Nucleotide sugar

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Nucleotide sugars are the activated forms of monosaccharides. Nucleotide sugars act as glycosyl donors in glycosylation reactions. Those reactions are catalyzed by a group of enzymes called glycosyltransferases.

History[edit]

The anabolism of oligosaccharides - and, hence, the role of nucleotide sugars - was not clear until the 1950s when Leloir and his coworkers found that the key enzymes in this process are the glycosyltransferases. These enzymes transfer a glycosyl group from a sugar nucleotide to an acceptor.[1]

Biological Importance and Energetics[edit]

To act as glycosyl donors, those monosaccharides should exist in a highly energetic form. This occurs as a result of a reaction between nucleoside triphosphate (NTP) and glycosyl monophosphate (phosphate at anomeric carbon). The recent discovery of the reversibility of many glycosyltransferase-catalyzed reactions calls into question the designation of sugar nucleotides as 'activated' donors.[2][3][4][5][6]

Activation of Monosaccharides

Types[edit]

There are ten sugar nucleotides in humans which act as glycosyl donors and they can be classified depending on the type of the nucleoside forming them:[7]

In other forms of life many other sugars are used and various donors are utilized for them. All five of the common nucleosides are used as a base for a nucleotide sugar donor somewhere in nature. As examples, CDP-glucose and TDP-glucose give rise to various other forms of CDP and TDP-sugar donor nucleotides.[9][10]

Structures[edit]

listed below are the structures of some nucleotide sugars (example from each type).

UDP-Gal CMP-NeuNAc GDP-Man
UDP-Gal CMP-Neu5Ac GDP-Man

Relationship to Disease[edit]

Normal metabolism of nucleotide sugars is very important. Any malfunction in any contributing enzyme will lead to a certain disease [11] for example:

  1. Inclusion body myopathy: is a congenital disease resulted from altered function of UDP-GlcNAc epimerase .
  2. Macular corneal dystrophy: is a congenital disease resulted from malfunction of GlcNAc-6-sulfotransferase.
  3. Congenital disorder in α-1,3 mannosyl transferase will result in a variety of clinical symptoms, e.g. hypotonia, psychomotor retardation, liver fibrosis and various feeding problems.

Relationship to Drug Discovery[edit]

The development of chemoenzymatic strategies to generate large libraries of non-native sugar nucleotides has enabled a process referred to as glycorandomization where these sugar nucleotide libraries serve as donors for permissive glycosyltransferases to afford differential glycosylation of a wide range of pharmaceuticals and complex natural product-based leads.[12][13]

See also[edit]

References[edit]

  1. ^ Derek Horton (2008). "The Development of Carbohydrate Chemistry and Biology". Carbohydrate Chemistry, Biology and Medical Applications: 1–28. doi:10.1016/B978-0-08-054816-6.00001-X. ISBN 978-0-08-054816-6. 
  2. ^ Zhang, C; Griffith, BR; Fu, Q; Albermann, C; Fu, X; Lee, IK; Li, L; Thorson, JS (1 September 2006). "Exploiting the reversibility of natural product glycosyltransferase-catalyzed reactions". Science. 313 (5791): 1291–4. doi:10.1126/science.1130028. PMID 16946071. 
  3. ^ Zhang, C; Albermann, C; Fu, X; Thorson, JS (27 December 2006). "The in vitro characterization of the iterative avermectin glycosyltransferase AveBI reveals reaction reversibility and sugar nucleotide flexibility". Journal of the American Chemical Society. 128 (51): 16420–1. doi:10.1021/ja065950k. PMID 17177349. 
  4. ^ Zhang, C; Fu, Q; Albermann, C; Li, L; Thorson, JS (5 March 2007). "The in vitro characterization of the erythronolide mycarosyltransferase EryBV and its utility in macrolide diversification". Chembiochem : a European journal of chemical biology. 8 (4): 385–90. doi:10.1002/cbic.200600509. PMID 17262863. 
  5. ^ Zhang, C; Moretti, R; Jiang, J; Thorson, JS (13 October 2008). "The in vitro characterization of polyene glycosyltransferases AmphDI and NysDI". Chembiochem : a European journal of chemical biology. 9 (15): 2506–14. doi:10.1002/cbic.200800349. PMC 2947747Freely accessible. PMID 18798210. 
  6. ^ Gantt, RW; Peltier-Pain, P; Cournoyer, WJ; Thorson, JS (21 August 2011). "Using simple donors to drive the equilibria of glycosyltransferase-catalyzed reactions". Nature Chemical Biology. 7 (10): 685–91. doi:10.1038/nchembio.638. PMC 3177962Freely accessible. PMID 21857660. 
  7. ^ Cold Spring Harbor Laboratory Press Essentials of Glycobiology, Second Edition
  8. ^ Gerin I, et al. (2016). "ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan". Nature Communications. 7: 11534. doi:10.1038/ncomms11534. PMID 27194101. 
  9. ^ Samuel G, Reeves P (2003). "Biosynthesis of O-antigens: genes and pathways involved in nucleotide sugar precursor synthesis and O-antigen assembly". Carbohydr. Res. 338 (23): 2503–19. doi:10.1016/j.carres.2003.07.009. PMID 14670712. 
  10. ^ Xue M. He; Hung-wen Liu (2002). "Formation of unusual sugars: Mechanistic studies and biosynthetic applications". Annu Rev Biochem. 71: 701–754. doi:10.1146/annurev.biochem.71.110601.135339. PMID 12045109. 
  11. ^ Encyclopedia of Biological Chemistry, Volume 2. 2004, Elsevier Inc. Hudson H. Freeze 302-307.
  12. ^ Langenhan, JM; Griffith, BR; Thorson, JS (November 2005). "Neoglycorandomization and chemoenzymatic glycorandomization: two complementary tools for natural product diversification". Journal of Natural Products. 68 (11): 1696–711. doi:10.1021/np0502084. PMID 16309329. 
  13. ^ Gantt, RW; Peltier-Pain, P; Thorson, JS (October 2011). "Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules". Natural Product Reports. 28 (11): 1811–53. doi:10.1039/c1np00045d. PMID 21901218. 

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