Nucleotide sugars are the activated forms of

monosaccharides Monosaccharides (from Greek ''monos'': single, '' sacchar'': sugar), also called simple sugars, are the simplest forms of sugar and the most basic units (monomers) from which all carbohydrates are built. Chemically, monosaccharides are polyhydr ...

Nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

sugars act as glycosyl donors in

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

reactions. Those reactions are catalyzed by a group of enzymes called

glycosyltransferase Glycosyltransferases (GTFs, Gtfs) are enzymes ( EC 2.4) that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar (also known as the "glycosyl donor") to a nucleophilic gl ...

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.

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 In carbohydrate chemistry, a pair of anomers () is a pair of near-identical stereoisomers or diastereomers that differ at only the anomeric carbon, the carbon atom that bears the aldehyde or ketone functional group in the sugar's open-chain f ...

). The recent discovery of the reversibility of many

-catalyzed reactions calls into question the designation of sugar nucleotides as 'activated' donors.

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: *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 ''N''-Acetylneuraminic acid (Neu5Ac or NANA) is the predominant sialic acid found in human cells, and many mammalian cells. Other forms, such as N-Glycolylneuraminic acid, may also occur in cells. This residue is negatively charged at physiologi ...

; in humans, it is the only nucleotide sugar in the form of nucleotide monophosphate. *Cytidine Diphosphate: CDP-D-

Ribitol Ribitol, or adonitol, is a crystalline pentose alcohol (C5H12O5) formed by the reduction of ribose. It occurs naturally in the plant '' Adonis vernalis'' as well as in the cell walls of some Gram-positive bacteria, in the form of ribitol phosp ...

(i.e. CMP- ibitol phosphate; 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 Cytidine diphosphate glucose, often abbreviated CDP-glucose, is a nucleotide-linked sugar consisting of cytidine diphosphate and glucose. This nucleotide saccharide participates in the synthesis of deoxy sugars such as paratose and tyvelose. ...

and

TDP-glucose Thymidine diphosphate glucose (often abbreviated dTDP-glucose or TDP-glucose) is a nucleotide-linked sugar consisting of deoxythymidine diphosphate linked to glucose. It is the starting compound for the syntheses of many deoxysugars. Biosynthes ...

give rise to various other forms of CDP and TDP-sugar donor nucleotides.

Structures

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

Relationship to disease

Normal metabolism of nucleotide sugars is very important. Any malfunction in any contributing enzyme will lead to a certain disease 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 Glycorandomization, is a drug discovery and drug development technology platform to enable the rapid diversification of bioactive small molecules, drug leads and/or approved drugs through the attachment of sugars. Initially developed as a facile me ...

where these sugar nucleotide libraries serve as donors for permissive

glycosyltransferases Glycosyltransferases (GTFs, Gtfs) are enzymes ( EC 2.4) that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar (also known as the "glycosyl donor") to a nucleophilic glyc ...

to afford differential glycosylation of a wide range of

pharmaceuticals Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

and complex

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...

-based leads.

References

External links

* {{Nucleotide sugars Metabolism Coenzymes Carbohydrate chemistry Carbohydrates Nucleotides