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.

Thioglycosides Are Efficient Metabolic Decoys of Glycosylation that Reduce Selectin Dependent Leukocyte Adhesion

“…The mammalian lactosamine motif is a common unit that is part of the molecular recognition epitope of various lectins, including selectins, siglecs and galectins (Neelamegham and Mahal, 2016; Varki, 2017). As GlcNAc based S-glycosides truncate the growth of this common motif on different types of glycoconjugates, these small molecules may be broadly useful as inhibitors for a variety of studies, although this may come at the cost of reduced specificity.…”

“…Glycans are a complex post-translational modification that regulate virtually all biological processes (Laine, 1994; Neelamegham and Mahal, 2016; Varki, 2017). Commonly, cell surface carbohydrates appear either as O- or N-linked glycans on glycoproteins, glycosphingolipids (GSLs), or glycosaminoglycans (GAGs).…”

Global and site‐specific analysis of protein glycosylation in complex biological systems with Mass Spectrometry

“…Among hundreds of known modifications, glycosylation is one of the most common and essential modifications. It determines protein folding, trafficking, and stability, and regulates many cellular activities, especially extracellular ones (Mahal et al, 1997;Gabius et al, 2002;Spiro, 2002;Lau et al, 2007;Kudelka et al, 2015;Chandler and Costello, 2016;Neelamegham and Mahal, 2016;Wang et al, 2016a). Many glycoproteins are of extremely low abundance compared to nonmodified proteins; meanwhile, glycosylation is very complex due to heterogeneous glycan structures and various amino acid residues covalently bound to glycans.…”

The Glyco-enzyme adaptor GOLPH3 Links Intra-Golgi Transport Dynamics to Glycosylation Patterns and Cell Proliferation

“…Glycosylation consists of orderly series of reactions catalyzed by glyco-enzymes (glycosyltransferases and glycosidases) (Colley et al, 2015;Stanley, 2011) organized in glycosylation pathways [i.e., the N-and O-linked glycosylation, the glycosphingolipid (GSL) pathway and the proteoglycan synthetic cascade (Stanley, 2011)]. The type and abundance of the glycans produced depend mainly on two factors: a) the gene expression pattern of the glyco-enzymes and accessory proteins (e.g., sugar and ion transporters) (Neelamegham and Mahal, 2016;Pothukuchi et al, 2019) and b) the order and frequency of the encounters between glyco-enzymes and substrates during transit through the Golgi stack Pothukuchi et al, 2019;Stanley, 2011). The latter process, in turn, depends on the organization and dynamics of intra-Golgi transport and hence on the Golgi traffic machinery.…”

“…The latter process, in turn, depends on the organization and dynamics of intra-Golgi transport and hence on the Golgi traffic machinery. Unfortunately, while significant progress has been made towards understanding the transcriptional programs that regulate glyco-enzymes expression and their effects on glycan structures (Neelamegham and Mahal, 2016;Varki and Gagneux, 2015), the mechanisms by which the intra-Golgi transport machinery controls glycosylation remain poorly understood.…”