Multi-level regulation of cellular glycosylation: from genes to transcript to enzyme to structure

Abstract

Glycosylation is a ubiquitous mammalian post-translational modification that both decorates a majority of expressed proteins and regulates their function. Cellular glycan biosynthesis is facilitated by a few hundred enzymes that are collectively termed 'glycoenzymes'. The expression and activity of these enzymes is controlled at the transcription, translation and post-translation levels. New wet-lab advances are providing analytical methods to collect large-scale data at these multiple levels, relational databases are starting to collate these results, and computer models are beginning to integrate this information across scales in order to gain new knowledge. These activities are likely to enable the qualitative and quantitative mapping of pathways regulating glycan production and function in proteins, cells and tissue.

Figure 1. Glycosylation overview

Commonly, nine types of monosaccharides in humans form corresponding sugar-nucleotides (UDP-Gal etc.). A variety of glycoenzymes (particularly the glycosyltransferases and glycosidases) enable the transfer of these monosaccharides to lipid and protein scaffolds. Additional monosaccharides can form, e.g. Iduronoic acid (IdoA), by the epimerization of Glucuronic acid (GlcA) on glycosaminoglycan chains. Carbohydrate structures thus formed decorate the cell surface, and they are also found in intra-cellular compartments. Most glycan families have a limited number of core-structures that are elaborated by repeat extensions (like N-Acetyllactosamine repeats) and terminal modifications.

Figure 2. Regulation of glycosylation

The central dogma of molecular biology states the passage of information from DNA to RNA to protein in all living organisms. These proteins can be further glycosylated by the glycoenzymes, mainly in the endoplasmic reticulum and Golgi compartments. RNA and protein degradation rates, shown using recycle bins, are important checkpoints that control cell surface carbohydrate structures. Additional parameters that track the process of information transfer from genes to RNA to proteins (including glycoenzymes) to glycoproteins are shown using purple text. Glycoproteins may provide feedback and feedforward control to regulate cellular transcription and translation. The parameter ‘k’ (e.g. k_{transcription} and k_degrad.) is used to denote lumped rate constants for individual steps.