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Current Medicinal Chemistry 2022The bacterial cell wall peptidoglycan (PG) is a dynamic structure that is constantly synthesized, re-modeled and degraded during bacterial division and growth.... (Review)
Review
The bacterial cell wall peptidoglycan (PG) is a dynamic structure that is constantly synthesized, re-modeled and degraded during bacterial division and growth. Postsynthetic modifications modulate the action of endogenous autolysis during PG lysis and remodeling for growth and sporulation, but also they are a mechanism used by pathogenic bacteria to evade the host innate immune system. Modifications of the glycan backbone are limited to the C-2 amine and C-6 hydroxyl moieties of either GlcNAc or MurNAc residues. This paper reviews the functional roles and properties of peptidoglycan de-Nacetylases (distinct PG GlcNAc and MurNAc deacetylases) and recent progress through genetic studies and biochemical characterization to elucidate their mechanism of action, 3D structures, substrate specificities and biological functions. Since they are virulence factors in pathogenic bacteria, peptidoglycan deacetylases are potential targets for the design of novel antimicrobial agents.
Topics: Anti-Infective Agents; Bacteria; Bacterial Proteins; Cell Wall; Muramic Acids; Peptidoglycan
PubMed: 34525907
DOI: 10.2174/0929867328666210915113723 -
Frontiers in Immunology 2019Monocytes are subdivided into three subsets, which have different phenotypic and functional characteristics and different roles in inflammation and malignancy. When in... (Review)
Review
Monocytes are subdivided into three subsets, which have different phenotypic and functional characteristics and different roles in inflammation and malignancy. When in man CD14 and CD16 monoclonal antibodies are used to define these subsets, then the distinction of non-classical CD14low and intermediate CD14high monocytes requires setting a gate in what is a gradually changing level of CD14 expression. In the search for an additional marker to better dissect the two subsets we have explored the marker 6-sulfo LacNAc (slan). Slan is a carbohydrate residue originally described to be expressed on the cell surface of a type of dendritic cell in human blood. We elaborate herein that the features of slan+ cells are congruent with the features of CD16+ non-classical monocytes and that slan is a candidate marker for definition of non-classical monocytes. The use of this marker may help in studying the role of non-classical monocytes in health and in diagnosis and monitoring of disease.
Topics: Amino Sugars; Animals; Biomarkers; Dendritic Cells; Humans; Inflammation; Monocytes; Neoplasms; Phenotype
PubMed: 31572354
DOI: 10.3389/fimmu.2019.02052 -
Chembiochem : a European Journal of... Jun 2021All human cells use O-GlcNAc protein modifications (O-linked N-acetylglucosamine) to rapidly adapt to changing nutrient and stress conditions through signaling,... (Review)
Review
All human cells use O-GlcNAc protein modifications (O-linked N-acetylglucosamine) to rapidly adapt to changing nutrient and stress conditions through signaling, epigenetic, and proteostasis mechanisms. A key challenge for biologists in defining precise roles for specific O-GlcNAc sites is synthetic access to homogenous isoforms of O-GlcNAc proteins, a result of the non-genetically templated, transient, and heterogeneous nature of O-GlcNAc modifications. Toward a solution, this review details the state of the art of two strategies for O-GlcNAc protein modification: advances in "bottom-up" O-GlcNAc peptide synthesis and direct "top-down" installation of O-GlcNAc on full proteins. We also describe key applications of synthetic O-GlcNAc peptide and protein tools as therapeutics, biophysical structure-function studies, biomarkers, and as disease mechanistic probes to advance translational O-GlcNAc biology.
Topics: Acetylglucosamine; Carbohydrate Conformation; Humans; Models, Molecular; Peptides; Protein Processing, Post-Translational; Proteins
PubMed: 33450137
DOI: 10.1002/cbic.202000843 -
Methods in Molecular Biology (Clifton,... 2022The sialome or display of sialic acids on the surface of human immune cells can vary according to immune response and activation state. Here, human peripheral blood...
The sialome or display of sialic acids on the surface of human immune cells can vary according to immune response and activation state. Here, human peripheral blood mononuclear cells (PBMCs) were isolated and activated with anti-CD3 antibody and the cell surface sialome was quantified using a combination of click chemistry, confocal microscopy and flow cytometry techniques. Carbohydrate click chemistry was used to detect and measure the incorporation of an azido-m65odified sialic acid precursor molecule, N-acetylmannosamine (ManNaz) sugar into the PBMC surface sialome. Incorporation of sialic acid into the PBMC glycocalyx was visualized using copper-catalyzed click conjugation of Alexa 488 alkyne and confocal microscopy and further quantified using flow cytometry. The use of these methods indicate that regulating the sialome content on the surface of activated immune cells may be monitored during immunomodulatory responses and anti-inflammatory therapies.
Topics: Alkynes; Click Chemistry; Humans; Leukocytes, Mononuclear; N-Acetylneuraminic Acid; Sialic Acids
PubMed: 34611878
DOI: 10.1007/978-1-0716-1685-7_17 -
Journal of Pharmaceutical and... Feb 2020Erythropoiesis stimulating agents (ESAs) are a group of therapeutic glycoproteins used to treat anaemia caused by chronic kidney disease or chemotherapy. A variety of...
Erythropoiesis stimulating agents (ESAs) are a group of therapeutic glycoproteins used to treat anaemia caused by chronic kidney disease or chemotherapy. A variety of ESA products are available in the European Union, including innovator, biosimilar and second-generation medicines. Glycosylation is a critical quality attribute of ESA products, as it has a crucial influence upon in vivo biological activity. In this study, a combination of chromatography and mass spectrometry analysis has been used to characterise and compare the glycosylation profiles of five ESA products; Eprex® (epoetin alfa), NeoRecormon® (epoetin beta), Binocrit® (epoetin alfa biosimilar), Silapo (epoetin alfa biosimilar) and Aranesp® (darbepoetin alfa). The methods utilised include mixed-mode anion-exchange/hydrophilic interaction chromatography (AEX/HILIC-MS) for N-glycan identification and quantitation, and HILIC-MS for O-glycan characterisation. The products exhibit notable differences in N- and O-glycosylation, including attributes such as sialic acid occupation, O-acetylation, N-acetyllactosamine extended antennae and sulphated/penta-sialylated N-glycans, which have the potential to cause divergence of therapeutic potencies. The study highlights the need for continued monitoring of ESA product glycosylation, ideally allied to pharmacological data, in order to ensure consistency and therapeutic equivalence between products and enhance our understanding of ESA structure-activity-relationships.
Topics: Acetylation; Amino Sugars; Biosensing Techniques; Chromatography, High Pressure Liquid; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Glycosylation; Hematinics; Molecular Structure; N-Acetylneuraminic Acid; Polysaccharides; Recombinant Proteins; Tandem Mass Spectrometry
PubMed: 31838284
DOI: 10.1016/j.jpba.2019.113031 -
Carbohydrate Research Sep 2021Polysialic acid (polySia), a homopolymer of α2,8-linked sialic acid residues, modifies a small number of proteins and has central functions in vertebrate signalling.... (Review)
Review
Polysialic acid (polySia), a homopolymer of α2,8-linked sialic acid residues, modifies a small number of proteins and has central functions in vertebrate signalling. Here, we review the regulatory functions of polySia in signalling processes and the immune system of adult humans, as well as functions based on their chemical properties. The main focus will be on the structure-function relationship of polySia with its interaction partners in humans. Recent studies have indicated that the degree of polymerisation is an important parameter that can guide the regulatory effect of polySia in addition to its binding to target proteins. Therefore, the structures of polySia in solution and bound to interaction partners are compared in order to identify the key factors that define binding specificity.
Topics: Animals; Sialic Acids; Signal Transduction
PubMed: 34273862
DOI: 10.1016/j.carres.2021.108376 -
Carbohydrate Research May 2024Sialic acid, the terminal structure of cell surface glycans, has essential functions in regulating immune response, cell-to-cell communication, and cell adhesion. More... (Review)
Review
Sialic acid, the terminal structure of cell surface glycans, has essential functions in regulating immune response, cell-to-cell communication, and cell adhesion. More importantly, an increased level of sialic acid, termed hypersialylation, has emerged as a commonly observed phenotype in cancer. Therefore, targeting sialic acid ligands (sialoglycans) and their receptors (Siglecs) may provide a new therapeutic approach for cancer immunotherapy. We highlight the complexity of the sialic acid metabolism and its involvement in malignant transformation within individual cancer subtypes. In this review, we focus on the dysregulation of sialylation, the intricate nature of sialic acid synthesis, and clinical perspective. We aim to provide a brief insight into the mechanism of hypersialylation and how our understanding of these processes can be leveraged for the development of novel therapeutics.
Topics: Humans; Neoplasms; N-Acetylneuraminic Acid; Animals
PubMed: 38669826
DOI: 10.1016/j.carres.2024.109123 -
Carbohydrate Research Sep 2022Sialic acids have been implicated in cancer initiation, progression, and immune evasion in diverse human malignancies. Sialylation of terminal glycans on cell surface... (Review)
Review
Sialic acids have been implicated in cancer initiation, progression, and immune evasion in diverse human malignancies. Sialylation of terminal glycans on cell surface and secreted glycoproteins is a long-recognized feature of cancer cells. Recently, immune checkpoint inhibitor immunotherapy has tremendously improved the outcomes of patients with various cancers. However, available immunotherapy approaches have had limited efficacy in metastatic castration-resistant prostate cancer. Sialic acid modified glycoproteins in prostate cancers and their interaction with Siglec receptors on tumor infiltrating immune cells might underlie immunosuppressive signaling in prostate cancer. Here, we summarize the function of sialic acids and relevant glycosynthetic enzymes in cancer initiation and progression. We also discuss the possible uses of sialic acids as biomarkers in prostate cancer and the potential methods for targeting Siglec-sialic acid interactions for prostate cancer treatment.
Topics: Biomarkers; Glycoproteins; Humans; Immunologic Factors; Male; N-Acetylneuraminic Acid; Prostatic Neoplasms; Sialic Acid Binding Immunoglobulin-like Lectins; Sialic Acids
PubMed: 35691122
DOI: 10.1016/j.carres.2022.108598 -
ChemMedChem Feb 2022Galectin-8 has gained attention as a potential new pharmacological target for the treatment of various diseases, including cancer, inflammation, and disorders associated...
Galectin-8 has gained attention as a potential new pharmacological target for the treatment of various diseases, including cancer, inflammation, and disorders associated with bone mass reduction. To that end, new molecular probes are needed in order to better understand its role and its functions. Herein we aimed to improve the affinity and target selectivity of a recently published galectin-8 ligand, 3-O-[1-carboxyethyl]-β-d-galactopyranoside, by introducing modifications at positions 1 and 3 of the galactose. Affinity data measured by fluorescence polarization show that the most potent compound reached a K of 12 μM. Furthermore, reasonable selectivity versus other galectins was achieved, making the highlighted compound a promising lead for the development of new selective and potent ligands for galectin-8 as molecular probes to examine the protein's role in cell-based and in vivo studies.
Topics: Fluorescence Polarization; Galectins; Humans; Ligands; Molecular Structure; Muramic Acids
PubMed: 34613662
DOI: 10.1002/cmdc.202100514 -
Biochimica Et Biophysica Acta. General... Jan 2023Metabolite sensing, a fundamental biological process, plays a key role in metabolic signaling circuit rewiring. Hexosamine biosynthetic pathway (HBP) is a glucose... (Review)
Review
Metabolite sensing, a fundamental biological process, plays a key role in metabolic signaling circuit rewiring. Hexosamine biosynthetic pathway (HBP) is a glucose metabolic pathway essential for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which senses key nutrients and integrally maintains cellular homeostasis. UDP-GlcNAc dynamically regulates protein N-glycosylation and O-linked-N-acetylglucosamine modification (O-GlcNAcylation). Dysregulated HBP flux leads to abnormal protein glycosylation, and contributes to cancer development and progression by affecting protein function and cellular signaling. Furthermore, O-GlcNAcylation regulates cellular signaling pathways, and its alteration is linked to various cancer characteristics. Additionally, recent findings have suggested a close association between HBP stimulation and cancer stemness; an elevated HBP flux promotes cancer cell conversion to cancer stem cells and enhances chemotherapy resistance via downstream signal activation. In this review, we highlight the prominent roles of HBP in metabolic signaling and summarize the recent advances in HBP and its downstream signaling, relevant to cancer.
Topics: Humans; Hexosamines; Biosynthetic Pathways; Acetylglucosamine; Neoplasms; Biological Phenomena; Uridine Diphosphate
PubMed: 36228878
DOI: 10.1016/j.bbagen.2022.130250