Discovery of Inhibitors of Leishmania β-1,2-Mannosyltransferases Using a Click-Chemistry-Derived Guanosine Monophosphate Library

Leishmania spp. are a medically important group of protozoan parasites that synthesize a novel intracellular carbohydrate reserve polymer termed mannogen. Mannogen is a soluble homopolymer of β-1,2-linked mannose residues that accumulates in the major pathogenic stages in the sandfly vector and mammalian host. While several steps in mannogen biosynthesis have been defined, none of the enzymes have been isolated or characterized. We report the development of a simple assay for the GDP-mannose–dependent β-1,2-mannosyltransferases involved in mannogen synthesis. This assay utilizes octyl α-d-mannopyranoside to prime the formation of short mannogen oligomers up to 5 mannose residues. This assay was used to screen a focussed library of 44 GMP-triazole adducts for inhibitors. Several compounds provided effective inhibition of mannogen β-1,2-mannosyltransferases in a cell-free membrane preparation. This assay and inhibitor compounds will be useful for dissecting the role of different mannosyltransferases in regulating de novo biosynthesis and elongation reactions in mannogen metabolism

Climatic control of denudation in the deglaciated landscape of the Washington cascades

Since the Last Glacial Maximum, the extent of glaciers in many mountainous regions has declined, and erosion driven by glacial processes has been supplanted by fluvial incision and mass wasting processes. This shift in the drivers of erosion is thought to have altered the rate and pattern of denudation of these landscapes. The Washington Cascades Mountains in the northwestern USA still bear the topographic imprint of Pleistocene glaciations, and are affected by large variations in precipitation, making them an ideal setting to assess the relative controls of denudation. Here we show that denudation rates over the past millennia, as determined by 10Be exposure ages, range from 0.08 to 0.57 mm yr−1, about four times higher than the rates inferred for million-year timescales. We find that the millennial timescale denudation rates increase linearly with modern precipitation rates. Based on our landscape analyses, we suggest that this relationship arises because intense precipitation triggers landslides, particularly on slopes that have been steepened by glacial erosion before or during the Last Glacial Maximum. We conclude that the high modern interglacial denudation rates we observe in the Washington Cascades are driven by a disequilibrium between the inherited topography and the current spatial distribution of erosional processes that makes this range particularly sensitive to spatial variations in climate