Enzymes of GDP-fucose biosynthesis pathway

The enzymes of the GDP-fucose biosynthesis pathway are responsible for producing guanosine diphosphate (GDP)-L-fucose, the essential donor substrate for all fucosyltransferases in the cell. This pathway consists of two main routes: the de novo pathway, which converts GDP-mannose to GDP-fucose via GDP-mannose 4,6-dehydratase (GMDS) and GDP-L-fucose synthase (TSTA3/FX), and the salvage pathway, which utilizes free fucose through fucokinase (FUK) and fucose-1-phosphate guanylyltransferase (FPGT) (Becker & Lowe, 2003; Wikipedia). Fucosylation of proteins and lipids is critical for various biological processes, including cell-cell adhesion, immune cell trafficking, and Notch signaling (Reactome; NIH). In oncology, these enzymes are targeted to reduce the fucosylation of tumor cells, which can inhibit metastasis and enhance the efficacy of therapeutic antibodies by promoting antibody-dependent cellular cytotoxicity (ADCC) (Cancer.gov; 1.2.1). Small molecule inhibitors like 2-fluorofucose (2-FF) act as decoy substrates or feedback inhibitors to deplete the cellular GDP-fucose pool, thereby serving as potential antineoplastic and immunomodulatory agents (NCI Drug Dictionary; 1.2.2).

Other names

GDP-fucose biosynthetic enzymesGDP-L-fucose biosynthesis pathwayDe novo and salvage fucose pathwaysFucosylation pathway enzymes

Inhibition of GDP-fucose synthesis through competitive inhibition of pathway enzymes (e.g., TSTA3 or FPGT), depletion of the cellular GDP-fucose pool, and feedback inhibition of the de novo pathway (e.g., GDP-2FF inhibiting GMDS).