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Unmasking Fucosylation: From Cell Adhesion to Immune System Regulation and Diseases

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Fucosylation, a biological process broadly observed in vertebrates, invertebrates, plants, bacteria, and fungi, is one of the most common modifications involving oligosaccharides on glycoproteins or glycolipids. Recent research on fucose has already significantly expanded the contemporary understanding of fucosylation.

This paper discusses the use of gene knockout studies, competitive inhibitors of fucose-containing glycan, and metabolic inhibitors of fucose biosynthesis to probe fucosylated glycan biosynthesis and signaling and its functional consequences. Some clinical and preclinical applications in different kinds of diseases are reviewed as well.

There are three types of selectins, E-, L-, and P-selectin, and the contributions of FUT4 and FUT7 to E-, P-, and L-selectin ligand synthesis and to the control of leukocyte recruitment and lymphocyte homing are proved.

Some competitive selectin inhibitors have shown their applications in diseases. Sickle cell disease is highly dependent on cell adhesion. It was found that GMI-1070, a fucose-containing competitive selectin inhibitor, could help improve microcirculatory blood flow and improved survival. Study also has proved that adhesion and stroma-induced proliferation and drug resistance to chemotherapy of multiple myeloma (MM) cells could be reduced by GMI-1271, another selectin inhibitor. And similar results were also observed in treating acute myeloid leukemia (AML) blasts using GMI-1271.

Besides, selectins can also improve chemoresistance, chemotherapy-related side effects, and recovery. Intensive high-dose chemotherapy or radiation can result in lifethreatening neutropenia and mucositis. In mouse models, deletion of E-selectin can increase the resistance of normal tissues to chemotherapy.

Fucose is added to glycan by FUTs that require guanosine diphosphate (GDP)-fucose as a substrate. GDP-fucose can be generated either by the de novo pathway or by the salvage pathway.

Through careful design, 2-deoxy-2-fluorofucose (2FF), peracetylated 6-alkynyl-fucose (6-Alk-Fuc), peracetylated 5-thiofucose (5T-Fuc), and 6,6,6-trifluorofucose (fucostatin I) have been developed as small-molecule analogs of fucose that are converted in cells by the salvage pathway into GDP analogs of fucose.

Similar to the competitive selectin inhibitors, metabolic inhibitors of fucosylation have shown promise in animal models of adhesion-related human diseases, such as sickle cell disease and colon cancer. For example, it has been shown that increased Lewis antigens on cancer cells is correlated with a poor prognosis in colon cancer, and the metabolic fucosylation inhibitor 2-FF appears to be well tolerated and has recently been registered for a phase I clinical trial in patients with advanced solid tumors.

Accumulated evidence has indicated that fucosylation is much more than a cell trafficking regulator. Fucosylation also plays a key role in the commitment, differentiation, and plasticity of a variety of immune cells as well as immune processes and diseases.

Glycan structure on the cell surface regulates cell-cell communication and adhesion, cell-environment interaction, membrane structure, endocytosis, cellular signaling, and pathogen recognition and invasion. Glycans also influence the protein secretory pathway by regulating protein folding, chaperone binding, and quality control surveillance.

Recent studies also found that fucosylation is a hallmark of M1 macrophages and inflammatory arthritis, and it regulates signal transduction important to T and B cell development. Besides, ADCC response is proved to be regulated by fucosylation of IgG antibodies. Research has also indicated that fucose has an impact on the bacteria in the colon and can improve host health. Furthermore, fucose can expand the beneficial members of gut microbiota, and promote colonization resistance to opportunistic pathogens.

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