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.
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]
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]
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: [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]
Listed below are the structures of some nucleotide sugars (one example from each type).
 |  |  |
| UDP-Gal | CMP-Neu5Ac | GDP-Man |
Normal metabolism of nucleotide sugars is very important. Any malfunction in any contributing enzyme will lead to a certain disease [11] for example:
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]
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.
Peptidoglycan or murein is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of most bacteria, forming the cell wall. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is a peptide chain of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. Peptidoglycan is also involved in binary fission during bacterial cell reproduction.
A nucleoside triphosphate is a molecule containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. It is an example of a nucleotide. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.
Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group.
Glycosyltransferases are enzymes that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar to a nucleophilic glycosyl acceptor molecule, the nucleophile of which can be oxygen- carbon-, nitrogen-, or sulfur-based.
Nucleic acid metabolism is the process by which nucleic acids are synthesized and degraded. Nucleic acids are the polymers of nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Destruction of nucleic acid is a catabolic reaction. Additionally, parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.
The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "caliche pits", located in Kerrville, Texas. The sample was collected by a scientist working for Lederle Labs. It is extremely toxic to all cells and, in 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calicheamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML). A second calicheamicin-linked monoclonal antibody, inotuzumab ozogamicin an anti-CD22-directed antibody-drug conjugate, was approved by the U.S. Food and Drug Administration on August 17, 2017, for use in the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.
Uridine diphosphate glucose is a nucleotide sugar. It is involved in glycosyltransferase reactions in metabolism.
Deoxyuridine monophosphate (dUMP), also known as deoxyuridylic acid or deoxyuridylate in its conjugate acid and conjugate base forms, respectively, is a deoxynucleotide.
Tunicamycin is a mixture of homologous nucleoside antibiotics that inhibits the UDP-HexNAc: polyprenol-P HexNAc-1-P family of enzymes. In eukaryotes, this includes the enzyme GlcNAc phosphotransferase (GPT), which catalyzes the transfer of N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to dolichol phosphate in the first step of glycoprotein synthesis. Tunicamycin blocks N-linked glycosylation (N-glycans) and treatment of cultured human cells with tunicamycin causes cell cycle arrest in G1 phase. It is used as an experimental tool in biology, e.g. to induce unfolded protein response. Tunicamycin is produced by several bacteria, including Streptomyces clavuligerus and Streptomyces lysosuperificus.
Uridine diphosphate N-acetylglucosamine or UDP-GlcNAc is a nucleotide sugar and a coenzyme in metabolism. It is used by glycosyltransferases to transfer N-acetylglucosamine residues to substrates. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. To be specific, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is UDP-GlcNAc, which is then used for making glycosaminoglycans, proteoglycans, and glycolipids.
CDP-4-dehydro-6-deoxyglucose reductase (EC 1.17.1.1) is an enzyme that catalyzes the chemical reaction
The enzyme UDP-glucose 4-epimerase, also known as UDP-galactose 4-epimerase or GALE, is a homodimeric epimerase found in bacterial, fungal, plant, and mammalian cells. This enzyme performs the final step in the Leloir pathway of galactose metabolism, catalyzing the reversible conversion of UDP-galactose to UDP-glucose. GALE tightly binds nicotinamide adenine dinucleotide (NAD+), a co-factor required for catalytic activity.
In enzymology, a dolichyl-phosphate beta-glucosyltransferase is an enzyme that catalyzes the chemical reaction
In enzymology, an aldose-1-phosphate nucleotidyltransferase is an enzyme that catalyzes the chemical reaction
In enzymology, an UDP-N-acetylglucosamine diphosphorylase is an enzyme that catalyzes the chemical reaction
In enzymology, an UTP-monosaccharide-1-phosphate uridylyltransferase is an enzyme that catalyzes the chemical reaction
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 method to manipulate carbohydrate substitutions of naturally occurring glycosides to afford the corresponding differentially glycosylated natural product libraries, glycorandomization applications have expanded to include both small molecules and even macromolecules (proteins). Also referred to as 'glycodiversification', glycorandomization has led to the discovery of new glycoside analogs which display improvements in potency, selectivity and/or ADMET as compared to the parent molecule.
Protein O-GlcNAc transferase also known as OGT is an enzyme that in humans is encoded by the OGT gene. OGT catalyzes the addition of the O-GlcNAc post-translational modification to proteins.
UDP-N-acetylglucosamine—undecaprenyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme with systematic name UDP-N-acetyl-alpha-D-glucosamine:ditrans,octacis-undecaprenyl phosphate N-acetyl-alpha-D-glucosaminephosphotransferase. This enzyme catalyses the following chemical reaction
