A New Concept for Glycosyltransferase Inhibitors: Nonionic Mimics of the Nucleotide Donor of the Human Blood Group B Galactosyltransferase

Schaefer, Katrin; Albers, Joachim; Sindhuwinata, Nora; Peters, Thomas; Meyer, Bernd

doi:10.1002/cbic.201100642

Cited by 21 publications

(22 citation statements)

References 32 publications

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“…[77] In 2012, Meyer andc o-workers reported that pentitol-linkedu ric acid derivatives 104 and 105 (acyclic nucleoside analogues in which the nucleobase had also been replaced by a7 ,9-dihydro-1H-purine-2,6,8(3 H)-trione ring) showed similar bindinga ffinities to that of the natural substrate (UDPÀGal) to human blood group Bg lycosyltranferase (GTB) in the presence of Mg II . [78] 6-Chloronitrouracil (99)w as condensed with d-arabinitylamine (100)t op rovide compound 101,w hichw as transformed into compound 103 in two steps. Further intramolecular cyclization induced by sodium ethoxide provided compound 104.…”

Section: Modification At the Riboseunit And The Nucleobasementioning

confidence: 99%

Nucleoside Diphosphate Sugar Analogues that Target Glycosyltransferases

et al. 2016

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Glycosyltransferases (GTs) are enzymes that transfer carbohydrates to ar ange of substrates and they play af undamental role in the recognition processes associated with severald iseases.T he design of glycomimeticso fn ucleoside diphosphate( NDP) sugars-the natural substrates that act as inhibitors or modulators of GTs-is not only necessary for the development of glycan-based therapeutic drugs, but is also ac rucial toolf or understanding their mechanismso fa ction.W hilst al arge number of inhibitors that consist of modifications of the carbohydrate unit and the pyrophosphate linkageh ave been designed,l ess attention has been paidt om odifications at the ribose moiety and the nucleobase. However,i nr ecent years, promising results have been obtainedt hrough such variations, which were prompted by the initial interest in the photolabeling of enzymes to study their structure. In this Focus Review,w e survey recentp rogress in the synthesis of NDP-sugar analogues that are modified at the ribose moiety or at the heterocyclic base.The ORCID identification number(s) for the author(s) of this articlecan be found under http://dx.

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Section: Modification At the Riboseunit And The Nucleobasementioning

confidence: 99%

Nucleoside Diphosphate Sugar Analogues that Target Glycosyltransferases

et al. 2016

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“…[28,31,[33][34][35][36] The main drawback of this approach is the anionic character of the inhibitors, which precludes their entry into cells due to repulsion by the anionic phospholipid bilayer. The preparation of neutral inhibitors of GTs [14,[37][38][39][40][41][42][43][44][45][46] is emerging as a promising strategy for in vivo biological applications. Because the diphosphate unit of the NDP sugars interacts with cations in metal-dependent GTs, any surrogate of this moiety should be capable of coordinating to the metal.…”

Section: Introductionmentioning

confidence: 99%

Design of Glycosyltransferase Inhibitors: Pyridine as a Pyrophosphate Surrogate

Wang

Cuesta-Seijo

Lafont

et al. 2013

Chemistry A European J

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A series of ten glycosyltransferase inhibitors has been designed and synthesized by using pyridine as a pyrophosphate surrogate. The series was prepared by conjugation of carbohydrate, pyridine, and nucleoside building blocks by using a combination of glycosylation, the Staudinger-Vilarrasa amide-bond formation, and azide-alkyne click chemistry. The compounds were evaluated as inhibitors of five metal-dependent galactosyltransferases. Crystallographic analyses of three inhibitors complexed in the active site of one of the enzymes confirmed that the pyridine moiety chelates the Mn(2+) ion causing a slight displacement (2 Å) from its original position. The carbohydrate head group occupies a different position than in the natural uridine diphosphate (UDP)-Gal substrate with little interaction with the enzyme.

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“…Non-competitive inhibitors have also been described that potentially alter the structure of the enzyme leading to inactive proteins ( 77 , 78 ). Modified nucleotide sugars are often recognized by GTs leading to transfer of unnatural sugars ( 143 ). Fluorescent groups modifying the base of the sugar-nucleotide can be useful as indicators of binding ( 144 ).…”

Section: Glycosyltransferase Inhibitorsmentioning

confidence: 99%

Crossroads between Bacterial and Mammalian Glycosyltransferases

Brockhausen

2014

Front. Immunol.

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Bacterial glycosyltransferases (GT) often synthesize the same glycan linkages as mammalian GT; yet, they usually have very little sequence identity. Nevertheless, enzymatic properties, folding, substrate specificities, and catalytic mechanisms of these enzyme proteins may have significant similarity. Thus, bacterial GT can be utilized for the enzymatic synthesis of both bacterial and mammalian types of complex glycan structures. A comparison is made here between mammalian and bacterial enzymes that synthesize epitopes found in mammalian glycoproteins, and those found in the O antigens of Gram-negative bacteria. These epitopes include Thomsen–Friedenreich (TF or T) antigen, blood group O, A, and B, type 1 and 2 chains, Lewis antigens, sialylated and fucosylated structures, and polysialic acids. Many different approaches can be taken to investigate the substrate binding and catalytic mechanisms of GT, including crystal structure analyses, mutations, comparison of amino acid sequences, NMR, and mass spectrometry. Knowledge of the protein structures and functions helps to design GT for specific glycan synthesis and to develop inhibitors. The goals are to develop new strategies to reduce bacterial virulence and to synthesize vaccines and other biologically active glycan structures.

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A New Concept for Glycosyltransferase Inhibitors: Nonionic Mimics of the Nucleotide Donor of the Human Blood Group B Galactosyltransferase

Cited by 21 publications

References 32 publications

Nucleoside Diphosphate Sugar Analogues that Target Glycosyltransferases

Nucleoside Diphosphate Sugar Analogues that Target Glycosyltransferases

Design of Glycosyltransferase Inhibitors: Pyridine as a Pyrophosphate Surrogate

Crossroads between Bacterial and Mammalian Glycosyltransferases

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