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Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness.

Abdelwahab NZ, Crossman AT, Sullivan L, Ferguson MA, Urbaniak MD - Chem Biol Drug Des (2012)

Bottom Line: We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups.Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme.Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC(50) values 0.1-1.5mM and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the α1-4-mannose transferase with an apparent IC(50)= 19±0.5μm.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.

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The GlcNAc-PI de-N-acetylase substrates and products used in this study.
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fig01: The GlcNAc-PI de-N-acetylase substrates and products used in this study.

Mentions: The structure, biosynthesis, and function of GPIs and related molecules have been extensively reviewed (1,9–11). The basic conserved GPI core of NH2CH2CH2PO4H-6Manα1-2Manα1-6Manα1-4GlcNα1-6-d-myo-inositol-1-HPO4-lipid, where the lipid can be diacylglycerol, alkylacylglycerol, or ceramide, is often further decorated with additional ethanolamine phosphate and/or carbohydrate groups in a species- and tissue-specific manner. Biosynthesis of GPI, which occurs in the endoplasmic reticulum, is initiated by the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI) to generate N-acetylglucosamine-phosphatidylinositol (GlcNAc-PI 1, Figure 1), which is de-N-acetylated by the enzyme GlcNAc-PI de-N-acetylase (EC3.5.1.89) to give GlcN-PI 2 (12). This de-N-acetylation is a prerequisite for the subsequent mannosylation of GlcN-PI that leads to mature GPI anchor precursors (13). From GlcN-PI onwards, there are significant differences in the GPI biosynthetic pathways of T. brucei and mammalian cells (14–17).


Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness.

Abdelwahab NZ, Crossman AT, Sullivan L, Ferguson MA, Urbaniak MD - Chem Biol Drug Des (2012)

The GlcNAc-PI de-N-acetylase substrates and products used in this study.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473218&req=5

fig01: The GlcNAc-PI de-N-acetylase substrates and products used in this study.
Mentions: The structure, biosynthesis, and function of GPIs and related molecules have been extensively reviewed (1,9–11). The basic conserved GPI core of NH2CH2CH2PO4H-6Manα1-2Manα1-6Manα1-4GlcNα1-6-d-myo-inositol-1-HPO4-lipid, where the lipid can be diacylglycerol, alkylacylglycerol, or ceramide, is often further decorated with additional ethanolamine phosphate and/or carbohydrate groups in a species- and tissue-specific manner. Biosynthesis of GPI, which occurs in the endoplasmic reticulum, is initiated by the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI) to generate N-acetylglucosamine-phosphatidylinositol (GlcNAc-PI 1, Figure 1), which is de-N-acetylated by the enzyme GlcNAc-PI de-N-acetylase (EC3.5.1.89) to give GlcN-PI 2 (12). This de-N-acetylation is a prerequisite for the subsequent mannosylation of GlcN-PI that leads to mature GPI anchor precursors (13). From GlcN-PI onwards, there are significant differences in the GPI biosynthetic pathways of T. brucei and mammalian cells (14–17).

Bottom Line: We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups.Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme.Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC(50) values 0.1-1.5mM and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the α1-4-mannose transferase with an apparent IC(50)= 19±0.5μm.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.

Show MeSH
Related in: MedlinePlus