Infection & Immunity

The Leishmania Laboratory - The Mannose biosynthetic pathway

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The Mannose biosynthetic pathway and its enzymes as novel drug targets

Leishmania synthesize a range of mannose-rich glycoconjugates that form the cell surface glycocalyx or are secreted. These glycoconjugates comprise GPI-anchored glycoproteins, the GPI-anchored lipophosphoglycan, the glycoinositolphospholipids (GIPLs) and the PPGs described above. Biosynthesis of all these macromolecules depends directly or indirectly on the availability of GDP-Mannose. As mentioned above, several of these molecules are considered virulence factors, and parasites lacking them cannot survive in macrophages or mice.

A prerequisite for the biosynthesis of glycoconjugates in Leishmania, like in other eukaryotes, is the conversion of monosaccharides to activated sugar nucleotides and dolicholphosphate derivatives. As shown in the figure below, the activation of Mannose involves phosphomannomutase (PMM), GDP-Man pyrophosphorylase (GDP-MP) and dolicholphosphate-Man synthase (DPMS) . GDP-mannose pyrophosphorylase (GDP-MP) is a critical enzyme in the mannose biosynthetic pathway. The consecutive action of PMM and GDP-MP transforms Man-6-PO4 to GDP-Man which is essential for glycoconjugate synthesis in eukaryotes.

Mannose Biosythetic Pathway

The gene encoding GDP-MP is a single copy gene expressed in both parasite life cycle stages. Deletion of the GDP-MP leads to the loss of virulence as reflected by survival in macrophages or mice. Its high expression in amastigotes and the loss of virulence in null parasites make the GDP-MP an attractive target for the design of anti Leishmania drugs. Tony Davis in the lab works on the determination of the 3D structure of the enzyme and in parallel has developed a high throughput screening assay to be used to design and/or select enzyme inhibitors.

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