Enzymatic glycosylation of multivalent scaffolds
10 May 2013-Chemical Society Reviews (The Royal Society of Chemistry)-Vol. 42, Iss: 11, pp 4774-4797
TL;DR: Though there is still a long way until the Nature's ideal of multivalent glycans is achievable in the laboratory, the sketched pathways to multivalent glycostructures open tremendous possibilities for the future glycobiological research.
Abstract: The design of glycoclusters, glycodendrimers, glycopolymers and other complex glycostructures that mimic the multivalent carbohydrate display on the cell surface is of immense interest for diagnosis and therapy. This review presents a detailed insight into the exciting possibilities of multiple glycosylation using enzymes, particularly glycosyltransferases (EC 2.4). A representative choice of available scaffolds for the enzyme action is practically infinite and comprises synthetic polymers, carbosilane dendrimers, multiantennary glycans or hyperbranched conjugates. The introduced glyco-patterns range from common sialyl Lewis(x) and sialyl lacto-chains to chemically functionalized carbohydrate units for detection purposes. The possibilities of in vitro enzymatic production of N- and O-glycans and other natural polymers are also discussed. In harmony with their natural tasks, glycosyltransferases may in vitro complete the imperfect glycosylation pattern of proteins, recombinantly produced in pro- and eukaryotic hosts. What is more, the required enzymatic battery may be directly co-expressed with the protein, in order to elegantly accomplish the production of eukaryotic glycans. Ingenious metabolic labeling enables facile imaging of glycostructures. The boom of glycoarray technology opens vast possibilities in high-throughput screening for novel enzymes and substrate specificities as well as in the synthesis. Though there is still a long way until the Nature's ideal of multivalent glycans is achievable in the laboratory, the sketched pathways to multivalent glycostructures open tremendous possibilities for the future glycobiological research.
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TL;DR: A review of the recent developments in liquid phase chemical conversions of monosaccharides, disaccharide, and polysaccharides can be found in this paper, followed by a process-driven approach where the existing carbohydrate conversion pathways are classified according to the types of chemical processes involved.
271 citations
TL;DR: This review is focused on smaller multivalent structures such as glycoclusters emphasizing carbohydrate-centered and heteromultivalent glycoconjugates and approaches to organize multivalency.
Abstract: The interactions of cell surface carbohydrates as well as of soluble glycoconjugates with their receptor proteins rule fundamental processes in cell biology. One of the supramolecular principles underlying and regulating carbohydrate recognition is multivalency. Many multivalent glycoconjugates have therefore been synthesized to study multivalency effects operative in glycobiology. This review is focused on smaller multivalent structures such as glycoclusters emphasizing carbohydrate-centered and heteromultivalent glycoconjugates. We are discussing primary, secondary and tertiary structural aspects including approaches to organize multivalency.
164 citations
TL;DR: This review focuses on the chemistry of biomolecule conjugation and provides a comprehensive overview of the key strategies for achieving controlled biomaterial functionalization and highlights the importance of carefully considering the impact and suitability of a particular technique during biomaterial design.
Abstract: The conjugation of biomolecules can impart materials with the bioactivity necessary to modulate specific cell behaviors While the biological roles of particular polypeptide, oligonucleotide, and glycan structures have been extensively reviewed, along with the influence of attachment on material structure and function, the key role played by the conjugation strategy in determining activity is often overlooked In this review, we focus on the chemistry of biomolecule conjugation and provide a comprehensive overview of the key strategies for achieving controlled biomaterial functionalization No universal method exists to provide optimal attachment, and here we will discuss both the relative advantages and disadvantages of each technique In doing so, we highlight the importance of carefully considering the impact and suitability of a particular technique during biomaterial design
151 citations
TL;DR: The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed in this article, where principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized.
Abstract: The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential “late-stage functionalization” exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C–H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C–C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-sel...
138 citations
TL;DR: Progress and limitations are shown in the development of Leloir glycosyltransferases into robust biocatalytic systems for use in Glycosylations for chemical production.
Abstract: Glycosylation is a chemical transformation that is centrally important in all glycoscience and related technologies. Catalysts offering good control over reactivity and selectivity in synthetic glycosylations are much sought. The enzymes responsible for glycosylations in natural biosynthesis are sugar-nucleotide-dependent (Leloir) glycosyltransferases. Discovery-oriented synthesis and pilot batch production of oligosaccharides and glycosylated natural products have previously relied on Leloir glycosyltransferases. However, despite their perceived synthetic utility, Leloir glycosyltransferases are yet to see widespread application in industrial biocatalysis. Here we show progress and limitations in the development of Leloir glycosyltransferases into robust biocatalytic systems for use in glycosylations for chemical production. Obtaining highly active and stable (whole-cell) catalysts that can promote the desired glycosylation(s) coupled to an in situ sugar nucleotide supply remains a difficult problem. Opt...
112 citations
References
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TL;DR: With the steady increase in sequence and structural data, it is suggested that the enzyme classification system should perhaps be revised.
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TL;DR: The expected two-step double-displacement mechanism is rendered less likely by the lack of conserved architecture in the region where a catalytic nucleophile would be expected, and a mechanism involving a short-lived oxocarbenium ion intermediate now seems the most likely, with the leaving phosphate serving as the base.
Abstract: Glycosyltransferases catalyze glycosidic bond formation using sugar donors containing a nucleoside phosphate or a lipid phosphate leaving group. Only two structural folds, GT-A and GT-B, have been identified for the nucleotide sugar-dependent enzymes, but other folds are now appearing for the soluble domains of lipid phosphosugar-dependent glycosyl transferases. Structural and kinetic studies have provided new insights. Inverting glycosyltransferases utilize a direct displacement S(N)2-like mechanism involving an enzymatic base catalyst. Leaving group departure in GT-A fold enzymes is typically facilitated via a coordinated divalent cation, whereas GT-B fold enzymes instead use positively charged side chains and/or hydroxyls and helix dipoles. The mechanism of retaining glycosyltransferases is less clear. The expected two-step double-displacement mechanism is rendered less likely by the lack of conserved architecture in the region where a catalytic nucleophile would be expected. A mechanism involving a short-lived oxocarbenium ion intermediate now seems the most likely, with the leaving phosphate serving as the base.
1,601 citations
TL;DR: Emerging data indicate that O-GlcNAc glycosylation has a role in the aetiology of diabetes and neurodegeneration.
Abstract: All animals and plants dynamically attach and remove O-linked β-N-acetylglucosamine (O-GlcNAc) at serine and threonine residues on myriad nuclear and cytoplasmic proteins. O-GlcNAc cycling, which is tightly regulated by the concerted actions of two highly conserved enzymes, serves as a nutrient and stress sensor. On some proteins, O-GlcNAc competes directly with phosphate for serine/threonine residues. Glycosylation with O-GlcNAc modulates signalling, and influences protein expression, degradation and trafficking. Emerging data indicate that O-GlcNAc glycosylation has a role in the aetiology of diabetes and neurodegeneration.
1,212 citations