Chemical Biology and Biomedicine of Glycosylated Natural Compounds

Křen, Vladimı́r

doi:10.1007/978-3-642-56874-9_60

Cited by 8 publications

(1 citation statement)

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“…Glycosylation increases the solubility and stability of the molecule in water, causing higher bioavailability of these compounds from the diet [ 6 ]. Due to altered polarity, size, and structure, access to the lipid phase and hydrophobic free radicals is limited [ 7 ]. Regarding biological activity, glycosylated flavonoids generally display lower antioxidant, antidiabetic, anti-inflammatory, antibacterial, antifungal, antitumor, anticoagulant, antiplatelet, antidegranulating, antitrypanosomal, immunomodulatory, and antitubercular activity compared to the corresponding aglycones [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Novel O-Methylglucoside Derivatives of Flavanone in Interaction with Model Membrane and Transferrin

et al. 2022

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Flavonoids were biotransformed using various microorganisms, in order to obtain new compounds with potentially high biological activity. The aim of this work was to determine and compare the biological activity of four novel 6-methylflavanone O-methylglucosides. The tested compounds have the same flavonoid core structure and an attached O-methylglucose and hydroxyl group at different positions of ring A or B. The studies on their biological activity were conducted in relation to phosphatidylcholine membrane, erythrocytes and their membrane, and with human transferrin. These studies determined the compounds’ toxicity and their impact on the physical properties of the membranes. Furthermore, the binding ability of the compounds to holo-transferrin was investigated. The obtained results indicate that used compounds bind to erythrocytes, change their shape and decrease osmotic fragility but do not disrupt the membrane structure. Furthermore, the used compounds ordered the area of the polar heads of lipids and increased membrane fluidity. However, the results indicate the binding of these compounds in the hydrophilic region of the membranes, like other flavonoid glycosides. The used flavanones formed complexes with transferrin without inducing conformational changes in the protein’s structure. The relationship between their molecular structure and biological activity was discussed.

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Section: Introductionmentioning

confidence: 99%

Novel O-Methylglucoside Derivatives of Flavanone in Interaction with Model Membrane and Transferrin

et al. 2022

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Structure‐Based Enhancement of the First Anomeric Glucokinase

2004

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Many pharmaceutically important compounds derive from carbohydrate-containing natural products, and sugar moieties of these molecules have been proven to play an important role in drug targeting, biological activity, and pharmacology. [1±7] Thus, altering the glycosylation of natural products would significantly contribute to the diversity of novel therapeutics. Among a number of routes for altering glycosylation, naturalproduct glycorandomization is one of the most efficient approaches for complex secondary metabolites.[8±14] In vitro glycorandomization (IVG) technology establishes a promiscuous chemoenzymatic system to quickly build diverse glycorandomized libraries based on natural-product structures (Figure 1 a). This process utilizes chemical synthesis to provide a repertoire of unique sugar precursors, and three promiscuous enzymes to activate (anomeric sugar kinases and nucleotidylyltransferases) and attach (glycosyltransferases) these carbohydrate libraries to various complex natural-product aglycons. Anomeric sugar kinases, as key components of glycorandomization, directly determine the availability of sugar phosphates for chemoenzymatic routes toward complex glycoconjugates. Thus, generation of a flexible sugar kinase capable of accepting a wide array of monosaccharide substrates would directly enhance the efficiency of IVG. Of particular interest are d-glucoconfigured scaffolds given their prevalence in glycosylated natural products (Figure 1 b), [1,3,4,6] glycoproteins, [15±18] as well as many bacterial and eukaryotic cell-surface glycosylation patterns.[18±20]To date, an enzyme capable of d-glucose (Figure 2, 13) anomeric phosphorylation (a glucokinase, or GlcK) remains elusive. Toward this goal, directed evolution of E. coli galactokinase (GalK) led to the Y371H variant with remarkably widened substrate flexibility at C-2, C-3, and C-5 of the sugar. Yet, all sugars tested containing alternative C-4 substitutions (e.g. 4-deoxy-d-galactose, 12 or 13, Figure 2) were not accepted as substrates for the evolved catalyst.[21] As an alternative approach, the recently elucidated structure of Lactococcus lactis GalK provides a template for rational sugar kinase engineering.[22] The L. lactis GalK structure reveals that the strongly conserved active-site residues Asp45 and Tyr233 hydrogen bond with the critical galactose C-4 axial hydroxyl.[22] While a recent saturation mutagenesis of the equivalent residues within the E. coli GalK revealed the role of the active-site tyrosine to be hydrophobic stacking and expanded the substrate range to include 12, [23] a GlcK has still not been found. To continue our quest for an anomeric GlcK and further explore the relevance of the L. lactis structural model to other GalKs, we report the generation and characterization of the Y385H L. lactis GalK mutant-the promiscuous E. coli equivalent of which was discovered through directed evolution.[21] Remarkably, we reveal that this L. lactis variant displays a substantial degree of kinase activity toward several C-4-substitut...

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Glycosidases

Divakar¹

2012

Enzymatic Transformation

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Chemical Biology and Biomedicine of Glycosylated Natural Compounds

Cited by 8 publications

References 162 publications

Novel O-Methylglucoside Derivatives of Flavanone in Interaction with Model Membrane and Transferrin

Novel O-Methylglucoside Derivatives of Flavanone in Interaction with Model Membrane and Transferrin

Structure‐Based Enhancement of the First Anomeric Glucokinase

Glycosidases

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