Nucleotide sugar

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

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.{{cite journal |author=Derek Horton|title=The Development of Carbohydrate Chemistry and Biology|journal=Carbohydrate Chemistry, Biology and Medical Applications|pages=1–28 |year=2008 |doi= 10.1016/B978-0-08-054816-6.00001-X |isbn=978-0-08-054816-6}}

Biological importance and energetics

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.{{cite journal|last1=Zhang|first1=C|last2=Griffith|first2=BR|last3=Fu|first3=Q|last4=Albermann|first4=C|last5=Fu|first5=X|last6=Lee|first6=IK|last7=Li|first7=L|last8=Thorson|first8=JS|title=Exploiting the reversibility of natural product glycosyltransferase-catalyzed reactions.|journal=Science|date=1 September 2006|volume=313|issue=5791|pages=1291–4|pmid=16946071|doi=10.1126/science.1130028|bibcode=2006Sci...313.1291Z|s2cid=38072017}}{{cite journal|last1=Zhang|first1=C|last2=Albermann|first2=C|last3=Fu|first3=X|last4=Thorson|first4=JS|title=The in vitro characterization of the iterative avermectin glycosyltransferase AveBI reveals reaction reversibility and sugar nucleotide flexibility.|journal=Journal of the American Chemical Society|date=27 December 2006|volume=128|issue=51|pages=16420–1|pmid=17177349|doi=10.1021/ja065950k}}{{cite journal|last1=Zhang|first1=C|last2=Fu|first2=Q|last3=Albermann|first3=C|last4=Li|first4=L|last5=Thorson|first5=JS|title=The in vitro characterization of the erythronolide mycarosyltransferase EryBV and its utility in macrolide diversification.|journal=ChemBioChem|date=5 March 2007|volume=8|issue=4|pages=385–90|pmid=17262863|doi=10.1002/cbic.200600509|s2cid=45058028}}{{cite journal|last1=Zhang|first1=C|last2=Moretti|first2=R|last3=Jiang|first3=J|last4=Thorson|first4=JS|title=The in vitro characterization of polyene glycosyltransferases AmphDI and NysDI.|journal=ChemBioChem|date=13 October 2008|volume=9|issue=15|pages=2506–14|pmid=18798210|doi=10.1002/cbic.200800349|pmc=2947747}}{{cite journal|last1=Gantt|first1=RW|last2=Peltier-Pain|first2=P|last3=Cournoyer|first3=WJ|last4=Thorson|first4=JS|title=Using simple donors to drive the equilibria of glycosyltransferase-catalyzed reactions.|journal=Nature Chemical Biology|date=21 August 2011|volume=7|issue=10|pages=685–91|pmid=21857660|doi=10.1038/nchembio.638|pmc=3177962}}

File:activatedmonosaccahride.png

Types

There are nine sugar nucleotides in humans which act as glycosyl donors and they can be classified depending on the type of the nucleoside forming them:[http://www.cshlpress.com/default.tpl?action=full&--eqskudatarq=666 Cold Spring Harbor Laboratory Press] {{Webarchive|url=https://web.archive.org/web/20110708212401/http://www.cshlpress.com/default.tpl?action=full&--eqskudatarq=666 |date=2011-07-08 }} Essentials of Glycobiology, Second Edition

Uridine Diphosphate: UDP-α-D-Glc, UDP-α-D-Gal, UDP-α-D-GalNAc, UDP-α-D-GlcNAc, UDP-α-D-GlcA, UDP-α-D-Xyl
Guanosine Diphosphate: GDP-α-D-Man, GDP-β-L-Fuc.
Cytidine Monophosphate: CMP-β-D-Neu5Ac; in humans, it is the only nucleotide sugar in the form of nucleotide monophosphate.
Cytidine Diphosphate: CDP-D-Ribitol (i.e. CMP-[ribitol phosphate]);{{cite journal |vauthors=Gerin I, et al. |title=ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan |journal=Nature Communications |volume=7 |pages=11534 |year=2016 |pmid=27194101 |doi=10.1038/ncomms11534 |pmc=4873967 |bibcode=2016NatCo...711534G }} though not a sugar, the phosphorylated sugar alcohol ribitol phosphate is incorporated into matriglycan as if it were a monosaccharide.

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.{{cite journal |vauthors=Samuel G, Reeves P |title=Biosynthesis of O-antigens: genes and pathways involved in nucleotide sugar precursor synthesis and O-antigen assembly |journal=Carbohydr. Res. |volume=338 |issue=23 |pages=2503–19 |year=2003 |pmid=14670712 |doi=10.1016/j.carres.2003.07.009}}{{cite journal |author1=Xue M. He |author2=Hung-wen Liu |title=Formation of unusual sugars: Mechanistic studies and biosynthetic applications |journal=Annu Rev Biochem |volume=71 |pages=701–754 |year= 2002 |doi=10.1146/annurev.biochem.71.110601.135339 |pmid=12045109}}

Structures

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

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Relationship to disease

Normal metabolism of nucleotide sugars is very important. Any malfunction in any contributing enzyme will lead to a certain disease Encyclopedia of Biological Chemistry, Volume 2. 2004, Elsevier Inc. Hudson H. Freeze 302-307.

for example:

Inclusion body myopathy: is a congenital disease resulted from altered function of UDP-GlcNAc epimerase .
Macular corneal dystrophy: is a congenital disease resulted from malfunction of GlcNAc-6-sulfotransferase.
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

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.{{cite journal|last1=Langenhan|first1=JM|last2=Griffith|first2=BR|last3=Thorson|first3=JS|title=Neoglycorandomization and chemoenzymatic glycorandomization: two complementary tools for natural product diversification.|journal=Journal of Natural Products|date=November 2005|volume=68|issue=11|pages=1696–711|pmid=16309329|doi=10.1021/np0502084}}{{cite journal|last1=Gantt|first1=RW|last2=Peltier-Pain|first2=P|last3=Thorson|first3=JS|title=Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules.|journal=Natural Product Reports|date=October 2011|volume=28|issue=11|pages=1811–53|pmid=21901218|doi=10.1039/c1np00045d}}