T1 - Glycosyltransferase inhibitors

Leukocyte count does not rise as high in response to infection in elderly individuals as in young people and that often the principal manifestation of a leukocyte response is an increase in the number of band forms in an otherwise normal leukocyte count. The leukocyte count and the proportion of neutrophils rise much less in response to bacterial pyrogen in individuals over age 70 than in young adults. Similarly, the neutrophilic leukocytosis that occurs 5 hours after the oral administration of 40 mg prednisolone is diminished in patients over 55 years of age [1]. These observations suggest a diminished marrow granulocyte reserve in the elderly and/or a decrease in hematopoietic growth factor release. The decreased responsiveness of older individuals to granulocyte colony-stimulating factor-induced release of neutrophils from the marrow supports these suppositions. Leukocyte function and serum opsonic capacity is well preserved in elderly individuals, but defects in phagocytic ability and diminished responses to chemotactic peptides and to oxidative stress have been documented. Defects in neutrophil function in elderly subjects may be due to inhibitory substances detected in plasma. Splenic function in elderly subjects may be impaired, as evidenced by an increase in the percentage of pitted erythrocytes in the blood. In the healthy elderly with no underlying pathologic condition, there are no statistically significant differences in the total leukocyte count or WBC differential between old-old compared with middle- aged adults [32].

Glycosyltransferase - Wikipedia

Studies on the synthesis of C-Glycoside sulfones as potential glycosyl transferase inhibitors

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.

T1 - Structure of the nucleotide-diphospho-sugar transferase, SpsA from Bacillus subtilis, in native and nucleotide-complexed forms

The catalytic, glycosyl transferase and acyl transferase ..

Red cell indices, red blood cell count, hemoglobin and hematocrit in cord blood at term fall after delivery; this reflects perinatal events, the amount of blood transferred from the placenta to the infant after delivery. Delay of cord clamping may increase the blood volume and red cell mass of the infant. The mean total blood volume after birth is 86.3ml/kg for the term infant and 89.4ml/kg for the premature infant. The blood volume per kilogram decreases over the weeks, reaching a mean value of about 65ml/kg by 3 to 4months of age. Normally the hemoglobin and hematocrit values rise in the first several hours after birth because of the movement of plasma from the intravascular to the extra vascular space [1,26]. Venous hemoglobin concentrations of less than 14g/dl in a term infant and/or a fall in hemoglobin or hematocrit level in the first day of life are abnormal. Capillary hematocrit values in newborns are higher than those in simultaneous venous samples; this difference reflects circulatory factors and is greater in preterm and sick infants. The RBC indices and RBC distribution width (RDW) provide a means for assessing and defining anemia.

Aromatase and glycosyl transferase inhibiting acridone alkaloids from fruits of ..

Glycosyltransferases: Tools for Synthesis and …

In the search for novel hOGT inhibitors, we have focussed our work on the synthesis and evaluation of novel hOGT substrate and product analogues (Fig. ). The inhibitory potency of these compounds revealed that they are all sub-millimolar inhibitors of hOGT (Table ). Structural data obtained from UDP-S-GlcNAc soaking experiments with XcOGT crystals revealed a competitive binding mode, yet different from the previously published UDP-C-GlcNAc complex (Clarke et al. ). The sugar moiety projects above the diphosphate group mimic positioning the thioglycosidic bond within hydrogen bonding distance of Asn385, which might play a role in catalysis [mutation of the equivalent Gln839 in hOGT generates an inactive species (Clarke et al. ; Martinez-Fleites et al. )]. This could be similar to the role of Gln189 in LgtC, a retaining galactosyltransferase from Neisseria meningitidis (Tvaroska ). On the basis of structural, biochemical and molecular modelling, Gln189 in LgtC was predicted to be involved in hydrogen bond formation with the donor and the acceptor in the transition state (Tvaroska ). However, the identity of the catalytic base in hOGT remains to be firmly established.

Glycosyltransferases from the Leloir pathway 6-8 ..

as human O-GlcNAc transferase inhibitors .

... identification of catalytic residues. MECHANISMS OF ACTION There are two major catalytic mechanisms for glycosyl transfer, regardless of the direction of the reaction (i.e., synthesis or hydrolysis) =-=(36)-=-. In both cases, the reactions proceed either by retention or by overall inversion of the anomeric configuration at the reaction center. For glycosyl hydrolases, the mechanisms have been shown to corr...