Glycosylation in Cellular Mechanisms of Health and Disease

Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.

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Biological Roles of Glycans

In the CST, there was a first fixation period of 1 s, followed by a brief presentation (100 ms) of a cue at 208 to the left or to the right The monkey had to maintain his gaze at the fixation spot during a delay period of 1 s The fixation spot then disappeared and the target appeared at the same position as the cue In half of the trials, another spot appeared at the alternative position (distracter) The monkey had to make a saccade to the target position within 500 ms, and was rewarded with a drop of water for a correct saccade After recording neurons in the CST (experiment 2), we re-applied the BST (experiment 1) for at least 80 trials to confirm the reproducibility of neuronal activity Data analysis Pre-target neurons were defined as neurons that showed a statistically reliable increase in the spike count 215 s to 0 s before target onset (‘pre-target window’) as compared with the spike count 2 3s to215 s before target onset All pair-wise comparisons were evaluated by two-tailed t-tests, P , 001 We used the Bonferroni procedure to correct for family-wise error with multiple t-tests To quantify the separation of population distributions from contralateral versus ipsilateral conditions, we calculated the area under the ROC in a sliding window of 200 ms To test the adaptation of saccade latency and pre-target activity to a reversal of position-reward contingency, we compared the second trial after a reversal against the third trial after a reversal (test 1) We also compared the second trial after a reversal against the pooled data from the sixth to twentieth trial (test 2) Both tests consisted of paired twotailed t-tests on the mean data from individual neurons Adaptation was judged complete if there was no significant difference between the measures Tests 1 and 2 produced similar results in all cases For comparison between the two tasks (BST versus CST), we considered the neuronal activity from 2500 to 0 ms before target onset in both tasks, in the computation of absolute firing rates as well as ROC areas

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Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies

Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

A developmental and genetic classification for malformations of cortical development

Increased understanding of the important roles that oligosaccharides and glycoconjugates play in biological processes has led to a demand for significant amounts of these materials for biological, medicinal, and pharmacological studies. Therefore, tremendous effort has been made to develop new procedures for the synthesis of glycosides, whereby the main focus is often the formation of the glycosidic bonds. Accordingly, quite a few review articles have been published over the past few years on glycoside synthesis; however, most are confined to either a specific type of glycoside or a specific strategy for glycoside synthesis. In this Review, new principles for the formation of glycoside bonds are discussed. Developments, mainly in the last ten years, that have led to significant advances in oligosaccharide and glycoconjugate synthesis have been compiled and are evaluated.

New principles for glycoside-bond formation.

Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1.

We describe a novel chemoenzymatic synthesis of eel calcitonin (eCT) glycopeptide analogues having natural N-linked oligosaccharides, such as a disialo biantennary complex-type [(NeuAc-Gal-GlcNAc-Man)2-Man-GlcNAc2], an asialo complex-type [(Gal-GlcNAc-Man)2-Man-GlcNAc2], and a high-mannose type [Man6-GlcNAc2] as model compounds for glycoprotein synthesis. First, a glycoprotein containing N-acetylglucosamine (GlcNAc) was prepared by a chemical synthesis. Next, natural oligosaccharides were added to the prepared glycopeptide containing GlcNAc by a transglycosylation reaction using endo-β-N-acetylglucosaminidase (endo-β-GlcNAc-ase) from Mucor hiemalis.

Synthesis of a Glycopeptide Containing Oligosaccharides: Chemoenzymatic Synthesis of Eel Calcitonin Analogues Having Natural N-Linked Oligosaccharides

A novel disaccharide substrate having 1,2-oxazoline moiety for detection of transglycosylating activity of endoglycosidases.

Transglycosylation of intact sialo complex-type oligosaccharides to the N-acetylglucosamine moieties of glycopeptides by Mucor hiemalis endo-β-N-acetylglucosaminidase

Toshiyuki Inazu

Papers

Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1.

Synthesis of a Glycopeptide Containing Oligosaccharides: Chemoenzymatic Synthesis of Eel Calcitonin Analogues Having Natural N-Linked Oligosaccharides

A novel disaccharide substrate having 1,2-oxazoline moiety for detection of transglycosylating activity of endoglycosidases.

Transglycosylation of intact sialo complex-type oligosaccharides to the N-acetylglucosamine moieties of glycopeptides by Mucor hiemalis endo-β-N-acetylglucosaminidase

Oligosaccharide synthesis on a fluorous support