Synthesis of Nucleotide Sugar

Nucleotide sugars consist of a monosaccharide and a nucleoside mono- or diphosphate molecule. The term usually refers to structures in which nucleotides are attached to isocarbons of sugar components. Such nucleotide sugars are sugar and phosphate sugar group donors in the biosynthesis of carbohydrates and sugar conjugates in all organisms.

As sugar group donors in glycan synthesis, nucleotide sugars are involved in processes that are essential for the correct function and survival of organisms. Sugars are involved in the communication and interaction of cells, and defects in glycosylation can lead to severe dysfunction and may even be fatal. Altered glycosylation can herald a pathological state, such as cancer. The hexylamine pathway that produces UDP-N-acetylglucosamine has been identified as an important target affecting the glycosylation process.

Therefore, enzymes involved in the biological processes of nucleotide sugars are potential targets for drug development, and nucleotide sugar analogs are potential inhibitors of these processes. Bacterial processes are particularly important to target because the structure and composition of bacterial carbohydrates differ markedly from those in humans. In addition, foreign or altered sugars activate defense mechanisms, and oligosaccharide sequences have been studied for use in vaccines against bacterial or fungal infections, as well as cancer.

Nucleotide Sugar Transporters

A nucleotide sugar transporter is a highly conserved type III transmembrane protein that provides a link between the synthesis of nucleotide sugars in the ER, nucleus, or cytoplasmic lysate and the glycosylation process. Nucleotide sugar transporters function as a reverse transporter protein, maintaining co-nucleotide sugar transporters levels of nucleotide sugars in the Golgi or endoplasmic reticulum lumen through an equimolar exchange of nucleotide sugars with nucleotide monophosphates.

Fig.1 Transmembrane transport of monosaccharides and nucleotide sugars. (Sosicka, et al., 2019)

Studies have identified several features common to nucleotide sugar transporters. (a) Translocation of the entire nucleotide sugar. (b) The translocation is saturable. (c) The translocation is insensitive to the presence of ATP and ion carriers and is energized by the coupled translocation of the corresponding nucleoside monophosphate in the opposite direction. (d) Translocation is competitively inhibited by the corresponding nucleoside monophosphate and nucleoside diphosphate, but not by free sugars. (e) Some nucleotide sugars translocate exclusively to the Golgi apparatus, some exclusively to the endoplasmic reticulum, and others translocate in both.

Disorders of Nucleotide Sugar Synthesis and Transport

Nucleotide sugars are necessary for enzymes to be able to transfer monosaccharides to proteins, lipids, or glycans. Usually, nucleotide sugars are monosaccharides linked to phosphorylated nucleosides, including UDP, GDP, or CMP. Disorders of nucleotide sugar synthesis and translocation can severely affect the glycosylation pathways associated with the corresponding nucleotide sugars. The synthesis of nucleotide sugars depends on a series of enzymatic reactions. Usually, the production of nucleotide sugars requires phosphate group-modified monosaccharides and phosphorylated nucleosides. Interconversions between nucleotide sugars can also be produced.

Glycosylation occurs within the ER and Golgi apparatus. The compartments of these organelles surrounded by membranes do not allow the passage of nucleotide sugars. These nucleotide sugar transporter proteins are involved in the movement of substances across the membrane. Nucleotide sugar transport proteins present in the ER and Golgi membranes transport nucleotide sugars from the cytoplasmic solute to the interior of these compartments. Therefore, if nucleotide sugar transport proteins are defective, they prevent the entry of nucleotide sugars into the endoplasmic reticulum and Golgi apparatus during glycosylation and may lead to congenital disorders of glycosylation.

Here we describe one of the disorders in the Disorders of Multiple Glycosylation and Other Pathways. CD BioGlyco provides comprehensive and deep insights into disorders of nucleotide sugar synthesis and transport. We provide various relevant services including but not limited to Custom Monosaccharide Synthesis, Cerebroside Analysis Service, and Custom Glycoconjugate Synthesis. We also provide a range of products such as β-Nicotinamide mononucleotide to customers. If you are interested in our services and products, please contact us for more details without any hesitation.

Reference:

1. McVeigh, P.; et al. In silico analyses of protein glycosylating genes in the helminth Fasciola hepatica (liver fluke) predict protein-linked glycan simplicity and reveal temporally-dynamic expression profiles. Scientific reports. 2018, 8(1): 1-15.