Fungal GPI ethanolamine phosphate transferase 1 (Mcd4) (Mcd4)

Fungal GPI ethanolamine phosphate transferase 1, also known as Mcd4, is an essential enzyme in the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway, catalyzing the transfer of ethanolamine phosphate to the first alpha-1 mannose residue (Man1) of the GPI core structure in the endoplasmic reticulum.[3][1][6] This modification is critical for GPI anchor maturation, enabling proper attachment and localization of >100 cell surface proteins that maintain fungal cell wall integrity, polarity, conidiation, and virulence.[1][2][5] In pathogens like Candida albicans and Aspergillus fumigatus, Mcd4 activity ensures organization of conidial cell walls and hides immunogenic components such as β-glucan; its inhibition exposes these pathogen-associated molecular patterns (PAMPs), triggering immune responses like TNFα secretion and Toll-like receptor activation.[1][2] Unlike mammalian orthologues (PIGN/Pig-N), fungal Mcd4 lacks certain functions, allowing selective inhibition by compounds like M743 and M720, which exhibit potent antifungal activity (MIC 0.25-1 μg/mL) against diverse fungi including C. albicans, C. glabrata, and A. fumigatus without significant human cell toxicity.[1] Disruption of Mcd4 leads to mislocalized GPI-anchored proteins, abnormal polarity, autophagy, and hypersensitivity to inhibitors, positioning it as a promising antifungal target distinct from current classes like azoles or echinocandins.[1][2]

Other names

MCD4Gpi7 (in some fungi like Aspergillus fumigatus)EtNP transferaseethanolamine phosphate transferase

Inhibition of ethanolamine phosphate transfer to mannose 1 (Man1) of GPI precursor, blocking GPI biosynthesis