Glycorandomization: Difference between revisions
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== ''Chemoenzymatic glycorandomization'' == |
== ''Chemoenzymatic glycorandomization'' == |
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This is a biocatalytic approach which relies on the promiscuous enzymes to catalyze the coupling between sugars and aglycons. The three enzymes involved in this strategy are anomeric [[kinase]], [[nucleotidyltransferase]] and [[glycosyltransferase]]. Altering the substrate specificities of these enzymes will enhance their [[promiscuity]] to catalyze additional reactions which leads to diverse randomized sugar libraries, like sugar phosphate library, NDP sugar library and glycosylated sugar library.<ref name=a/> Modifying any one of these three enzymes will eventually lead to final glycorandomization of the natural products. |
This is a biocatalytic approach which relies on the promiscuous enzymes to catalyze the coupling between sugars and aglycons. The three enzymes involved in this strategy are anomeric [[kinase]], [[nucleotidyltransferase]] and [[glycosyltransferase]]. Altering the substrate specificities of these enzymes will enhance their [[promiscuity]] to catalyze additional reactions which leads to diverse randomized sugar libraries, like sugar phosphate library, NDP sugar library and glycosylated sugar library.<ref name=a/> Modifying any one of these three enzymes will eventually lead to final glycorandomization of the natural products.(Figure adapted from </ref><ref name=a>Langenhan, J. M.; Griffith, B. R., Thorson, J. S. “Neoglycorandomization and chemoenzymatic glycorandomization: two complementary tools for natural product diversification”. ''J. Nat. Prod.'' '''2005''', ''68'', 1696-1711.</ref>) |
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[[File:Chemoenzymatic glycorandomization.png|center]] |
[[File:Chemoenzymatic glycorandomization.png|center]] |
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Revision as of 19:13, 15 April 2009
 | This article has no lead section. (April 2009) |
Concept
Glycorandomization, literally means “diversify the sugar-containing compounds”, is a tool currently used in pharmaceutical industry to modify the sugar residues of the glycosylated natural products by using unique glycosylation strategies. It’s an efficient and convenient way to achieve libraries of natural product derivatives which only differ in the attached sugars.[1][2][3]
Classification
The traditional method to obtain the natural product analogues is by total synthesis via laborious and time consuming protection and deprotection. To generate the analogues more efficiently, recently, chemists have developed two complementary strategies to achieve glycorandomization: chemoenzymatic glycorandomization and neoglycorandomization. These two methods do not need any protected sugars and aglycons. Both of them start with unprotected and unactivated reducing sugars and end with a library of sugars attached to the same aglycon.
Chemoenzymatic glycorandomization
This is a biocatalytic approach which relies on the promiscuous enzymes to catalyze the coupling between sugars and aglycons. The three enzymes involved in this strategy are anomeric kinase, nucleotidyltransferase and glycosyltransferase. Altering the substrate specificities of these enzymes will enhance their promiscuity to catalyze additional reactions which leads to diverse randomized sugar libraries, like sugar phosphate library, NDP sugar library and glycosylated sugar library.[2] Modifying any one of these three enzymes will eventually lead to final glycorandomization of the natural products.(Figure adapted from </ref>[2])
Currently available strategies to alter the substrate specificities include directed evolution and structure-based engineering. Directed evolution[4] takes advantage of natural selection to produce the desired promiscuous enzyme mutant via mutation, recombination, screening and selection. While structure-based engineering[5] modifies the active site pocket of the wild type enzyme to allow it accommodate unnatural substrates, thus, enhance the substrate flexibility of the enzyme.
Neoglycorandomization
This is a chemical approach using one step ligation between reducing sugar and secondary alkoxylamine containing aglycon to form glycosides which are termed as “neoglycosides”.[2] [6]In this chemoselective ligation, two reactive functional groups selectively form covalent bond to produce oxy-iminium intermediate, which then undergoes ring closure immediately under physiological conditions. In this strategy, the only requirement is the installation of the alkoxylamine into the aglycon before glycosylation.
Comparison
Both chemoenzymatic glycorandomization and neoglycorandomization do not need any protected sugars and aglycons. However, the biocatalytic approach is limited by the availability of either the promiscuous enzymes or the engineering techniques to alter the substrate specificities of enzymes. Without enzymes involved, the chemical approach is only limited by the efficiency to install the alkoxylamine into the aglycon. However, the anomeric selectivity of the chemical approach might be scrambled in some cases, depending on the structure of the involved reducing sugars.
Uses
Glycorandomization is widely used in pharmaceutical industry to alter the glycosylation patterns of the sugar-containing natural products. It provides a fast way to investigate the effect of subtle sugar modification towards the pharmacological properties of the natural products analogues, thus, afford a new alternative to the future drug discovery.
References
- ^ Yang, J.; Hoffmeister, D.; Liu, L.; Thorson, J. S. “Natural product glycorandomization”. Bioorg. Med. Chem. 2004, 12, 1577-1584.
- ^ a b c d Langenhan, J. M.; Griffith, B. R., Thorson, J. S. “Neoglycorandomization and chemoenzymatic glycorandomization: two complementary tools for natural product diversification”. J. Nat. Prod. 2005, 68, 1696-1711.
- ^ Griffith, B. R.; Langenhan, J. M.; Thorson, J. S. “’Sweetening’ natural products via glycorandomization”. Curr. Opin. Biotechnol. 2005, 16, 622-630.
- ^ Williams, G. J.; Zhang, C. ; Thorson, J. S. “Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution”. Nat. Chem. Biol. 2007, 3, 657-662.
- ^ Thorson, J. S.; Barton, W. A.; Hoffmeister, D.; Albermann, C.; Nikolov, D. B. “Structure-based enzyme engineering and its impact on in vivo glycorandomization”. Chembiochem. 2004, 5, 16-25.
- ^ Langenhan, J. M.; Peters, N. R.; Guzei, I. A.; Hoffmann, F. M.; Thorson, J. S. “Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization”. Proc. Natl. Acad. Sci. 2005, 102, 12305-12310.