SFU

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O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers

The aggregation of the microtubule-associated protein tau into paired helical filaments to form neurofibrillary tangles constitutes one of the pathological hallmarks of Alzheimer's disease. Tau is post-translationally modified by the addition of N-acetyl-D-glucosamine O-linked to several serine and threonine residues (O-GlcNAc). Previously, increased O-GlcNAcylation of tau has been shown to block the accumulation of tau [...]

January 18th, 2014|Tags: , , , |

Structural snapshots of the reaction coordinate for O-GlcNAc transferase

Visualization of the reaction coordinate undertaken by glycosyltransferases has remained elusive but is critical for understanding this important class of enzyme. Using substrates and substrate mimics, we describe structural snapshots of all species along the kinetic pathway for human O-linked β-N-acetylglucosamine transferase (O-GlcNAc transferase), an intracellular enzyme that catalyzes installation of a dynamic post-translational modification. [...]

October 28th, 2012|Tags: , |

Alectos Supports NSERC Funding for Prof. B.M. Pinto at SFU

July 16, 2012 – Alectos today announced its support for NSERC funding for the group of Prof. B.M. Pinto at Simon Fraser University, Department of Chemistry, in a project titled “Molecular dynamics simulations of Ligand-Enzyme complexes for a novel target involved in cancer metabolism". The collaboration between Alectos Therapeutics and the Pinto group at SFU [...]

July 16th, 2012|Tags: , , , |

Alectos Supports NSERC Funding for Prof. L. Craig at SFU

April 30, 2012 – Alectos today announced its support for NSERC funding for the group of Prof. L. Craig at Simon Fraser University, Department of Molecular Biology and Biochemistry, in a project titled “Structural analysis of small molecule inhibitors of a novel target for the treatment of cancer". Compared to normal cells, cancer cells exhibit [...]

April 30th, 2012|Tags: , , , |

Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation

Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer’s disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of [...]

February 26th, 2012|Tags: , , , , , |

Insights into O-linked N-acetylglucosamine ((0-9)O-GlcNAc) processing and dynamics through kinetic analysis of O-GlcNAc transferase and O-GlcNAcase activity on protein substrates

Cellular O-linked N-acetylglucosamine (O-GlcNAc) levels are modulated by two enzymes: uridine diphosphate-N-acetyl-D-glucosamine:polypeptidyltransferase (OGT) and O-GlcNAcase (OGA). To quantitatively address the activity of these enzymes on protein substrates, we generated five structurally diverse proteins in both unmodified and O-GlcNAc-modified states. We found a remarkably invariant upper limit for k(cat)/K(m) values for human OGA (hOGA)-catalyzed processing of [...]

February 6th, 2012|Tags: , , |

Alectos Supports NSERC Funding for Prof. R.A. Britton at SFU

Feb 1, 2012 – Alectos today announced its support for NSERC funding for the group of Prof. R.A. Britton at Simon Fraser University, Department of Chemistry, in a project titled “Synthesis of small molecule modulators of cancer metabolism". Cancer is a worldwide health problem and is the leading cause of death in Canada. Novel treatment [...]

February 1st, 2012|Tags: , , , |

Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells

Glycosyltransferases are ubiquitous enzymes that catalyze the assembly of glycoconjugates throughout all kingdoms of nature. A long-standing problem is the rational design of probes that can be used to manipulate glycosyltransferase activity in cells and tissues. Here we describe the rational design and synthesis of a nucleotide sugar analog (Ac-5SGlcNAc) that inhibits, with high potency [...]

January 23rd, 2011|Tags: , , , |

Elevation of Global O-GlcNAc in rodents using a selective O-GlcNAcase inhibitor does not cause insulin resistance or perturb glucohomeostasis

The O-GlcNAc modification is proposed to be a nutrient sensor with studies suggesting that global increases in O-GlcNAc levels cause insulin resistance and impaired glucohomeostasis. We address this hypothesis by using a potent and selective inhibitor of O-GlcNAcase, known as NButGT, in a series of in vivo studies. Treatment of rats and mice with NButGT, [...]

September 24th, 2010|Tags: , |

Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes

To probe increased O-GlcNAc levels as an independent mechanism governing insulin resistance in 3T3-L1 adipocytes, a new class of O-GlcNAcase (OGA) inhibitor was studied. 6-Acetamido-6-deoxy-castanospermine (6-Ac-Cas) is a potent inhibitor of OGA. The structure of 6-Ac-Cas bound in the active site of an OGA homolog reveals structural features contributing to its potency. Treatment of 3T3-L1 [...]

September 24th, 2010|Tags: , |