Probing Enzymes Late in the Trypanosomal Glycosylphosphatidylinositol Biosynthetic Pathway with Synthetic Glycosylphosphatidylinositol Analogues

Urbaniak, Michael D.; Yashunsky, Dmitry V.; Crossman, Arthur; Nikolaev, Andrei V.; Ferguson, Michael A. J.

doi:10.1021/cb800143w

Cited by 27 publications

(21 citation statements)

References 40 publications

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“…The GPI lipid anchor is a complex organic structure made up of an inositol phospholipid, a tetrasaccharide with variable elaborations and phosphoethanolamine subunits (Paulick and Bertozzi, 2008). Although the general outline of the GPI lipid anchor biosynthesis pathway is common among eukaryotes, there are distinctive taxon-specific differences that might be useful for species-specific inhibitor design (Izquierdo et al, 2009;Smith et al, 2004;Urbaniak et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Structural insight into the glycosylphosphatidylinositol transamidase subunits PIG-K and PIG-S from yeast

Toh¹,

Kamariah²,

Maurer‐Stroh

et al. 2011

Journal of Structural Biology

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Section: Introductionmentioning

confidence: 99%

Structural insight into the glycosylphosphatidylinositol transamidase subunits PIG-K and PIG-S from yeast

Toh¹,

Kamariah²,

Maurer‐Stroh

et al. 2011

Journal of Structural Biology

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“…Mannosyltransferase III (MTIII) has been found to be substrate specific. There is a difference in the structure of the substrates for the mammalian and the trypanosomal MTIII which suggests that species-specific inhibition can be achieved by synthesizing small molecule inhibitors (Urbaniak et al 2008). The mannose donor for all GPI-mannosyl transferases is dolichol-P-mannose (Dol-P-Man).…”

Section: Gpi Biosynthetic Pathway As Drug Targetmentioning

confidence: 99%

Drug targets in Leishmania

2010

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Leishmaniasis is a major public health problem and till date there are no effective vaccines available. The control strategy relies solely on chemotherapy of the infected people. However, the present repertoire of drugs is limited and increasing resistance towards them has posed a major concern. The first step in drug discovery is to identify a suitable drug target. The genome sequences of Leishmania major and Leishmania infantum has revealed immense amount of information and has given the opportunity to identify novel drug targets that are unique to these parasites. Utilization of this information in order to come up with a candidate drug molecule requires combining all the technology and using a multi-disciplinary approach, right from characterizing the target protein to high throughput screening of compounds. Leishmania belonging to the order kinetoplastidae emerges from the ancient eukaryotic lineages. They are quite diverse from their mammalian hosts and there are several cellular processes that we are getting to know of, which exist distinctly in these parasites. In this review, we discuss some of the metabolic pathways that are essential and could be used as potential drug targets in Leishmania.

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“…[61] Intact GPI anchors are essential for the viability of bloodstream T. brucei, and their biosynthesis has been validated chemically and genetically as a target for the development of novel, antitrypanosomal drugs. [62,63] GPI-anchor biosynthesis [64] involves several mannosyltransferases (ManT), which use dolicholphosphate mannose (DPM) as their donor [65] (Scheme 4). DPM formation in turn is catalysed by the GDPMan-dependent ManT, dolicholphosphate mannose synthase (DPMS) that acts as a "gatekeeper enzyme" for GPI-anchor biosynthesis.…”

Section: Biological Roles and Potential As Therapeutic Targetsmentioning

confidence: 99%

Glycosyltransferases and their Assays

Wagner¹,

Pesnot²

2010

ChemBioChem

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Glycosyltransferases (GTs) are a large family of enzymes that are essential in all domains of life for the biosynthesis of complex carbohydrates and glycoconjugates. GTs catalyse the transfer of a sugar from a glycosyl donor to a variety of acceptor molecules, for example, oligosaccharides, peptides, lipids or small molecules. Such glycosylation reactions are central to many fundamental biological processes, including cellular adhesion, cell signalling and bacterial- and plant-cell-wall biosynthesis. GTs are therefore of significant interest as molecular targets in chemical biology and drug discovery. In addition, GTs have found wide application as synthetic tools for the preparation of complex carbohydrates and glycoconjugates. In order to exploit the potential of GTs both as molecular targets and synthetic tools, robust and operationally simple bioassays are essential, especially as more and more protein sequences with putative GT activity but unknown biochemical function are being identified. In this minireview, we give a brief introduction to GT biochemistry and biology. We outline the relevance of GTs for medicinal chemistry and chemical biology, and describe selected examples for recently developed GT bioassays, with a particular emphasis on fluorescence-based formats.

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Probing Enzymes Late in the Trypanosomal Glycosylphosphatidylinositol Biosynthetic Pathway with Synthetic Glycosylphosphatidylinositol Analogues

Cited by 27 publications

References 40 publications

Structural insight into the glycosylphosphatidylinositol transamidase subunits PIG-K and PIG-S from yeast

Structural insight into the glycosylphosphatidylinositol transamidase subunits PIG-K and PIG-S from yeast

Drug targets in Leishmania

Glycosyltransferases and their Assays

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