Sialobiology: Structure, Biosynthesis and Function. Sialic Acid Glycoconjugates in Health and Disease

Sialic acids (Sia) are a family of 9-carbon α-keto acid aminosugars found predominantly at the non-reducing end of oligosaccharide chains on glycoproteins and glycolipids. Since their discovery in the late 1930s, and subsequent naming by Blix, Gottschalk and Klenk (Nature. 1957; 179: 1088), Sia are now recognized as occurring ubiquitously in nature (except plants), and being involved in numerous biologically important processes. In particular, the growing awareness of the significance of Sia in human health and disease has led to an increase in research into Sia chemistry, biochemistry and cell biology. In this chapter, the structure and occurrence of Sia will be summarized, as well as aspects of Sia chemistry, biochemistry and cell biology not covered in subsequent chapters of this eBook are also presented. Throughout this, and subsequent chapters of this eBook the abbreviations and nomenclature summarised in Schauer and Varki, (In Essentials of Glycobiology 2^nd Ed, Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009) will be used. Importantly, wherever appropriate the reader will be directed to the relevant chapters of this eBook, or extensive reviews for further detail.

Sialic acids (Sia) are involved in many biological activities and are commonly present as monosialyl residues at the non-reducing terminal end of glycoconjugates. Occasionally, polymerized structures in the form of disialic acid (diSia), oligosialic acid (oligoSia), and polysialic acid (polySia) appear in glycoconjugates. In particular, polySia is known to be a common epitope from bacteria to humans and is one of the most famous, biologically-important glycotopes in vertebrates. The biological functions of polySia, especially on neural cell adhesion molecules (NCAMs), have been well studied and an indepth body of knowledge concerning polySia has been accumulated. However, considerably less attention has been paid to glycoproteins containing di- and oligoSia groups. As the analytical methods used to detect oligo/polymerized structures have been improved, glycoproteins containing di/oligo/polySia chains have been identified with an increasing frequency in nature. In addition, more sophisticated genetic techniques have helped elucidate the underlying mechanisms of polySia-mediated activities. In this chapter, the recent advances in the study of di-, oligo- and polySia residues on glycoproteins, including their distribution, chemical properties, biosynthetic pathways, and functions are described.

Sialic acids (Sia) represent a family of nine-carbon keto-sugars with an unusual high structural diversity. However, all members are biosynthetic derivatives of either N-acetylneuraminic acid or 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid. In this chapter, we describe the biosynthesis of these two Sia precursors in vertebrates with a focus on the characteristiscs of the involved enzymes. In addition, the activation of the sugars as well as the degradation is included. Furthermore, dieseases and mouse models associated to the Sia biosynthesis pathway as well as biomedical implications are addressed.

Sialylation reactions take place in the lumen of the Golgi apparatus where sialyltransferases (STs) decorate glycan moieties of both the cell surfaces associated and secreted proteins and lipids with sialic acids (Sia) predominantly, but not exclusively employing, CMP-Neu5Ac as donor substrate. Because of its physical and chemical properties, CMP-Neu5Ac is unable to diffuse across the Golgi membrane and must be translocated from the cell cytosol into the lumen of the Golgi apparatus. Such translocation is performed by the CMP-Sia transporter, a member of an evolutionary conserved family of proteins together referred to as nucleotide sugar transporters. Although several nucleotide sugar transporters, including the CMP-Sia transporter, have been biochemically characterized over the last 30 years, the lack of a three-dimensional structure of any nucleotide sugar transporter requires alternative approaches to elucidating the structure-function relationship of this class of protein. We describe in this chapter the latest data reporting the elucidation of CMP-Sia transporter structurefunction relationship.

Sialyltransferases are a subset of glycosyltransferases catalyzing the transfer of sialic acid (Sia) residues from an activated sugar donor onto glycoconjugates. The aim of this chapter is to summarize in a comprehensive review what is known about vertebrate sialyltransferases structural features, the lessons drawn from molecular biology and the production of recombinant proteins and to explore the relationships between their primary structure and function. Insights into vertebrate sialyltransferases origin and evolution using bioinformatic approaches, screening of nucleotide databases of various animal organisms (vertebrates and invertebrates), molecular phylogeny and phylogenomic will be discussed.

Sialic acids (Sia) play major roles in glycan-mediated recognition/interaction processes, which are mediated by various intrinsic and extrinsic sialic acid-binding proteins. Cells therefore require fine-tuned mechanisms to regulate cell-surface expression of sialoglycoconjugates. In mammalian cells, there are 4 distinct sialidases, termed NEU1, NEU2, NEU3 and NEU4, involved in the removal of sialic acid residues from glycoconjugates; they play pivotal roles in diverse biological processes. In this chapter we summarize our current knowledge on mammalian sialidases.

Several pathogenic bacteria decorate their cell surface with sialoglycoconjugates that in many cases mimic host structures and serve as important virulence factors. In addition to N-acetyl neuraminic acid, the prevalent sialic acid in the humans, O-acetylated sialic acids are observed in bacteria that carry acetyl groups at position C-7, C-8 and/or C-9. The ability to modify cell surface sialo-glycoconjugates by O-acetylation depends on the presence of sialate O-acetyltransferases, an enzyme class that catalyzes the transfer of acetyl groups from acetyl Coenzyme A to hydroxyl groups of either free or CMP-activated sialic acid or particularly sialylated carbohydrate structures. On the genetic level, distinct mechanisms were observed which lead to an ‘on/off’ switch of sialate O-acetyltransferase expression and/or modification of the enzymatic activity. The resulting changes in the degree of surface O-acetylation of these bacteria can lead to a huge structural variety that make them difficult targets for the immune system. Structural and biochemical analyzes demonstrated that bacterial sialate O-acetyltransferases evolved independently on two distinct structural frameworks, the left-handed β-helix fold and the α/β-hydrolase fold.