GDP-mannose 4,6-dehydratase (GMDS)

GDP-mannose 4,6-dehydratase (GMDS) is an enzyme that catalyzes the first and regulatory step in the de novo biosynthesis of GDP-L-fucose from GDP-D-mannose, making it essential for the generation of fucose-containing glycans and glycoproteins[1][2][3][4]. Fucose is critical for multiple cellular processes, including immunity, leukocyte adhesion, and cell signaling. GMDS is a member of the short-chain dehydrogenase/reductase (SDR) family, functioning as a homodimer with each subunit binding a molecule of NADP(H) and GDP-mannose. Catalysis proceeds via oxidation of GDP-mannose, dehydration, and reduction steps, employing two key active-site residues (typically Glu and Tyr) and tightly bound NADP(H). Genetic defects in GMDS disrupt fucose biosynthesis and cause immune deficiency syndromes such as leukocyte adhesion deficiency type II[2][1][3]. There are currently no approved drugs that directly target GMDS, but it is experimentally inhibited by guanosine-5'-diphosphate and is subject to feedback inhibition by its product, GDP-fucose[3][2].

Other names

GDP-mannose 4,6 dehydrataseGMDSDR3E1GDP-D-mannose dehydrataseGDP-mannose 4,6-hydro-lyaseguanosine 5'-diphosphate-D-mannose oxidoreductaseguanosine diphosphomannose oxidoreductase

Competitive inhibition at the sugar nucleotide binding site (GDP-fucose-mediated feedback inhibition)[2]