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Nature Communications Mar 2023The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the...
The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the role of neuraminidase 1 (NEU1) in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models. We find that NEU1 is significantly upregulated in the fibrotic kidneys of patients and mice. Functionally, tubular epithelial cell-specific NEU1 knockout inhibits epithelial-to-mesenchymal transition, inflammatory cytokines production, and collagen deposition in mice. Conversely, NEU1 overexpression exacerbates progressive renal fibrosis. Mechanistically, NEU1 interacts with TGFβ type I receptor ALK5 at the 160-200aa region and stabilizes ALK5 leading to SMAD2/3 activation. Salvianolic acid B, a component of Salvia miltiorrhiza, is found to strongly bind to NEU1 and effectively protect mice from renal fibrosis in a NEU1-dependent manner. Collectively, this study characterizes a promotor role for NEU1 in renal fibrosis and suggests a potential avenue of targeting NEU1 to treat kidney diseases.
Topics: Animals; Male; Mice; Fibrosis; Gene Expression; Kidney; Kidney Diseases; Mice, Inbred C57BL; Neuraminidase; Ureteral Obstruction
PubMed: 36973294
DOI: 10.1038/s41467-023-37450-8 -
Influenza and Other Respiratory Viruses Jul 2012Influenza neuraminidase is the target of two licensed antivirals that have been very successful, with several more in development. However, neuraminidase has been... (Review)
Review
Influenza neuraminidase is the target of two licensed antivirals that have been very successful, with several more in development. However, neuraminidase has been largely ignored as a vaccine target despite evidence that inclusion of neuraminidase in the subunit vaccine gives increased protection. This article describes current knowledge on the structure, enzyme activity, and antigenic significance of neuraminidase.
Topics: Antiviral Agents; Enzyme Inhibitors; Influenza Vaccines; Models, Molecular; Neuraminidase; Orthomyxoviridae; Protein Conformation; Viral Proteins
PubMed: 22085243
DOI: 10.1111/j.1750-2659.2011.00304.x -
Journal of Medicinal Chemistry Oct 2022Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By... (Review)
Review
Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.
Topics: Humans; Neuraminidase; Zanamivir; Oseltamivir; N-Acetylneuraminic Acid; Enzyme Inhibitors; Sialic Acids; Antiviral Agents; Biological Products
PubMed: 36252951
DOI: 10.1021/acs.jmedchem.2c01258 -
Science Advances May 2023Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases...
Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases (sialidases). Neuraminidase-1 (sialidase-1 or NEU1) is a ubiquitously expressed mammalian sialidase located in lysosomes and on the cell membrane. Because of its modulation of multiple signaling processes, it is a potential therapeutic target for cancers and immune disorders. Genetic defects in NEU1 or in its protective protein cathepsin A (PPCA, CTSA) cause the lysosomal storage diseases sialidosis and galactosialidosis. To further our understanding of this enzyme's function at the molecular level, we determined the three-dimensional structure of murine NEU1. The enzyme oligomerizes through two self-association interfaces and displays a wide substrate-binding cavity. A catalytic loop adopts an inactive conformation. We propose a mechanism of activation involving a conformational change in this loop upon binding to its protective protein. These findings may facilitate the development of selective inhibitor and agonist therapies.
Topics: Animals; Mice; Cell Membrane; Lysosomes; Neuraminidase; Sialic Acids
PubMed: 37205763
DOI: 10.1126/sciadv.adf8169 -
Frontiers in Cellular and Infection... 2019is an important human and animal pathogen that is the primary causative agent of necrotizing enteritis and enterotoxemia in many types of animals; it causes traumatic... (Review)
Review
is an important human and animal pathogen that is the primary causative agent of necrotizing enteritis and enterotoxemia in many types of animals; it causes traumatic gas gangrene in humans and animals and is associated with cases of food poisoning in humans. produces a variety of toxins as well as many enzymes, including three sialidases, NanH, NanI, and NanJ. Sialidases could be important virulence factors that promote the pathogenesis of . Among them, NanI promotes the colonization of in the intestinal tract and enhances the cytotoxic activity and association of several major toxins with host cells. In recent years, studies on the structure and functions of sialidases have yielded interesting results, and the functions of sialic acid and sialidases in bacterial pathogenesis have become a hot research topic. An in-depth understanding and additional studies of sialidases will further elucidate mechanisms of pathogenesis and could promote the development and clinical applications of sialidase inhibitors. This article reviews the structural characteristics, expression regulation, roles of sialidases in pathogenesis, and effects of their inhibitors.
Topics: Animals; Bacterial Adhesion; Bacterial Toxins; Clostridium Infections; Clostridium perfringens; Enzyme Inhibitors; Flavanones; Humans; Intestines; Models, Molecular; N-Acetylneuraminic Acid; Neuraminidase; Protein Conformation; Virulence Factors
PubMed: 31998664
DOI: 10.3389/fcimb.2019.00462 -
Glycoconjugate Journal Aug 2018The sialylated glyconjugates (SGC) are found in abundance on the surface of brain cells, where they form a dense array of glycans mediating cell/cell and cell/protein... (Review)
Review
The sialylated glyconjugates (SGC) are found in abundance on the surface of brain cells, where they form a dense array of glycans mediating cell/cell and cell/protein recognition in numerous physiological and pathological processes. Metabolic genetic blocks in processing and catabolism of SGC result in development of severe storage disorders, dominated by CNS involvement including marked neuroinflammation and neurodegeneration, the pathophysiological mechanisms of which are still discussed. SGC patterns in the brain are cell and organelle-specific, dynamic and maintained by highly coordinated processes of their biosynthesis, trafficking, processing and catabolism. The changes in the composition of SGC during development and aging of the brain cannot be explained based solely on the regulation of the SGC-synthesizing enzymes, sialyltransferases, suggesting that neuraminidases (sialidases) hydrolysing the removal of terminal sialic acid residues also play an essential role. In the current review we summarize the roles of three mammalian neuraminidases: neuraminidase 1, neuraminidase 3 and neuraminidase 4 in processing brain SGC. Emerging data demonstrate that these enzymes with different, yet overlapping expression patterns, intracellular localization and substrate specificity play essential roles in the physiology of the CNS.
Topics: Animals; Brain; Glycoconjugates; Humans; Neuraminidase; Neurodegenerative Diseases
PubMed: 30088207
DOI: 10.1007/s10719-018-9837-4 -
The Journal of Physical Chemistry... Nov 2023All protein simulations are conducted with varying degrees of simplification, oftentimes with unknown ramifications about how these simplifications affect the...
All protein simulations are conducted with varying degrees of simplification, oftentimes with unknown ramifications about how these simplifications affect the interpretability of the results. In this work, we investigated how protein glycosylation and lateral crowding effects modulate an array of properties characterizing the stability and dynamics of influenza neuraminidase. We constructed three systems: (1) glycosylated neuraminidase in a whole virion (i.e., crowded membrane) environment, (2) glycosylated neuraminidase in its own lipid bilayer, and (3) unglycosylated neuraminidase in its own lipid bilayer. We saw that glycans tend to stabilize the protein structure and reduce its conformational flexibility while restricting the solvent movement. Conversely, a crowded membrane environment encouraged exploration of the free energy landscape and a large-scale conformational change, while making the protein structure more compact. Understanding these effects informs what factors one must consider in attempting to recapture the desired level of physical accuracy.
Topics: Humans; Influenza, Human; Neuraminidase; Glycosylation; Lipid Bilayers; Viral Proteins
PubMed: 37903229
DOI: 10.1021/acs.jpclett.3c02524 -
Biochemical Society Transactions Feb 2016Sialidases are a large group of enzymes, the majority of which catalyses the cleavage of terminal sialic acids from complex carbohydrates on glycoproteins or... (Review)
Review
Sialidases are a large group of enzymes, the majority of which catalyses the cleavage of terminal sialic acids from complex carbohydrates on glycoproteins or glycolipids. In the gastrointestinal (GI) tract, sialic acid residues are mostly found in terminal location of mucins via α2-3/6 glycosidic linkages. Many enteric commensal and pathogenic bacteria can utilize sialic acids as a nutrient source, but not all express the sialidases that are required to release free sialic acid. Sialidases encoded by gut bacteria vary in terms of their substrate specificity and their enzymatic reaction. Most are hydrolytic sialidases, which release free sialic acid from sialylated substrates. However, there are also examples with transglycosylation activities. Recently, a third class of sialidases, intramolecular trans-sialidase (IT-sialidase), has been discovered in gut microbiota, releasing (2,7-anhydro-Neu5Ac) 2,7-anydro-N-acetylneuraminic acid instead of sialic acid. Reaction specificity varies, with hydrolytic sialidases demonstrating broad activity against α2,3-, α2,6- and α2,8-linked substrates, whereas IT-sialidases tend to be specific for α2,3-linked substrates. In this mini-review, we summarize the current knowledge on the structural and biochemical properties of sialidases involved in the interaction between gut bacteria and epithelial surfaces.
Topics: Bacteria; Gastrointestinal Tract; Glycoproteins; Hydrolysis; Neuraminidase; Sialic Acids
PubMed: 26862202
DOI: 10.1042/BST20150226 -
Influenza and Other Respiratory Viruses Jan 2013There are two major classes of antivirals available for the treatment and prevention of influenza, the M2 inhibitors and the neuraminidase inhibitors (NAIs). The M2... (Review)
Review
There are two major classes of antivirals available for the treatment and prevention of influenza, the M2 inhibitors and the neuraminidase inhibitors (NAIs). The M2 inhibitors are cheap, but they are only effective against influenza A viruses, and resistance arises rapidly. The current influenza A H3N2 and pandemic A(H1N1)pdm09 viruses are already resistant to the M2 inhibitors as are many H5N1 viruses. There are four NAIs licensed in some parts of the world, zanamivir, oseltamivir, peramivir, and a long-acting NAI, laninamivir. This review focuses on resistance to the NAIs. Because of differences in their chemistry and subtle differences in NA structures, resistance can be both NAI- and subtype specific. This results in different drug resistance profiles, for example, the H274Y mutation confers resistance to oseltamivir and peramivir, but not to zanamivir, and only in N1 NAs. Mutations at E119, D198, I222, R292, and N294 can also reduce NAI sensitivity. In the winter of 2007-2008, an oseltamivir-resistant seasonal influenza A(H1N1) strain with an H274Y mutation emerged in the northern hemisphere and spread rapidly around the world. In contrast to earlier evidence of such resistant viruses being unfit, this mutant virus remained fully transmissible and pathogenic and became the major seasonal A(H1N1) virus globally within a year. This resistant A(H1N1) virus was displaced by the sensitive A(H1N1)pdm09 virus. Approximately 0.5-1.0% of community A(H1N1)pdm09 isolates are currently resistant to oseltamivir. It is now apparent that variation in non-active site amino acids can affect the fitness of the enzyme and compensate for mutations that confer high-level oseltamivir resistance resulting in minimal impact on enzyme function.
Topics: Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza B virus; Influenza, Human; Neuraminidase
PubMed: 23279894
DOI: 10.1111/irv.12047 -
Drug Design, Development and Therapy 2018The demand for novel anti-influenza drugs persists, which is highlighted by the recent pandemics of influenza affecting thousands of people across the globe. One of the... (Review)
Review
The demand for novel anti-influenza drugs persists, which is highlighted by the recent pandemics of influenza affecting thousands of people across the globe. One of the approaches to block the virus spreading is inhibiting viral sialidase (neuraminidase). This enzyme cleaves the sialic acid link between the newly formed virions and the host cell surface liberating the virions from the cell and maintaining the cycle of infection. Viral neuraminidases appear therefore as attractive therapeutic targets for preventing further spread of influenza infection. Compared to ion channel blockers that were the first approved anti-influenza drugs, neuraminidase inhibitors are well tolerated and target both influenza A and B viruses. Moreover, neuraminidase/sialidase inhibitors may be useful for managing some other human pathologies, such as cancer. In this review, we discuss the available knowledge on neuraminidase or sialidase inhibitors, their design, clinical application, and the current challenges.
Topics: Animals; Antiviral Agents; Enzyme Inhibitors; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Neuraminidase
PubMed: 30349196
DOI: 10.2147/DDDT.S176220