Interaction of substituted hexose analogues with the Trypanosoma brucei hexose transporter

Azéma, Laurent; Claustre, Samantha; Alric, Isabelle; Blonski, Casimir; Willson, Michèle; Périé, Jacques; Baltz, Théo; Tétaud, Emmanuel; Bringaud, Frédéric; Cottem, Dominique; Opperdoes, Frederik; Barrett, Michael P.

doi:10.1016/j.bcp.2003.09.005

Cited by 42 publications

(39 citation statements)

References 44 publications

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“…However, the ability to biosynthetically radiolabel T. brucei and L. major glycoconjugates with [ 3 H]GlcN (30,91) shows that a salvage pathway, presumably via the action of hexokinase (GlcN 3 GlcN-6-P), also exists. Most likely, the former pathway is the most important in vivo, since free GlcN is not an abundant sugar in either mammals or insects and, at least in T. brucei, its N-acetyl derivative (GlcNAc) is not taken up (6). Since GlcNAc and/or GlcN is present in every known type of trypanosomatid glycoconjugate carbohydrate chain, with the exception of the side chains of leishmania and T. cruzi PPGs, UDP-GlcNAc biosynthesis has potential as a therapeutic target against all three parasites, so long as parasite-selective inhibitors can be found.…”

Section: Cruzi) Gdp-man Is Also the Precursor Of Gdp-fuc (See Below)mentioning

confidence: 99%

“…The proposed route to GDP-Ara re-VOL. 6,2007 TRYPANOSOMATID SUGAR NUCLEOTIDES 1459 quires a GDP-Ara pyrophosphorylase activity, but no candidate genes (e.g., homologues of mammalian GDP-Fuc pyrophosphorylase genes) are apparent in the L. major genome. In L. major promastigotes, the proportion of phosphosaccharide repeats with ␤-D-Arap-terminating side chains is under developmental control, such that levels of Ara are low in logarithmically growing procyclic promastigotes and significantly higher in metacyclic promastigotes (67,87).…”

Section: Cruzi) Gdp-man Is Also the Precursor Of Gdp-fuc (See Below)mentioning

confidence: 99%

“…6,2007 TRYPANOSOMATID SUGAR NUCLEOTIDES 1451 only in T. cruzi. T. cruzi is also unique in expressing abundant O-linked glycans with GlcNAc␣1-O-Thr linkages (89).…”

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Sugar Nucleotide Pools of Trypanosoma brucei , Trypanosoma cruzi , and Leishmania major

2007

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The cell surface glycoconjugates of trypanosomatid parasites are intimately involved in parasite survival, infectivity, and virulence in their insect vectors and mammalian hosts. Although there is a considerable body of work describing their structure, biosynthesis, and function, little is known about the sugar nucleotide pools that fuel their biosynthesis. In order to identify and quantify parasite sugar nucleotides, we developed an analytical method based on liquid chromatography-electrospray ionization-tandem mass spectrometry using multiple reaction monitoring. This method was applied to the bloodstream and procyclic forms of Trypanosoma brucei, the epimastigote form of T. cruzi, and the promastigote form of Leishmania major. The trypanosomatids are protozoan parasites that impose a major health burden on many countries in the developing world, causing a wide range of diseases over three continents. Like most eukaryotes, the cell surfaces and endosomal/lysosomal systems of these organisms are rich in glycoconjugates, some of which play essential roles in their survival, infectivity, or virulence. The glycoconjugate repertoires of the three trypanosomatids studied here, Trypanosoma brucei, T. cruzi, and Leishmania major, are fundamentally different, reflecting their disparate life cycles, modes of infection, and disease pathologies (see references 5,27,28,38,47,65, and 69 and references therein). The monosaccharides that make up these glycoconjugates vary between the three trypanosomatid species. For example, all three contain D-mannose (Man), D-Nacetylglucosamine (GlcNAc), D-glucosamine (GlcN), D-glucose (Glc), and D-galactopyranose (Galp), while only T. cruzi and L. major contain D-galactofuranose (Galf), only T. cruzi contains D-xylose (Xyl), L-rhamnopyranose (Rha), and L-fucose (Fuc), and only L. major contains D-arabinopyranose (Ara) ( Table 1). However, a unifying theme of their glycobiology is an abundance of cell surface glycosylphosphatidylinositol (GPI)-anchored glycoproteins and/or non-proteinlinked GPI structures.The protein-linked GPI glycans of the leishmania are the simplest in structure, consisting of the conserved Man␣1-2Man␣1-6Man␣1-4GlcN core. Those of T. cruzi are principally Man␣1-2Man␣1-2Man␣1-6Man␣1-4GlcN, and those of T. brucei are the most complex, with ␣-D-Galp and ␤-D-Galp side chains in the bloodstream form and sialylated poly-N-acetyllactosamine (poly-LacNAc) side chains in the procyclic form (27).The non-protein-linked GPI structures include the so-called glycoinositolphospholipids, or GIPLs, that are most abundant in the leishmania and T. cruzi species (58, 64, 90) but are also found in procyclic-form T. brucei (60,73,122) and bloodstream form T. brucei (39,63). Non-protein-linked GPIs also include the more exotic leishmania-specific lipophosphoglycan (LPG) structures (38,47,64,65). The leishmania LPGs contain characteristic phosphosaccharide repeats of Galp␤1-4Man␣1-P, which in L. major can have ␤-D-Galp and ␣-D-Arap side chains (66,67). These repeats are also found in the secr...

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Section: Cruzi) Gdp-man Is Also the Precursor Of Gdp-fuc (See Below)mentioning

confidence: 99%

Section: Cruzi) Gdp-man Is Also the Precursor Of Gdp-fuc (See Below)mentioning

confidence: 99%

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Sugar Nucleotide Pools of Trypanosoma brucei , Trypanosoma cruzi , and Leishmania major

2007

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“…The GlcNAc sugar is present in the N-acetylchitobiosyl cores of all glycoprotein N-linked glycans; and glucosamine (GlcN), derived from GlcNAc by de-N-acetylation (11), is present in protein-linked and free GPI structures. N-Acetylglucosamine is also found in N-acetyllactosamine (LacNAc) units of Gal␤ (1)(2)(3)(4)GlcNAc that decorate conventional complex N-linked glycans (28) and appear in unusual giant polyLacNAc-containing N-linked glycans throughout the flagellar pocket and endosomal/lysosomal system of the bloodstream form of the parasite (3). LacNAc repeats and lacto-N-biose repeats of Gal␤(1-3)GlcNAc also appear as side chains of the procyclin GPI anchor and free GPIs in the procyclic form of the organism (35,42,48).…”

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confidence: 99%

“…1). The de novo pathway from glucose is probably the most important in vivo, since T. brucei does not take up GlcNAc (4) and free GlcN is not an abundant sugar in either mammals or insects.…”

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Characterization, Localization, Essentiality, and High-Resolution Crystal Structure of Glucosamine 6-Phosphate N -Acetyltransferase from Trypanosoma brucei

et al. 2011

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A gene predicted to encode Trypanosoma brucei glucosamine 6-phosphate N-acetyltransferase (TbGNA1; EC 2.3.1.4) was cloned and expressed in Escherichia coli. The recombinant protein was enzymatically active, and its high-resolution crystal structure was obtained at 1.86 Å. Endogenous TbGNA1 protein was localized to the peroxisome-like microbody, the glycosome. A bloodstream-form T. brucei GNA1 conditional null mutant was constructed and shown to be unable to sustain growth in vitro under nonpermissive conditions, demonstrating that there are no metabolic or nutritional routes to UDP-GlcNAc other than via GlcNAc-6-phosphate. Analysis of the protein glycosylation phenotype of the TbGNA1 mutant under nonpermissive conditions revealed that poly-N-acetyllactosamine structures were greatly reduced in the parasite and that the glycosylation profile of the principal parasite surface coat component, the variant surface glycoprotein (VSG), was modified. The significance of results and the potential of TbGNA1 as a novel drug target for African sleeping sickness are discussed.

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Drug Discovery Strategies for the Generation of Multitarget Ligands against Neglected Tropical Diseases

Gandini

Prati

Uliassi

et al. 2017

Methods and Principles in Medicinal Chemistry

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Interaction of substituted hexose analogues with the Trypanosoma brucei hexose transporter

Cited by 42 publications

References 44 publications

Sugar Nucleotide Pools of Trypanosoma brucei , Trypanosoma cruzi , and Leishmania major

Sugar Nucleotide Pools of Trypanosoma brucei , Trypanosoma cruzi , and Leishmania major

Characterization, Localization, Essentiality, and High-Resolution Crystal Structure of Glucosamine 6-Phosphate N -Acetyltransferase from Trypanosoma brucei

Drug Discovery Strategies for the Generation of Multitarget Ligands against Neglected Tropical Diseases

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