The N-Acetyl-D-glucosaminylphosphatidylinositol De-N-acetylase of Glycosylphosphatidylinositol Biosynthesis Is a


(GlcNAc-PI) is the second step of mammalian and trypanosomal glycosylphosphatidylinositol biosynthesis. Glycosylphosphatidylinositol biosynthesis is essential for Trypanosoma brucei, the causative agent of African sleeping sickness, and GlcNAc-PI de-N-acetylase has previously been validated as a drug target. Inhibition of the trypanosome cell-free system and recombinant rat GlcNAc-PI de-N-acetylase by divalent metal cation chelators demonstrates that a tightly bound divalent metal cation is essential for activity. Reconstitution of metal-free GlcNAc-PI de-N-acetylase with divalent metal cations restores activity in the order Zn 2 �> Cu 2 �> Ni 2 �> Co 2 �> Mg 2 �. Site-directed mutagenesis and homology modeling were used to identify active site residues and postulate a mechanism of action. The characterization of GlcNAc-PI de-N-acetylase as a zinc metalloenzyme will facilitate the rational design of antiprotozoan parasite drugs. Glycosylphosphatidylinositol (GPI) 1 acts as a membrane anchor for a significant proportion of eukaryotic cell surface glycoproteins. The structure, biosynthesis, and function of GPI anchors and related molecules have been extensively reviewed (1–6). The basic conserved GPI core of NH 2CH 2CH 2PO 4H

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