approaches, the methodologies are discussed according to the synthesis procedures: building block preparation, chain elongation, and backbone modification.

DOI: https://doi.org/10.1016/j.carbpol.2024.122220
J Exp Bot. 2024 Jun 06. pii: erae252. [Epub ahead of print]

Adaptive Modifications in Plant Sulfur Metabolism over Evolutionary Time.

Stanislav Kopriva, Parisa Rahimzadeh Karvansara, Hideki Takahashi.

Sulfur (S) is an essential element for life on Earth. Plants are able to take up and utilize sulfate (SO42-), the most oxidized inorganic form of S compounds on Earth, through the reductive S assimilatory pathway that couples with the photosynthetic energy conversion. Organic S compounds are subsequently synthesized in plants and made accessible to animals, primarily as the amino acid methionine. Thus, the plant S metabolism clearly has nutritional importance in the global food chain. The S metabolites may be part of the redox regulation and drivers of essential metabolic pathways as cofactors and prosthetic groups, such as Fe-S centers, coenzyme A, thiamine, and lipoic acid. The evolution of the S metabolic pathways and enzymes reflects critical importance of the functional innovation and diversifications. Here we review the major evolutionary alterations that took place in the S metabolism across different scales and outline research directions that may take advantage of understanding the evolutionary adaptations.

DOI: https://doi.org/10.1093/jxb/erae252
Acta Pharm Sin B. 2024 Jun;14(6): 2773-2785

Genome mining of sulfonated lanthipeptides reveals unique cyclic peptide sulfotransferases.

Meng Wang, Wen-Wei Li, Zhe Cao, Jianong Sun, Jiang Xiong, Si-Qin Tao, Tinghong Lv, Kun Gao, Shangwen Luo, Shi-Hui Dong.

  Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads, it is rare and underexplored in ribosomally synthesized and post-translationally modiﬁed peptides (RiPPs). Biosynthesis of RiPPs typically entails modification of hydrophilic residues, which substantially increases their chemical stability and bioactivity, albeit at the expense of reducing water solubility. To explore sulfonated RiPPs that may have improved solubility, we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase (ST), and discovered two distinctive biosynthetic gene clusters (BGCs) encoding both lanthipeptide synthetase (LanM) and ST. Upon expressing these BGCs, we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST. We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM. Both LanM and ST are promiscuous towards residues in the A ring, but ST displays strict regioselectivity toward Tyr5. The recognition of cyclic peptide by ST was further discussed. Bioactivity evaluation underscores the significance of the ST-catalyzed sulfonation. This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement.

Keywords:  Biosynthesis; Genome mining; Lanthipeptides; Sulfonation; Sulfotransferases

DOI:  https://doi.org/10.1016/j.apsb.2024.02.016