Glycosyltransferase - Wikipedia
Sulfones as Potential Glycosyl Transferase ..
Reversible post-translational modification of many cytoplasmic and nuclear proteins in eukaryotic cells by glycosylation of serine and threonine residues with β-linked N-acetylglucosamine (O-GlcNAc) has been shown to regulate cellular processes as diverse as transcription, translation, insulin sensitivity, protein trafficking and degradation (Torres and Hart ; Zachara and Hart ; Love and Hanover ; Hart et al ). Only two enzymes are responsible for the dynamic cycling of O-GlcNAc. The O-GlcNAc transferase (OGT) transfers GlcNAc, using UDP–GlcNAc as the sugar donor, via an inverting mechanism involving as yet unidentified active site residues. The O-GlcNAc hydrolase (OGA) cleaves the glycosidic bond, thus reversing the modification. Dysregulation of O-GlcNAc is thought to play a role in human pathogenesis, such as cancer (Chou and Hart ; Liu et al. ; Donadio et al. ), Alzheimer’s (Griffith and Schmitz ; Yao and Coleman ; Liu et al. ; Wells and Hart ; Dias and Hart ) and diabetes (McClain et al. ; Copeland et al. ). Hundreds of cytoplasmic and nucleoplasmic proteins have been shown to be O-GlcNAc modified, although the precise glycosylation sites and functional implications have been determined for only a few of these. Interestingly, examples of crosstalk between protein O-GlcNAcylation and phosphorylation have been recently reported, with the O-GlcNAcylation site being either identical or adjacent to protein phosphorylation sites (Yang et al. ). However, the precise molecular mechanisms by which OGT and OGA recognise and act on hundreds of proteins, thereby regulating cellular signalling cascades, remain to be discovered (Hurtado-Guerrero et al. ). The OGA enzyme has been characterised in humans, rat, Drosophila and C. elegans (Kelly and Hart ; Dong and Hart ; Gao et al. ; Comtesse et al. ; Forsythe et al. ). The OGA reaction mechanism has been elucidated and structural insights have been obtained recently from bacterial OGA homologues (Macauley et al. ; Rao et al. ; Dennis et al. ; Ficko-Blean et al. ). A wealth of chemical biological tools exist to raise intracellular O-GlcNAc levels in living cells by inhibition of O-GlcNAcase. Until recently the only inhibitors of hOGA were the aspecific compounds PUGNAc (Haltiwanger et al. ) and streptozotocin (STZ) (Liu et al. ). Lately, several new compounds have been described that selectively and potently inhibit human OGA (Macauley et al. ; Dennis et al. ; Dorfmueller et al. ; Dorfmueller et al. ; Stubbs et al. ; Yuzwa et al. ). These chemical tools are currently enabling studies towards the role of O-GlcNAc in a range of signal transduction pathways, although it is becoming clear that certain cell types are remarkably tolerant of inhibitor-induced hyper-O-GlcNAcylation.
Glycosyltransferases | Sigma-Aldrich
The first insights into OGT structure have recently been obtained from an apparent bacterial OGT orthologue from Xanthomonas campestris (XcOGT) (Clarke et al. ; Martinez-Fleites et al. ). Structural complexes with UDP and an UDP–GlcNAc phosphonate analogue revealed features of the active site and three distinct domains: (1) multiple tetratricopeptide repeats (TPRs), (2) a linker region and (3) the catalytic (glycosyltransferase activity) domain, belonging to the GT41 family in the CAZy database (Coutinho et al. ). The active site is located between the two lobes of the GT41 domain. While hOGT mutants informed by the structural complexes (Clarke et al. ; Martinez-Fleites et al. ) have helped to identify several inactive mutants, however, the precise catalytic mechanism of OGT yet remains to be discovered.