OGT

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Alectos Announces Preclinical Data for Novel Cancer Metabolism Target

May 22, 2014 – Alectos today announced publication of preclinical studies showing that both knockdown and pharmacological inhibition of O-GlcNAc transferase (OGT) result in reduced metabolic output, increased apoptosis, and impaired survival in tumor cells.  This data strongly supports OGT as a novel cancer metabolism target. For details, see: Ferrer, C.M. et al. Mol Cell [...]

May 22nd, 2014|Tags: , , , |

O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway

The hexosamine biosynthetic pathway elevates posttranslational addition of O-linked β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via hypoxia-inducible factor 1 (HIF-1α) and its transcriptional target GLUT1. Reducing O-GlcNAcylation [...]

May 22nd, 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: , |

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: , , |

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: , , , |

Structure of an O-GlcNAc transferase homolog provides insight into intracellular glycosylation

N-Acetylglucosamine (O-GlcNAc) modification of proteins provides a mechanism for the control of diverse cellular processes through a dynamic interplay with phosphorylation. UDP-GlcNAc:polypeptidyl transferase (OGT) catalyzes O-GlcNAc addition. The structure of an intact OGT homolog and kinetic analysis of human OGT variants reveal a contiguous superhelical groove that directs substrates to the active site. Source: Martinez-Fleites, [...]

June 8th, 2008|Tags: , |