Protein-Specific Glycoprofiling for Patient Diagnostics.

Abstract

Protein glycosylation is increasingly recognized as a crucial modulator of protein function, offering a third layer of biological information over genomics and proteomics. Modern tools for analyzing released N-glycans from cells and body fluids, i.e., the glycome, have shown abnormal protein glycosylation in numerous human diseases. These include both genetic and acquired diseases, ranging from diabetes, cancer, and inflammatory disease to neurodegenerative and neuromuscular disease. Insights from this novel field in human medicine provide exciting perspectives toward understanding disease processes, identifying therapeutic targets, and designing individualized diagnostics based on protein concentrations and glycosylation status. However, the main question is how we can translate this information into concrete biomarkers in a clinical diagnostic setting, with high demands on technical robustness and the ability to interpret results within specific patient groups. Unlike the genetic template for protein synthesis, the process of protein glycosylation is not directly encoded by the genome. Protein N-glycosylation, the best-studied ubiquitous type of glycosylation, follows a sequential pathway in the organelles of the secretory pathway. First, a dolichol-linked glycan composed of 14 monosaccharides is assembled in the endoplasmic reticulum (ER)2 and transferred to nascent proteins that enter the ER via the translocon complex. In the final stages in the ER, and further in the Golgi apparatus, the protein-bound glycan is remodeled to a mature glycan that is present on cellular receptors, ion channels, and secreted proteins in plasma. It is becoming increasingly apparent that this process is influenced by many factors, genetic, metabolic, and environmental (such as medication and alcohol abuse). The congenital disorders of glycosylation (CDG) form an ideal group of well-defined genetic defects to derive important lessons on novel biochemical mechanisms and clinical diagnostic approaches with relevance to more common diseases. More than 100 different genetic defects in various glycosylation pathways are already known, approximately …