Glycosylphosphatidylinositol inositol-acyltransferase (Gwt1p) (Gwt1p)

Glycosylphosphatidylinositol inositol-acyltransferase (Gwt1p) is an essential, highly conserved enzyme in fungi and yeasts responsible for the acylation of the inositol ring of glucosaminyl-phosphatidylinositol (GlcN-PI) early in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors[1][3][5][6][7][8]. The GPI anchor serves to tether many proteins to the cell surface, crucial for normal cell wall structure and function in fungi and yeast. Gwt1p is a polytopic membrane protein localized to the endoplasmic reticulum, predicted to contain 13 transmembrane domains and a conserved catalytic tunnel structure[1][5]. Its human ortholog is PIG-W. Gwt1p is considered an important antifungal drug target, with manogepix as a potent, selective clinical inhibitor currently in use and development[5]. Inhibiting Gwt1p leads to defective GPI-anchor formation and is lethal to fungal cells, making it a promising target for antifungal therapy[3][5]. There are currently no well-established clinical biomarkers for patient selection or monitoring, and known safety concerns are limited to potential cross-reactivity with mammalian PIG-W if selectivity is inadequate.

Other names

GPI inositol acyltransferaseGPI anchor biosynthesis protein Gwt1GPI-anchored wall transfer protein 1PIG-W (human/mammalian ortholog)YJL011C (gene locus in S. cerevisiae)

Inhibition of Gwt1p blocks inositol acylation in GPI anchor biosynthesis, disrupting localization of GPI-anchored proteins and cell wall formation in fungi[3][5]. Competitive inhibitor at the palmitoyl-CoA binding site (e.g., manogepix acts by occupying this active site)[5].