Nucleotide Sugars: Structure, Function, and Synthesis (2025)

Loading...

What is nucleotide sugar?

Nucleotide sugar is an active form in the process of carbohydrate conversion and synthesis. It is widely found in eukaryotes and prokaryotes. As a sugar base donor in glycan synthesis, nucleotide sugar is crucial to the physiological function and survival of organisms. Structurally, nucleotide sugars can be divided into nucleoside monophosphate (NMP)-sugar and nucleoside diphosphate (NDP)-sugar, wherein NDP-sugar is the more common nucleotide sugar, and uridine diphosphate (UDP) -sugar is the most common nucleotide sugar donor, which is transferred to the glycoside receptor by glycosyltransferase or synthetase in the glycan biosynthesis pathway to construct the glycoside bond.

Nucleotide sugars act as universal sugar donors in the synthesis of polysaccharides, glycoproteins, glycolipids and glycosylated secondary metabolites, and participate in cell wall synthesis, protein glycosylation and signal transduction. In bacteria, they are particularly important for the biosynthesis of cellular structures, such as helping pathogens evade recognition by the host immune system. Glycosylation reactions are usually catalyzed by highly specific glycosyltransferases, in which NDP-sugars, as monomer substrates for more than 90% of glycosylation reactions, form an important part of natural polysaccharides and glycoconjugates.

Due to their critical role, nucleotide sugars and their associated metabolic pathways are potential targets for drug development. By inhibiting the synthesis or transport of nucleotide sugars, it can interfere with the growth and survival of pathogens, providing new strategies for the development of novel antibiotics and other therapeutic drugs. In addition, the study of these metabolic pathways also provides rich research and application prospects for the treatment of other diseases.

Nucleotide sugar structure

Nucleotide sugar is a compound formed by combining a sugar molecule with a nucleotide (such as adenylate, guanylate, cytidylate, etc.) through a phosphodiester bond. The monosaccharide can vary, ranging from glucose to specialized sugars, while the nucleotide component is generally a mono- or diphosphate group attached to a nitrogenous base. The linkage between the sugar and the nucleotide is typically formed at the anomeric carbon of the sugar, which is the carbon that would normally be involved in the glycosidic bond if the sugar were part of a disaccharide. For example, UDP-N-acetylglucosamine (UDP-GlcNAc) consists of the sugar N-acetylglucosamine linked to the nucleotide uridine diphosphate (UDP). Similarly, ADP-ribose is composed of the sugar ribose attached to the nucleotide adenosine diphosphate (ADP).

Structures of common nucleotide sugars found in human cells^1,2.

Nucleotide sugar type

Within the cell, nucleotide sugars, as glycosyl donors, play an important role in glycosylation reactions, transferring sugar residues to receptor molecules such as proteins, lipids, or other sugar molecules. Nucleotide sugars can be divided into different types depending on the type of nucleotide they are composed of. The following are several common types of nucleotide sugars:

Uridine diphosphate sugar (UDP): UDP is one of the most common nucleotide sugars in the human body and is widely involved in glycosylation reactions. Common types are UDp-α-D-glucose (UDP-α-D-Glc), UDp-α-D-galactose (UDP-α-D-Gal), and UDp-α-D-galactose aminoglycose (UDP-α-D-GalNAc).

Guanosine diphosphate sugar (GDP): GDP nucleotide sugar plays an important role in the synthesis of glycosaminoglycans. Common ones are GDP-α-D-mannose (GDP-α-D-Man) and GDP-β-L-fucose (GDP-β-L-Fuc).

Cytidine monophosphate (CMP): Cytidine monophosphate is the only form of monophosphate in the human body and is mainly involved in the synthesis of sialic acid, such as CMP-β-D-neuramic acid (CMP-β-D-Neu5AC).

Cytidine diphosphate sugar (CDP): CDP-type nucleotide sugars also play an important role in polysaccharide synthesis, such as CDP-D-ribitol.

Nucleotide sugar at BOC Sciences

Biosynthetic routes of nucleotide sugar

Nucleotide sugars are synthesized through a series of enzymatic reactions, and the pathways vary depending on the organism. While the basic principles of nucleotide sugar biosynthesis are conserved across species, there are significant differences in the specific enzymes and intermediates involved.

Mammalian nucleotide sugar biosynthesis

In mammals, the biosynthesis of nucleotide sugars occurs primarily in the cytoplasm and endoplasmic reticulum. Key enzymes include nucleoside diphosphokinase, UDP-glucose dehydrogenase, and UDP-glucose pyrophosphorylase. One important pathway is the hexosamine biosynthesis pathway, which produces UDP-GlcNAc, a key nucleotide sugar involved in the glycosylation process.

Biosynthesis of nucleotide sugars in plants

Plant cell walls are complex, so plants have a wide range of nucleotide sugars. For example, UDP-GlcA is a precursor to the synthesis of cell wall polysaccharides, while UDP-arabinose and UDp-apiose are involved in the synthesis of branched oligosaccharides. In addition, these pathways produce intermediates of secondary metabolites, such as flavonoids and alkaloids.

Bacterial nucleotide sugar biosynthesis

Bacteria, especially Gram-negative bacteria, show significant diversity in nucleotide sugar biosynthesis. In addition to the common UDP-glucose and UDP-N-acetylglucosamine, many bacteria also synthesize unique nucleotide sugars that are used to build cell wall components such as lipopolysaccharides and muricoic acids. These biosynthetic pathways are tightly regulated, and bacterial enzymes such as glycosyltransferase play a key role in this process.

Function of nucleotide sugars in glycoconjugate

Nucleotide sugars play a crucial role in the biosynthesis of glycosylated complexes, and their functions are mainly reflected in the following aspects:

As a glycosyl donor: Nucleotide sugars are key substrates in glycosylation reactions, catalyzed by glycosyl transferases (GTs) to transfer glycosyl groups from the donor to the receptor. These glycosyltransferases typically use nucleotide sugars as activated glycosylated donors, such as UDP-glucose or NADP-glucose. Nucleotide sugars are activated through their high energy states (such as the reaction between NTP and nucleoside monophosphate) and become intermediates in the glycosylation reaction.

Synthesis of glycoproteins and proteoglycans in eukaryotic cells: Nucleotide sugars are involved in a wide range of biosynthesis processes of glycoproteins and proteoglycans in eukaryotic cells. For example, N-link and O-link glycosylation are common forms of glycosylation in eukaryotic cells, where N-link glycosylation usually attaches a glycogroup to the side chain of aspartate, while O-link glycosylation attaches to serine or threonine. These glycosylation processes are essential for protein folding, quality control, and intracellular transport.

Bacterial cell wall carbohydrate contribution: In bacteria, nucleotide sugars also play an important role. Polysaccharides in bacterial cell walls, such as lipopolysaccharides (LPS) and capsular polysaccharides (capsular), are synthesized from nucleotide sugars by glycosyltransferase. These polysaccharides not only constitute the cell wall structure of bacteria, but also have important biological functions such as immune escape and virulence factor formation.

Glycosylation pathways in bacterial pathogens: In some bacterial pathogens, nucleotide sugars are involved in complex glycosylation pathways, forming highly specific sugar chain structures. For example, in Mycobacterium tuberculosis, nucleotide sugars are transferred to polymers on the bacterial surface by specific glycosyltransferases, resulting in the formation of O antigens and other important surface polysaccharides. These sugar chain structures are not only critical to the survival and pathogenicity of bacteria, but also important targets for vaccine development.

Chemical reactions of nucleotide sugars

In the absence of enzymes, nucleotide sugars undergo chemical reactions that involve substitution at the anomeric carbon or at the phosphate group. These reactions can occur under acidic or alkaline conditions and lead to the formation of different products. For example, under acidic conditions, nucleotide sugars can undergo hydrolysis to release the sugar moiety. These reactions are important in understanding the reactivity of nucleotide sugars and their potential use in synthetic chemistry.

Synthesis of nucleotide sugar

The synthesis methods of nucleotide sugar mainly include chemical synthesis, enzymatic synthesis and chemical enzymatic synthesis. Here are the details of these methods:

Chemical synthesis method

Chemical synthesis is one of the most commonly used methods in nucleotide sugar synthesis. The main challenge lies in the selection of protective groups and the stereoselectivity of glucoside bonds. Chemical synthesis usually involves the following steps:

Monosaccharide/oligosaccharide construction: By using different protective groups, monosaccharides are joined into oligosaccharide structures.

Oligosaccharide chain extension: oligosaccharide chain is gradually prolonged by the reaction of glycosidic bond formation.

Skeleton modification: The oligosaccharide skeleton is further modified to obtain the target structure.

Enzymatic synthesis method

Enzymatic synthesis uses biocatalysts to simulate the process of biosynthesis in vivo, which has specificity and high efficiency. This approach usually involves the following steps:

Formation of glycoside phosphate: Conversion of glycosidic acid to glycoside phosphate using glycosidtransferases such as the Leloir pathway.

Synthesis of nucleoside diphosphate: The conversion of glycoside phosphate to nucleoside diphosphate by enzyme-catalyzed reaction.

Formation of the glycoside bond: The nucleoside diphosphate is bound to the receptor molecule using the glycoside transferase to form the final glycoside product.

Chemical enzymatic synthesis method

Chemical enzymatic synthesis combines the advantages of chemical synthesis and enzyme catalysis, which is a high efficiency and selectivity method. This approach typically includes:

Substrate preparation: Preparation of glycosidic acid or related precursors using chemical methods.

Enzyme-catalyzed reactions: The use of specific enzymes (such as glucosidtransferase) to catalyze reactions between substrates to form glucosidic bonds.

Post-treatment: The target glycoside product is obtained through purification and modification steps.

Special synthesis method

Some studies have also explored other AD hoc approaches, such as:

Cascade reaction strategy: Through multiple enzymatic steps, complex sugars are efficiently synthesized from simple sugars.

Automated platform: An automated platform has been developed for glycosidation reactions to improve reaction efficiency and product purity.

Synthesis of unnatural glycosides: Through improved chemical and enzymatic methods, the synthesis of unnatural glycosides for drug development and biomedical research.

Nucleotide sugars in drug development

Nucleotide sugars, as key precursors of carbohydrate biosynthesis, have shown great potential in the treatment of a variety of diseases, such as infections, cancer, and genetic diseases. They participate in the synthesis of complex carbohydrates such as glycoproteins, glycolipids and polysaccharides, and have become important targets for drug development. The following are specific applications of nucleotide sugars and their analogues in different fields:

Nucleotide sugar analogues as inhibitors

Nucleotide sugar analogues can specifically interfere with specific glycosylation reactions by imitating the natural nucleotide sugar structure and introducing chemical modifications, thereby preventing the formation of disease-related sugar complexes. For example, UDP-GlcNAc analogues have been studied for the treatment of cancer metastases due to their inhibitory effect on glycoprotein glycosylation. In addition, these analogues are also used to inhibit glycosyltransferases, which are responsible for transferring sugar moieties from nucleotide sugars to receptor molecules. Their inhibition can disrupt the glycosylation of important biological molecules, thereby slowing or preventing the development of cancer, autoimmune diseases and infections.

Development of antibiotics for bacterial infections

Bacteria rely on nucleotide sugars to build cell wall components (such as peptidoglycans and lipopolysaccharides) that are critical to their survival and toxicity. Therefore, inhibitors targeting nucleotide sugar biosynthesis pathways have become a hot topic in antibiotic research and development. For example, enzymes that inhibit the biosynthesis of UDP-N-acetylglucosamine (UDP-GlcNAc) destroy bacterial cell walls and inhibit bacterial growth. Because the structure of bacterial carbohydrates is significantly different from that of human cells, drugs targeting the bacterial nucleotide sugar pathway are highly specific, reducing the risk of off-target effects and host toxicity.

Cancer treatment

Abnormal glycosylation patterns are often observed in cancer, which affects the growth, invasion and metastasis of tumor cells. Enzymes that target glycosyltransferases or their substrates nucleotide sugars, such as UDP-glucose or UDP-GlcNAc, can inhibit glycosylation of cancer cells and reduce their ability to metastasize. In addition, by regulating the glycosylation pattern of cancer cell surface proteins, nucleotide sugar analogues can also enhance the effectiveness of immunotherapy or promote the development of vaccines targeting specific tumor-associated glycan structures.

Enzyme replacement therapy for hereditary diseases

Many genetic diseases stem from defects in enzymes involved in nucleotide sugar metabolism or glycosylation pathways, leading to conditions such as congenital glycation disorders (CDG) and lysosomal storage disorders. Enzyme replacement therapy (ERT) treats these diseases by providing functional versions of defective enzymes. Another strategy is to use nucleotide sugar analogues to restore normal glycosylation patterns, improve cell function and relieve symptoms.

Nucleotide sugar in vaccine development

Nucleotide sugars also play an important role in vaccine development, especially for bacterial and viral infections. Pathogen surface polysaccharides contain unique glycan structures that can be recognized by the immune system. Nucleotide sugar analogues are used to mimic these structures and stimulate immune responses without causing infection. For example, bacterial vaccines can synthesize oligosaccharide antigens through nucleotide sugars to induce immune responses against specific glycan epitopes; a similar strategy has also been applied to develop vaccines against viral infections to enhance the immune system's ability to fight viruses.

Price Inquiry