The N-acetyl-D-glucosaminylphosphatidylinositol De-N-acetylase of glycosylphosphatidylinositol biosynthesis is a zinc metalloenzyme

Urbaniak, Michael D. and Crossman, Arthur and Chang, Tunhan and Smith, Terry K. and van Aalten, Daan M. F. and Ferguson, Michael A. J. (2005) The N-acetyl-D-glucosaminylphosphatidylinositol De-N-acetylase of glycosylphosphatidylinositol biosynthesis is a zinc metalloenzyme. Journal of Biological Chemistry, 280 (24). pp. 22831-22838. ISSN 0021-9258

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Abstract

The de-N-acetylation of N-acetyl-D-glucosaminylphosphatidylinositol (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 anti-protozoan parasite drugs.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Biological Chemistry
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1312
Subjects:
ID Code:
66399
Deposited By:
Deposited On:
17 Sep 2013 08:08
Refereed?:
Yes
Published?:
Published
Last Modified:
06 May 2020 02:51