Glyco-stripping and glyco-swapping (original) (raw)
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Unusual sugar biosynthesis and natural product glycodiversification
Nature, 2007
The enzymes involved in the biosynthesis of carbohydrates and the attachment of sugar units to biological acceptor molecules catalyse an array of chemical transformations and coupling reactions. In prokaryotes, both common sugar precursors and their enzymatically modified derivatives often become substituents of biologically active natural products through the action of glycosyltransferases. Recently, researchers have begun to harness the power of these biological catalysts to alter the sugar structures and glycosylation patterns of natural products both in vivo and in vitro. Biochemical and structural studies of sugar biosynthetic enzymes and glycosyltransferases, coupled with advances in bioengineering methodology, have ushered in a new era of drug development.
Altering the glycosylation pattern of bioactive compounds
Trends in Biotechnology, 2001
Many bioactive natural products are glycosylated compounds in which the sugars are important or essential for biological activity. The isolation of several sugar biosynthesis gene clusters and glycosyltransferases from different antibiotic-producing organisms, and the increasing knowledge about these biosynthetic pathways opens up the possibility of generating novel bioactive compounds through combinatorial biosynthesis in the near future. Recent advances in this area indicate that antibiotic glycosyltransferases show some substrate flexibility that might allow us to alter the types of sugar transferred to the different aglycons or, less frequently, to change the position of its attachment.
Applied Microbiology and Biotechnology, 2013
Bioactive natural products, such as polyketides, flavonoids, glycopeptides, and aminoglycosides, have been used as therapeutic agents. Many of them contain structurally diverse sugar moieties attached to the aglycone core structures. Glycosyltransferases (GTs) catalyze the attachment of nucleotide-activated sugar substrates to acceptor aglycones. Because these sugar moieties are usually essential for biological activity, in vivo pathway engineering in prokaryotic hosts and in vitro enzymatic approaches coupled with GT engineering are currently being used to synthesize novel glycosylated derivatives, and some of them exhibited improved biological activities compared to the parent molecules. Therefore, harnessing the potential of diverse glycosylation reactions in prokaryotes will increase the structural diversity of natural products and the possibility to generate new bioactive products.
Rational Design of an Aryl-C-Glycoside Catalyst from a Natural Product O-Glycosyltransferase
Chemistry & Biology, 2011
Because the sugar moieties of natural products are primarily O-linked, the hydrolytic sensitivity of the glycosidic linkage limits their therapeutic application. One potential solution to this problem is to replace the labile O-glycosidic bond with an enzymatically and chemically stable C-glycosidic bond. In this study, computational analysis of the O-glycosyltransferase LanGT2 and the C-glycosyltransferase UrdGT2 was used to predict the changes necessary to switch the O-glycosylating enzyme to a C-glycosyltransferase. By screening rationally designed LanGT2 mutants a number of LanGT2 variants with C-glycosyltransferase activity were identified. One variant, having 10 amino acid substitutions, revealed the primary region that determines O-versus C-glycosylation. By modeling the active site of this mutant and probing the role of active site residues with alanine substitutions, this work also illuminates the mechanistic features of O-and C-glycosylation.
Introducing N-glycans into natural products through a chemoenzymatic approach
Carbohydrate Research, 2008
The present study describes an efficient chemoenzymatic method for introducing a core N-glycan of glycoprotein origin into various lipophilic natural products. It was found that the endo-β-Nacetylglucosaminidase from Arthrobactor protophormiae (Endo-A) had broad substrate specificity and can accommodate a wide range of glucose (Glc)-or N-acetylglucosamine (GlcNAc)-containing natural products as acceptors for transglycosylation, when an N-glycan oxazoline was used as a donor substrate. Using lithocholic acid as a model compound, we have shown that introduction of an Nglycan could be achieved by a two-step approach: chemical glycosylation to introduce a monosaccharide (Glc or GlcNAc) as a handle, and then Endo-A catalyzed transglycosylation to accomplish the site-specific N-glycan attachment. For those natural products that already carry terminal Glc or GlcNAc residues, direct enzymatic transglycosylation using sugar oxazoline as the donor substrate was achievable to introduce an N-glycan. It was also demonstrated that simultaneous double glycosylation could be fulfilled when the natural product contains two Glc residues. This chemoenzymatic method is concise, site-specific, and highly convergent. Because N-glycans of glycoprotein origin can serve as ligands for diverse lectins and cell-surface receptors, introduction of a defined N-glycan into biologically significant natural products may bestow novel properties onto these natural products for drug discovery and development.
Pure and applied chemistry, 2007
Changing the sugar structures and glycosylation patterns of natural products is an effective means of altering the biological activity of clinically useful drugs. Several recent strategies have provided researchers with the opportunity to manipulate sugar structures and to change the sugar moieties attached to these natural products via a biosynthetic approach. In this review, we explore the utility of contemporary in vivo and in vitro methods to achieve natural product glycodiversification. This study will focus on recent progress from our laboratory in elucidating the biosynthesis of D-desosamine, a deoxysugar component of many macrolide antibiotics, and will highlight how we have engineered the D-desosamine biosynthetic pathway in Streptomyces venezuelae through targeted disruption and heterologous expression of the sugar biosynthetic genes to generate a variety of new glycoforms. The in vitro exploitation of the substrate flexibility of the endogenous D-desosamine glycosyltransferase (GT) to generate many non-natural glycoforms will also be discussed. These experiments are compared with recent work from other research groups on the same topics. Finally, the significance of these studies for the future prospects of natural product glycodiversification is discussed. © 2007 IUPAC, Pure and Applied Chemistry 79, 785-799 786