GDPfucose

GDP-fucose, or guanosine diphosphate fucose, is the activated sugar nucleotide used as the donor substrate by fucosyltransferase enzymes to attach fucose residues to glycoproteins and glycolipids in the secretory pathway. Fucosylation modulates protein folding, stability, cell–cell adhesion, signaling, and immune recognition. The pattern and extent of fucosylation influence the formation of selectin ligands, blood group antigens, and various glycan epitopes, impacting development and physiology.

In humans, de novo biosynthesis of GDP-fucose occurs in the cytosol from GDP-mannose. The pathway proceeds via GDP-mannose 4,6-dehydratase (GMDS), which forms GDP-4-keto-6-deoxymannose, followed by GDP-fucose synthase (also known as TSTA3) that converts this intermediate to GDP-fucose. This GDP-fucose then serves as the substrate for a family of fucosyltransferases that generate diverse fucosylated glycans on proteins and lipids.

GDP-fucose must be transported into the Golgi lumen by the GDP-fucose transporter SLC35C1, where it is used by fucosyltransferases to modify glycans on nascent glycoproteins and glycolipids. Disruptions to GDP-fucose production, its transport, or the activity of fucosyltransferases lead to hypofucosylation and altered glycan structures, with clinical consequences.

Clinically, defects in GDP-fucose synthesis or transport are associated with disorders of glycosylation, most notably leukocyte adhesion deficiency II (LAD II, also called SLC35C1 deficiency). LAD II is characterized by recurrent infections, growth and developmental abnormalities, and impaired leukocyte trafficking due to reduced fucosylation of selectin ligands and other glycans. The study of GDP-fucose underscores its essential role in immune function and developmental processes.