Glycosyltransferase Inhibitors

Jung, Karl‐Heinz; Schmidt, Richard R.

doi:10.1002/3527602437.ch23

Cited by 20 publications

(8 citation statements)

References 136 publications

(185 reference statements)

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“…In this sense, the Notch-modifying XXYLT1 may be a target for anticancer drug development, and our detailed structure and function studies will facilitate such efforts. Few GT inhibitors have been developed due to the extended GT catalytic site as relatively large oligosaccharide substrates and products have to be accommodated 36 , 37 . In this regard, the recognition interface between XXYLT1 and the acceptor substrate described here may provide a new venue away from the catalytic site for small inhibitor/drug development.…”

Section: Discussionmentioning

confidence: 99%

Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism

Takeuchi

LeBarron

et al. 2015

Nat Chem Biol

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A major remaining question in glycobiology is how a glycosyltransferase (GT) that retains the anomeric linkage of a sugar catalyzes the reaction. Xylosideα1–3 Xylosyltransferase (XXYLT1) is a retaining GT that regulates Notch receptor activation by adding xylose to the Notch extracellular domain. Here, using natural acceptor and donor substrates and active Mus musculus XXYLT1, we report a series of crystallographic snapshots along the reaction, including an unprecedented natural and competent Michaelis reaction complex for retaining enzymes. These structures strongly support the SNi-like reaction as the retaining mechanism for XXYLT1. Unexpectedly the Epidermal Growth Factor-like repeat acceptor substrate undergoes a large conformational change upon binding to the active site, providing a structural basis for substrate specificity. Our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations where dysregulation of Notch is known to cause cancer or developmental disorders.

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Section: Discussionmentioning

confidence: 99%

Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism

Takeuchi

LeBarron

et al. 2015

Nat Chem Biol

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“…They catalyze direct glycosylation of saccharides or proteins to create linear or branched oligosaccharides or glycoproteins . Most interest has been devoted to N‐acetylglucosaminyltransferases I, II, and V, which catalyze the transfer of N‐acetylglucosamine from UDP−N‐acetylglucosamine (UDP‐GlcNAc) to the terminal mannose residue of the core pentasaccharide of glycoproteins at specific positions . This glycosylation is the first step in the development of the oligomannose structures to yield hybrid and complex type of N‐glycans.…”

Section: Introductionmentioning

confidence: 99%

Novel 1‐O‐Sulfono‐α‐d‐Fructofuranosyl Sulfones as Possible Inhibitors of Human GnT‐I Enzyme

et al. 2020

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The present work is dedicated to Professor Ladislav Petruš on the occasion of his 70th birthday.Library of a new class of C-1 monosulfated saccharide derivatives derived from D-fructofuranose have been synthesized as potential GnT-I inhibitors. To increase stability of originally proposed thioglycosides, the compounds were oxi-dized to sulfones bearing three different aglycons; ethyl, 2methyl propyl (isopropyl) and phenyl. Here we present molecular modelling, synthesis and biological assays of prepared compounds. Scheme 2. Reagent and Conditions: a) TBDMSCl, pyridine, À 20°C!r.t., overnight; b) DMTrCl, DMAP, pyridine, r.t. overnight; c) 1 M TBAF in THF, THF, r.t., 90 min; d) BnBr, DMF, NaH, 0°C!r.t., 2 h; e) CF 3 COOH, DCM, triethylsilane, r.t., 1.5-4 h. Scheme 3. Reagent and Conditions: a) SO 3 ⋅py complex, DCM, r.t., 48 h; b) 3chloroperbenzoic acid, DCM, 0°C!r.t., 0.5-1.5 h. Scheme 4. Reagent and Conditions: a) SO 3 .py complex, DCM, r.t., 48 h; b) cat. 10 % Pd/C, H 2 , MeOH, 2 h.

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“…UDP-sugar analogues (sugar donor analogues) design is based on modifications of one of the three building blocks of these molecules: the nucleoside part, the carbohydrate moiety, or the diphosphate connection [ 21 , 22 , 23 , 24 , 25 ]. The pyrophosphate bridge of the sugar donor molecule binds to a bivalent metal ion (Mn 2+ or Mg 2+ ) present in the active site of the enzyme therefore several analogues of UDP-sugar substrates with modifications of the diphosphate moiety have been researched and described [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Preliminary Evaluation of Biological Activity of Glycoconjugates Analogues of Acyclic Uridine Derivatives

et al. 2018

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Herein we present the methodology for obtaining glycosyltransferase inhibitors, analogues of natural enzyme substrates of donor-type: UDP-glucose and UDP-galactose. The synthesis concerned glycoconjugates, nucleoside analogues containing an acyclic ribose mimetic linked to a uracil moiety in their structure. The biological activity of the synthesised compounds was determined on the basis of their ability to inhibit the model enzyme action of β-1,4-galactosyltransferase from bovine milk. The obtained results allowed to expand and supplement the existing library of synthetic compounds that are able to regulate the biological activity of enzymes from the GT class.

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Glycosyltransferase Inhibitors

Cited by 20 publications

References 136 publications

Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism

Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism

Novel 1‐O‐Sulfono‐α‐d‐Fructofuranosyl Sulfones as Possible Inhibitors of Human GnT‐I Enzyme

Synthesis and Preliminary Evaluation of Biological Activity of Glycoconjugates Analogues of Acyclic Uridine Derivatives

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