Advances in the Biology and Chemistry of Sialic Acids

Abstract

Sialic acids are a subset of nonulosonic acids, which are nine-carbon alpha-keto aldonic acids. Natural existing sialic acid-containing structures are presented in different sialic acid forms, various sialyl linkages, and on diverse underlying glycans. They play important roles in biological, pathological, and immunological processes. Sialobiology has been a challenging and yet attractive research area. Recent advances in chemical and chemoenzymatic synthesis as well as large-scale E. coli cell-based production have provided a large library of sialoside standards and derivatives in amounts sufficient for structure-activity relationship studies. Sialoglycan microarrays provide an efficient platform for quick identification of preferred ligands for sialic acid-binding proteins. Future research on sialic acid will continue to be at the interface of chemistry and biology. Research efforts will not only lead to a better understanding of the biological and pathological importance of sialic acids and their diversity, but could also lead to the development of therapeutics. Keywords biology; carbohydrate; chemistry; CMP-sialic acid synthetase; glycan; sialic acid; sialic acid aldolase; sialidase; sialoside; sialyltransferase Diversity of Sialic Acids in Nature Sialic acids are a Subset of Nonulosonic AcidsNot long ago, it was thought that sialic acids (Sias) were unique inventions of the deuterostome lineage of animals, which emerged around the time of the Cambrian expansion ~530 million years ago, with certain pathogenic bacteria having then "acquired" them from hosts by gene transfer (1-2). However, the relevant genes of bacterial pathogens were then found to be only distantly homologous to corresponding host genes (3). Meanwhile, work from multiple investigators over the last few decades has shown that the unusual 9-carbon backbone of Sias is in fact shared by a larger family of nonulosonic acids (NulOs), which are much more widely distributed in nature (4-6). Furthermore, the key steps in the biosynthesis of nonulosonic acids share remarkable similarities, and the genes involved are homologous. These aspects have recently been discussed extensively in a phylogenomic evaluation of nonulosonic acids (7). Although the other forms of nonulosonic acids, such as legionaminic acid and pseudaminic acid, have sometimes been called "bacterial sialic acids" (4), we prefer to reserve the term Sia for the 9-carbon sugars found both in the deuterostome lineage of animals and in certain bacteria that are based on a neuraminic acid (Neu) or a 2-keto-3-deoxy-nonulosonic acid (Kdn) backbone (7) (Figure 1). Thus, this review will focus only on these "traditional" Sias, emphasizing recent challenges and advances at the interface of chemistry and biology.

A Sialylated Glycan Microarray Reveals Novel Interactions of Modified Sialic Acids with Proteins and Viruses

“…Glycan 20, which is an ␣2-6 monosialylated derivative of NA2, bound RCA-I before and after neuraminidase, although binding was not enhanced after neuraminidase treatment. RCA-I bound weakly to ␣2-6-sialylated lactose and LNnT (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), unlike the corresponding ␣2-3-sialylated lactose and LNnT (41-57), which were not bound. Although most sialic acid derivatives moderately decreased RCA-I binding to NA2, ␣2-6-sialylation with Neu5Ac8Me (19) and Neu5Gc9Ac (25) greatly inhibit RCA-I binding.…”

“…in chemoenzymatic synthesis of sialosides containing natural and non-natural sialic acid residues using multiple promiscuous sialoside biosynthetic enzymes (5,(15)(16)(17)(18)(19)(20).…”

“…To further explore the recognition and function of modified sialic acid residues, we exploited the development of new chemoenzymatic methods to synthesize modified sialic acids (5), along with recent developments of glycan microarray technology, which provide an innovative approach to studying glycan recognition and function by glycan-binding proteins. We adapted our recent development of natural glycan microarrays (21)(22)(23)(24) to the production of a diverse array of sialylated glycans using fluorescent derivatives of glycans that terminate with ␤-linked galactose, which are sialyltransferase acceptors, in a one-pot three-enzyme approach for the microscale chemoenzymatic synthesis of sialosides (19,20,25).…”

Chemo-enzymatic synthesis of Neu5Gc-containing sialylated lactulose

“…The sialic acid modification on cell surface glycoproteins and glycolipids plays a crucial role in many biological processes, including cell adhesion, antigen recognition and signal transduction [17]. Studies have shown that sialylated glycans have a good prospect in food, especially the developing nervous system in infants [18].…”

Diseases of glycosylation beyond classical congenital disorders of glycosylation

“…The addition of Sia is catalyzed by a family of 20 sialyltransferase enzymes, which transfer Sia via 2-3, 2-6 and 2-8 linkages to various glycan acceptors [46]. The disruption of sialyltransferase genes in mice often results in immune and hematologic phenotypes [47][48][49].…”