Abstract
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.
Highlights
Glycosyltransferases (GTs), a superfamily of enzymes, are involved in synthesising the carbohydrate moieties of glycoproteins, glycolipids, and glycosaminoglycans, which are involved in many important biological functions
Taking into account that the acceptor binding site is created by a conformational change after sugar nucleotide andand metal ion inion theinactive site of the in our approach ordered binding bindingofofthe the sugar nucleotide metal the active siteenzyme, of the enzyme, in our to design inhibitors, we focus on the synthesis of the nucleoside part of the inhibitor strongly bonded approach to design inhibitors, we focus on the synthesis of the nucleoside part of the inhibitor by a flexible loop by andaweakly with a metal ion, sowith as thea creation of the catalytic enzyme strongly bonded flexiblebonded loop and weakly bonded metal ion, so as the creation ofpart the will be difficult
We focused on a simple and efficient synthesis of the analogues of a natural glycosyl donor substrate of β4GalT
Summary
Glycosyltransferases (GTs), a superfamily of enzymes, are involved in synthesising the carbohydrate moieties of glycoproteins, glycolipids, and glycosaminoglycans, which are involved in many important biological functions. One of the most extensively studied and characterised glycosyltransferase is β-1,4-galactosyltransferase I (β4GalT) This enzyme transfers D-galactose moiety from a donor molecule to a hydroxyl group of a specific acceptor molecule which can be an oligosaccharide, a protein or a lipid [16,17]. The long flexible loop contains the primary metal binding site at its terminal hinge region. Both flexible loops undergo a notable conformational change from an open to a closed conformation upon binding of sugar–nucleotide and metal ion
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