COSTBI-1937; NO. OF PAGES 3 Please cite this article in press as: Wells L, Feizi T: Editorial overview: Carbohydrates: O-glycosylation, Curr Opin Struct Biol (2019), https://doi.org/10.1016/j.sbi.2019.05.010 Editorial overview: Carbohydrates: O-glycosylation Lance Wells and Ten Feizi Current Opinion in Structural Biology 2019, 56:xx–yy https://doi.org/10.1016/j.sbi.2019.05.010 0959-440X/ã 2019 Published by Elsevier Ltd. Carbohydrates, one of the four major biomolecules of life, are generated by the concerted actions of glycosyltransferases (encoded by 204 genes in the human genome), hydrolases, and modification enzymes to produce the diversity of structures termed glycans. Unlike the other three classes, glycans can co-translationally or post-translationally modify the other three biomolecules: proteins, lipids, and nucleic acids. With regard to protein modification, glycosylation is primarily of two types: N-linked glycosylation with attachment of the reducing end of the glycan to an Asn residue, and O-linked glycosylation with attachment of the reducing end of the glycan to a hydroxyl side-chain-containing amino acid, most commonly Ser or Thr and less commonly hydroxylysine or hydroxyproline. In this special issue, we focus on all classes of O-linked glycosylation with the exception of the special case of O-linked glycosylation that involves the generation of proteoglycans by the attachment of glycosaminoglycans initiated by a xylose (Xyl) attachment to Ser or Thr residues. Historically, the term O-glycosylation was coined for post-translational modification of proteins with a glycan initiated by the transfer of N-acetylgalactosamine (GalNAc) to a Ser or Thr residue. However, knowl- edge on O-glycosylation has greatly expanded over the last two to three decades, and various classes of O-glycosylation are now recognized as being variously initiated with one or other of the common mammalian neutral sugars: GalNAc, mannose (Man), fucose (Fuc), glucose (Glc), galactose (Gal), N-acetylglucosamine (GlcNAc), and Xyl (Figure 1). Classical glycosylation (O-GalNAc) The most common and well-known form of O-glycosylation is that initiated by a GalNAc. O-GalNAc modification is thought to occur on as much as 80% of the proteins synthesized through the secretory pathway. Gerken and Hurtado-Guerrero focus on the initiating step that is catalyzed by a family of polypeptide GalNAc transferases that can number higher than 20 in some organisms. By focusing their review on the structural differences of these isoenzymes and their substrate preferences, they provide a rationale for such a large group of enzymes catalyzing essentially the same reaction. Protein-specific glycosylation (O-Man) Joshi and Halim elaborate on their and others’ recent findings that, remi- niscent of O-GalNAc, there is a plethora of related but distinct enzymes capable of catalyzing the first step of O-Mannose modification of proteins. Further, they review their recent finding of intracellular O-Man in Saccha- romyces cerevisiae. Hohenester continues to explore O-Man but focuses on the repeating disaccharide sequence, termed matriglycan, that appears to be added only to functional O-Man glycans at two sites on the protein Lance Wells Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA e-mail: lwells@ccrc.uga.edu Lance Wells, Director of Integrated Life Sciences and Professor of Biochemistry and Molecular Biology, is a Member of the Complex Carbohydrate Research Center (CCRC) at the University of Georgia (Athens, GA, USA). He is also Co-Director of the ThermoFisher-appointed Center of Excellence in Glycoproteomics. Lance has a long-standing interest in understanding how post-translational modifications increase functional diversity of enzymes/proteins. Currently his laboratory is primarily focused on understanding the biological function of N-linked microheterogeneity and the underlying molecular mechanisms of congenital disorders of O-glycosylation, specifically roles for O-mannosylation in congenital muscular dystrophy and O- GlcNAc in X-linked intellectual disability. Ten Feizi Glycosciences Laboratory, Department of Surgery and Cancer, Imperial College London, London, UK e-mail: t.feizi@imperial.ac.uk Ten Feizi is Director of the Glycosciences Laboratory at imperial College, London. Her research is focused on assignments of glycan ligands in carbohydrate-mediated biomolecular interactions. Central to her investigations has been the neoglycolipid technology to generate glycan probes with lipid tags for microscale analyses of glycan– protein interactions. The approach was the foundation of the first microarray for sequence-defined glycans, an advanced platform, which is being applied in the unraveling of the ligands in endogenous recognition systems and pathogen host Available online at www.sciencedirect.com ScienceDirect www.sciencedirect.com Current Opinion in Structural Biology 2019, 56:1–3