engleski

Complex genetics of glycans

In spite great expectations deciphering of human genome did not provided many desired answers, furthermore it addressed novel questions which focused scientists on investigations on complex new biology like glycosylation and other posttranslational modifications, epigenetics, non- coding DNA, inheritance of acquired characteristics and searching for still unknown mechanisms. Glycosylation, a complex and highly coordinated biosynthetic process, which although involves hundreds of enzymes and other gene products is not template derived and consequently it is highly affected by environmental conditions. Products of glycosylation, glycans are the most diverse biopolymers in nature and thanks to their enormous structural complexity serves as a powerful tool for storing biological information. Glycans can be attached to proteins or lipids thus yielding different glycoconjucates ; gylcoproteins, glyolipids, proteoglycans and glycosylphosphatidyl inositol anchors. Nearly all membrane and secreted proteins, as well as numerous intracellular proteins are glycosylated. Recent studies suggested that at least 5-10% of the human genome is involved in glycosylation what makes this process the most complex biosynthetic pathway. In addition to polymorphisms in the genes encoding the proteins participating in glycosylation, regulation of expression, posttranslational modifications, and their activity other mechanisms, including altered intracellular localization, competition with endogenous acceptor substrates and variable access to monosaccharide donor substrates, affect the final structure of a glycan. The “glycome” (the collection of all glycan structures) by far exceeds genome and proteome. Despite the genetic conservation of organisms, glycan variations could possibly serve to bridge the gap between genotype and vast phenotypic variety. The composition of the individual's glycomes is highly variable and it seems to be a consequence of both inherited genetic polymorphisms and environmental effects. The main sources of human variability derives mainly from single nucleotide polymorphisms (SNPs) which individually, in general do not yield visible phenotypes, but when present in particular combinations could result in specific phenotypic characteristics. In that sense, glycosylation is particularly compliant to such kind of cumulated variability. Some combinations of individual SNPs can be manifested as specific glyco-phenotypes, which might represent potential evolutionary advantages or disadvantages. The most prominent example is the various types of congenital disorders of glycosylation (CDGs) which are usually caused by a combination of several individual mutations. Most of individual mutations causing reduced enzyme activity do not have particular (patho)physiological manifestation, but when combined, they result in a complex phenotype associated with severe pathologies characterized with psycomotoric, immunological, digestive and neurological symptoms. Analogously to a complex genetic diseases, the composition of an individual's glycome is a combination of genetic background and all relevant past events in the cell. Glycan structures appear far downstream in the biological information flow and for that reason they are closer to the fluctuating complexity of the actual state. Therefore disruption of homeostasis, even in its earliest stages, reflects strongly on glycan structure and expression. Changes of glycosylation highly affect physiological function of many proteins, such as immunoglobulins G and A, acetylcholinesterase, epidermal growth factor receptor, insulin receptor, haptoglobin, MHC class II molecules, human chorionic gonadotropin, trensferrin, plsaminogen, γ-glutamyl transpeptidase, and many others. This is why many pathological conditions are associated with specific changes of structures and expression of glycans and their specific physiological receptors, lectins. Consequently, in the last few years glycosylation changes emerged as new and powerful diagnostic and prognostic markers. In addition, common polymorphisms in the glycosylation machinery and consequential differences in glycome composition (e.g. plasma glycome) were recognized as potential tools which could contribute to the better diagnostic and prognostic procedures in the near future. Although structural complexity of glycans was a great obstacle for their analysis, recent development of high throughput methods for analyzing glycans using HPLC, mass spectrometry and capillary electrophoresis provides the possibility that the analyses of glycosylation changes of particular protein(s) or entire glycome could be routinely used in clinical practice. In addition, development of a new chip technology based upon arrays of carbohydrates provides a tool for studying protein-glycan interactions, which are crucial for many cell-cell and cell-matrix interactions in immune reactions, cancer development and metastasis, transplantation etc. Additionally, understanding of these reactions is crucial for drug discovery, identification of inhibitors of protein-glycan interactions as well as in discovering of biomarkers unique to a specific patient population. Interaction of particular drug with differently glycosylated proteins, carriers or receptors represents additional challenge in drug design and tailoring the therapy. In near future individualization of therapy will require identifying glycan's biomarkers unique to a specific patient population - "glycomics profiles" that can be use to determine how well an individual will respond to different drugs in terms of efficacy and toxicity (pharmacoglycomics). Although still at a very early stage of development, the investigation of the effects of genetic variation on individuals' physiology and effects on glycosylation opens the door for novel post-genomic approaches in biomarker identification, pharmacoglycomics, and drug development. In this workshop basic knowledge as well as recent achievements in the field of pharmacoglycomics will be discussed.

glycosylation; glycans; genetics

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