α-fucosyltransferase

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α-Fucosyltransferases (α-FTs) are a family of enzymes that play a crucial role in the biosynthesis of fucosylated glycans. These enzymes catalyze the transfer of a fucose residue from a donor molecule to an acceptor molecule, thereby generating various fucosylated structures. α-FTs are involved in several biological processes, such as cell signaling, immune response, and development.

Structure

α-Fucosyltransferases belong to the glycosyltransferase (GT) family 10 in the Carbohydrate-Active Enzymes (CAZy) classification. They are predominantly type II transmembrane proteins consisting of a catalytic domain located in the lumen of the Golgi apparatus. These enzymes possess conserved motifs, including the DXD motifs essential for binding the nucleotide sugar donor substrate (GDP-fucose) and a fucose-binding motif responsible for donor and acceptor recognition. α-FTs exhibit structural variability, with different isoforms showing distinct substrate specificities and acceptor preferences.

Functions

• Glycan biosynthesis: α-FTs are essential for the biosynthesis of fucosylated glycans, which play key roles in cell-cell recognition, adhesion, and signaling. These glycans mediate cell adhesion in a variety of biological processes, including embryogenesis, immune responses, and inflammatory processes.
• Cell adhesion and migration: Fucosylation of cell surface molecules such as selectins and integrins mediated by α-FTs is essential for cell adhesion and migration. These processes are essential for immune cell migration, tissue development, and wound healing.
• Immune Response: Fucosylation of glycoproteins on immune cells is involved in immune recognition and regulation of immune responses. α-FTs are responsible for the fucosylation of antibodies and cell-surface receptors, which promotes immune cell functions including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC).
• Cancer progression: Aberrant fucosylation is frequently observed in cancer cells. altered α-FT expression and activity contribute to cancer progression, metastasis, and evasion of immune surveillance. Understanding the role of α-FTs in cancer may help in the development of targeted therapies.

Biotechnology Applications

• Disease Biomarkers: Changes in α-FT expression and glycosylation patterns of glycosylated fucoidan have been identified as potential diagnostic and prognostic biomarkers for a variety of diseases, including cancer, inflammatory diseases, and autoimmune diseases.
• Therapeutic Targets: Due to their involvement in cancer progression and immune response, α-FTs have emerged as therapeutic targets. Inhibition of α-FT activity helps to modulate the immune system, enhance antibody therapies and prevent cancer metastasis.
• Antibody Engineering: α-FTs have enabled the development of glycoengineered antibodies with enhanced effector functions. By fucosylating the antibody, α-FTs reduce the affinity of the antibody for the FcγRIIIa receptor, thereby increasing ADCC.
• Congenital Diseases: Defects or mutations in the α-FT gene can lead to congenital diseases such as hoof lobitis and leukocyte adhesion deficiency type II (LAD-II). These diseases are characterized by impaired immune system function and abnormal glycosylation patterns.

Conclusion

α-Fucosyltransferases are important enzymes involved in glycan biosynthesis, cell adhesion, immune response regulation, and cancer progression. the structural diversity and substrate specificity of α-fucosyltransferases make them intriguing targets for therapeutic intervention. Understanding the function and clinical significance of α-FTs has the potential to facilitate the development of novel diagnostic, prognostic, and targeted therapies for a variety of diseases, thereby advancing the development of personalized medicine.

Future Perspectives

Further research is needed to fully understand the function of α-FT and its role in various physiologic and pathologic processes. Exploration of new inhibitors and the development of more selective α-FT targeting strategies may provide therapeutic opportunities for cancer treatment and immune-related diseases. In addition, studying the structural variants of different α-FT isozymes could help to understand their substrate specificity and design isozyme-specific inhibitors.