- Semi-Synthetic Sialic Acid Probes for Challenging the Substrate Promiscuity of Enzymes in the Sialoconjugation Pathway
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A series of unusual sialic acid analogs were prepared using a semi-synthetic strategy. Truncation of natural N-acetylneuraminic acid was followed by diastereoselective carbon backbone reconstruction using Barbier-type carboligations as well as different functional group interconversions, which provided access to a variety of functional motifs in the terminal carbon backbone, including examples of saturated and unsaturated, linear and branched alkyl chains, partially deoxygenated sialic acids, sialic diacids and a first truncated legionaminic acid analog. The synthetic sialic acid probes were studied for nucleotide activation by the CMP-sialic acid synthetase from Neisseria meningitidis using a universal pH-shift assay for kinetic analysis. One-pot enzymatic nucleotide activation and sialyltransfer to lactose was performed using a selection of five probes together with an engineered α2,3-sialyltransferase from Photobacterium phosphoreum to furnish five new-to-nature analogs of the GM3 trisaccharide, which were finally utilized to test the substrate tolerance of two bacterial sialidases. The obtained set of sialic acid analogs and neo-sialocojugates provides interesting opportunities for further glycobiology studies. (Figure presented.).
- Mertsch, Alexander,Poschenrieder, Silvan,Fessner, Wolf-Dieter
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- Differential recognition of diet-derived Neu5Gc-Neoantigens on glycan microarrays by carbohydrate-specific pooled human IgG and IgA antibodies
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Sialic acids (Sias) cover vertebrate cell surface glycans. N-Acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc) are common Sia in mammals. Humans cannot synthesize Neu5Gc but accumulate it on cells through red-meat rich diets, generating numerous immunogenic Neu5Gc-neoantigens. Consequently, humans have diverse anti-Neu5Gc antibodies affecting xenotransplantation, cancer, atherosclerosis, and infertility. Anti-Neu5Gc antibodies circulate as IgG, IgM, and IgA isotypes; however, repertoires of the different isotypes in a large population have not been studied yet. Here, we used glycan microarrays to investigate anti-Neu5Gc IgGs and IgAs in intravenous immunoglobulin (IVIG) or pooled human IgA, respectively. Binding patterns on microarrays fabricated with Neu5Gc- and Neu5Ac-glycans, together with inhibition assays, revealed that different IVIG preparations have highly specific anti-Neu5Gc IgG reactivity with closely related repertoires, while IgAs show cross-reactivity against several Neu5Ac-glycans. Such different anti-Neu5Gc IgG/IgA repertoires in individuals could possibly mediate distinctive effects on human diseases.
- Leviatan Ben-Arye, Shani,Schneider, Christoph,Yu, Hai,Bashir, Salam,Chen, Xi,Von Gunten, Stephan,Padler-Karavani, Vered
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p. 1565 - 1574
(2019/05/22)
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- SIALIDASE INHIBITORS AND PREPARATION THEREOF
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New 2-deoxy-2,3-dehydro-sialic acids and 2,7-anhydro-sialic acids, which are useful as sialidase inhibitors, and enzymatic methods for preparing them are disclosed. The methods include forming a reaction mixture comprising a glycoside acceptor, a sialic acid donor, and a sialyltransferase; maintaining the reaction mixture under conditions sufficient to form a sialoside; and contacting the sialoside with a Streptococcus pneumoniae sialidase to form the sialic acid product. Methods for the inhibition and sialidases and the treatment of cancer and infectious diseases are also disclosed.
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- Tuning mechanism-based inactivators of neuraminidases: Mechanistic and structural insights
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3-Fluorosialosyl fluorides are inhibitors of sialidases that function by the formation of a long-lived covalent active-site adduct and have potential as therapeutics if made specific for the pathogen sialidase. Surprisingly, human Neu2 and the Trypanosoma cruzi trans-sialidase are inactivated more rapidly by the reagent with an equatorial fluorine at C3 than by its axial epimer, with reactivation following the same pattern. To explore a possible stereoelectronic basis for this, rate constants for spontaneous hydrolysis of the full series of four 3-fluorosialosyl fluorides were measured, and ground-state energies for each computed. The alpha (equatorial) anomeric fluorides hydrolyze more rapidly than their beta anomers, consistent with their higher ground-state energies. However ground-state energies do not explain the relative spontaneous reactivities of the 3-fluoro-epimers. The three-dimensional structures of the two 3-fluoro-sialosyl enzyme intermediates of human Neu2 were solved, revealing key stabilizing interactions between Arg21 and the equatorial, but not the axial, fluorine. Because of changes in geometry these interactions will increase at the transition state, likely explaining the difference in reaction rates. Understanding reactivity and selectivity: The mechanistic basis for the surprisingly different rates of inactivation and reactivation of human and Trypanosoma cruzi sialidases by the two 3-fluoro epimers of 2,3-difluorosialic acid was probed through spontaneous hydrolysis kinetics, computational analysis, and X-ray crystallography.
- Buchini, Sabrina,Gallat, Francois-Xavier,Greig, Ian R.,Kim, Jin-Hyo,Wakatsuki, Soichi,Chavas, Leonard M. G.,Withers, Stephen G.
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p. 3382 - 3386
(2014/04/03)
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- CST-II's recognition domain for acceptor substrates in α-(2→8)- sialylations
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CST-II is a bacterial sialyltransferase known for its ability to perform α-(2→8)-sialylations using GM3 related trisaccharide substrates. Previously, we probed the enzyme's substrate specificity and developed an efficient synthesis for α-(2→8)-oligosialos
- Li, Wenling,Zhang, Ping,Zuccolo, Amir J.,Zheng, Ruxiang Blake,Ling, Chang-Chun
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p. 1692 - 1704
(2011/12/02)
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- Molecular recognition of sialic acid end groups by phenylboronates
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A multinuclear NMR study of the interaction between phenylboronic acid (PBA) and sialic acid (Neu5 Ac) has been performed. The latter compound is known to be over-expressed on the cell surface of tumor cells. The results of this investigation suggest that the binding of PBA to sialic acid is pH dependent. 17O NMR experiments with glycolic acid as the model compound prove that an interaction at the α-hydroxycarboxylate occurs at pH 9, while a study with threonic and erythronic acids shows that the PBA group interacts selectively with the vicinal diol functions at higher pH. Similarly, Neu5 Ac binds PBA through its α-hydroxycarboxylate at low pH ( 9) and through its glycerol side chain at higher pH values. The conditional stability constant of the phenylboronate ester at pH 7.4 is 11.4. On cell surfaces, sialic acid is connected to the neighboring sugar unit through the 2-hydroxy group. To mimic this the 2-α-O-methyl derivative of Neu5 Ac was included in this study. The erythro configuration of the hydroxy substituants prevents stable-complex formation at positions C7 and C8 and, consequently, the strongest interaction is observed at positions C8 and C9, leading to a five-membered 2-boron-1,3-dioxalate. In addition, a relatively small amount of the C7-C9 six-membered complex was observed. Molecular modeling studies confirm that the C8-C9 boronate complex has the lowest energy.
- Djanashvili, Kristina,Frullano, Luca,Peters, Joop A.
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p. 4010 - 4018
(2007/10/03)
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- Ring opening of sialyllactones with glycine esters: Synthesis of selectively protected glycinyl-NeuAc saccharopeptides
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Two different classes of sialyllactones were prepared as potential substrates for ring opening reactions with naturally occurring amino acids. The sialyllactones underwent reaction with Glycine ethyl ester hydrochloride salt to afford selectively protected glycine-NeuAc adducts. The reactions could be performed on NeuAc derivatives capable of serving as glycosylation donors. These compounds represent a new class of saccharopeptides, composed of sugar amino acids and naturally occurring amino acids.
- Gervay, Jacquelyn,Ramamoorthy,Mamuya, Nellie N.
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p. 11039 - 11048
(2007/10/03)
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- Synthesis of 13C enriched sialyllactones and their characterization using isotope edited inverse detected NMR spectroscopy
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13C enriched monosaccharide based sialyllactones were prepared in order to perform isotope edited NMR experiments for their characterization. In the inverse detected experiments only those protons long-range coupled to the enriched nuclei are detected, providing a potentially powerful tool for studying in vitro sialyllactone formation.
- Gervay, Jacquelyn,Mamuya, Nellie N.,Barber, Andrew R.
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p. 1865 - 1868
(2007/10/03)
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- Synthesis of potential inhibitors of hemagglutination by influenza virus: Chemoenzymic preparation of N-5 analogs of N-acetylneuraminic acid
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A chemoenzymic route to neuraminic acid 2 is described. This method is based on conversion of N-carbobenzoxymannosamine (ManCBz) 3 to N-carbobenzoxyneuraminic acid (Neu5CBz) 4, catalyzed by Neu5Ac aldolase. The Neu5CBz 4 was converted to the α-methyl glyc
- Sparks, Michelle A.,Williams, Kevin W.,Lukacs, Christine,Schrell, Andreas,Priebe, Gregory,Spaltenstein, Andreas,Whitesides, George M.
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- Synthesis of sialic acid through aldol condensation of glucose with oxalacetic acid
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N-Acetylneuraminic acid (sialic acid) 1 was synthesized through relatively short steps from D-glucose via a key intermediate 1,5-lactone derivative obtained from the pyranose isomer of the aldol condensation products of D-glucose with oxalacetic acid.
- Yamamoto,Teshima,Inami,Shiba
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p. 325 - 328
(2007/10/02)
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- Structural Variations of N-Acetylneuraminic Acid, 14. Synthesis of the &β-Methyl Ketosides of 4-oxo-, 7-oxo-, and 8-oxo-N-Acetylneuraminic Acid and the Corresponding 7,7- and 8,8-Dimethoxy Derivatives Their Behaviour Towards CMP-Sialate Synthase
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The 4-, 7-, and 8-oxo-sialic acid β-methyl ketosides 7, 10a, and 11a were obtained by transformation of easily available derivatives of N-acetylneuraminic acid (1a).The carbonyl migration from C-7 to C-8 can be carried out under well-defined conditions wi
- Hartmann, Michael,Christian, Rudolf,Zbiral, Erich
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- (13)C-N.M.R.-SPECTRAL STUDY OF THE MODE OF BINDING OF Mn2+ AND Gd3+ TO N-ACETYL-α-NEURAMINIC ACID
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Natural-abundance, (13)C-n.m.r. spectroscopy was used to study the binding of Gd3+ and Mn2+ to N-acetyl-2-O-methyl-α-neuraminic acid (2) and to methyl N-acetyl-2-O-methyl-α-neuraminate (3).The results showed that Gd3+ , and Mn2+ bind in the region of the glycerol-1-yl side-chain and the 5-acetamido group of compound 3.When the α-NeuAc derivative contains a carboxylate anion, as in compound 2, multiple, metal-ion-binding sites occur, involving the head (the carboxyl end) and the tail (the glycerol-1-yl and 5-acetamido groups) of the molecule.
- Daman, Marsha E.,Dill, Kilian
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