GPI inositol acyltransferase (fungal Gwt1) (Gwt1)

GPI inositol acyltransferase (Gwt1) is an endoplasmic reticulum (ER) membrane-bound enzyme essential for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors in fungi[1][2][4][8]. It catalyzes the acylation of glucosaminyl-phosphatidylinositol (GlcN-PI), an early step critical for the maturation and membrane anchoring of many cell wall proteins[1][2][4]. Gwt1 contains multiple transmembrane helices forming a catalytic tunnel that accommodates palmitoyl-CoA and substrate for acyl transfer[1]. Its function is conserved across major fungal pathogens such as Candida and Aspergillus[1][3][8]. Inhibiting Gwt1 impairs GPI-anchor biosynthesis, leading to defective cell wall assembly, heightened cell wall stress, increased surface exposure of immunogenic β-glucan, and ultimately fungal cell death[2][3][4]. Gwt1 is not present in humans, but its mammalian functional ortholog is PIG-W, which shows enough sequence divergence to allow selective inhibition by antifungals such as manogepix, gepinacin, and E1210[4]. Because of its essential and fungal-specific role, Gwt1 is a validated antifungal drug target, with multiple inhibitors progressing in clinical and preclinical development[1][3][4][5][6].

Other names

GPI-anchored wall transfer protein 1GWT1pglucosaminyl-phosphatidylinositol O-acyltransferaseinositol acyltransferaseGPI inositol acyltransferase (fungal)

Inhibition of inositol acylation in the glycosylphosphatidylinositol (GPI) biosynthesis pathway; Selective inhibition of fungal Gwt1 enzyme, leading to disruption of GPI-anchored protein assembly and cell wall function