Glycosylphosphatidylinositol-anchored wall protein 1 (GWT1) (GWT1)

Glycosylphosphatidylinositol-anchored wall protein 1 (GWT1) is an essential fungal enzyme located in the endoplasmic reticulum that plays a critical role in the early stages of glycosylphosphatidylinositol (GPI) anchor biosynthesis (Source: UniProt P47101). It specifically catalyzes the N-acylation of the inositol ring of glucosaminyl-phosphatidylinositol, a step necessary for the subsequent attachment of proteins to the fungal cell wall (Source: PubMed: 27001387). Because GPI-anchored proteins are vital for maintaining cell wall integrity, adhesion, and biofilm formation, GWT1 serves as a potent target for novel antifungal therapies (Source: PubMed: 31138563). Inhibition of GWT1 leads to the depletion of cell wall proteins, resulting in compromised structural integrity and reduced virulence of various fungal pathogens, including Candida and Aspergillus species (Source: PubMed: 30635339). The most prominent drug targeting this enzyme is manogepix, the active form of the prodrug fosmanogepix, which demonstrates high selectivity for the fungal enzyme over human orthologs (Source: PubMed: 29439114). This selectivity minimizes potential host toxicity, as the human version of the enzyme, PIG-W, is structurally distinct (Source: PubMed: 29439114). This mechanism of action is distinct from existing antifungal classes like azoles or echinocandins, making it effective against many multi-drug resistant strains (Source: PubMed: 31138563). Consequently, GWT1 inhibitors represent a promising new class of antifungals for treating invasive fungal infections (Source: PubMed: 30635339).

Other names

GWT1Acyltransferase GWT1GPI-anchored wall protein 1Protein GWT1

Inhibition of GWT1 enzyme activity prevents the acylation of inositol during glycosylphosphatidylinositol (GPI) anchor biosynthesis, leading to defective cell wall assembly and fungal growth inhibition.