Glucosamine-6-phosphate synthase (GlmS) (GlmS)

Glucosamine-6-phosphate synthase (GlmS) is an essential enzyme in fungi that catalyzes the first and rate-limiting step of the hexosamine biosynthetic pathway. It facilitates the conversion of L-glutamine and D-fructose-6-phosphate into D-glucosamine-6-phosphate and L-glutamate (UniProt: P53704). This reaction is critical because glucosamine-6-phosphate is the universal precursor for the synthesis of chitin and mannoproteins, which are indispensable components of the fungal cell wall (PubMed: 15608112). Since human cells lack a cell wall, GlmS is a highly attractive target for antifungal therapy, particularly for treating systemic mycoses caused by pathogens like Candida albicans and Aspergillus fumigatus. Inhibitors such as FMDP and bacilysin act by blocking the enzyme's active site, leading to cell wall weakening and fungal lysis (PubMed: 11028915). However, achieving selectivity over the human homolog, glutamine-fructose-6-phosphate aminotransferase (GFAT), remains a significant challenge in drug development. Most known inhibitors are analogs of the substrates and often require specialized transport systems to enter the fungal cell. Despite these challenges, GlmS remains a focus for developing novel antifungals due to its essentiality and the unique composition of the fungal cell wall.

Other names

L-glutamine:D-fructose-6-phosphate amidotransferaseGlucosamine-6-phosphate isomerase (glutamine-forming)GFAT (fungal)GlmS

Inhibition of the enzyme's catalytic activity by competing with or irreversibly binding to the glutamine or fructose-6-phosphate binding sites, thereby preventing the synthesis of glucosamine-6-phosphate (PubMed: 15608112).