Polysialic acid: Biosynthesis, novel functions and applications

Abstract

As an anti-adhesive, a reservoir for key biological molecules, and a modulator of signaling, polysialic acid (polySia) is critical for nervous system development and maintenance, promotes cancer metastasis, tissue regeneration and repair, and is implicated in psychiatric diseases. In this review, we focus on the biosynthesis and functions of mammalian polySia, and the use of polySia in therapeutic applications. PolySia modifies a small subset of mammalian glycoproteins, with the neural cell adhesion molecule, NCAM, serving as its major carrier. Studies show that mammalian polysialyltransferases employ a unique recognition mechanism to limit the addition of polySia to a select group of proteins. PolySia has long been considered an anti-adhesive molecule, and its impact on cell adhesion and signaling attributed directly to this property. However, recent studies have shown that polySia specifically binds neurotrophins, growth factors, and neurotransmitters and that this binding depends on chain length. This work highlights the importance of considering polySia quality and quantity, and not simply its presence or absence, as its various roles are explored. The capsular polySia of neuroinvasive bacteria allows these organisms to evade the host immune response. While this "stealth" characteristic has made meningitis vaccine development difficult, it has also made polySia a worthy replacement for polyetheylene glycol in the generation of therapeutic proteins with low immunogenicity and improved circulating half-lives. Bacterial polysialyltransferases are more promiscuous than the protein-specific mammalian enzymes, and new studies suggest that these enzymes have tremendous therapeutic potential, especially for strategies aimed at neural regeneration and tissue repair.

Engineering of complex protein sialylation in plants

“…PolySia produced in planta blocked cytotoxicity of free histones and attenuated the nitric oxide production of LPS-stimulated microglia cells. These results are in line with findings on the impact of polySia structures recently reviewed (2). The physical and biological characteristics of polySia may confer novel functions to these molecules, such as protection of host cells during inflammatory processes (5) or promoting cell migration required for regeneration (43), to name two.…”

“…These negatively charged sugar residues (i.e., N-acetylneuraminic acid) play essential roles in many aspects of life: e.g., in cell-cell interactions, in cell signaling, and for protein stability (1,2). A unique feature of Sia is that, unlike other sugars, it often forms homo-oligomers or polymers, with its most complex form polysialic acid (polySia) reaching a degree of polymerization up to 400 (3).…”

“…This sugar polymer is remarkable in that it plays multiple roles across different species from bacteria to humans. Its exceptional physicochemical properties provide the polySia with a large exclusion volume that physically inhibits interactions mediated by polySia-containing molecules, as shown for the major polySia carrier in humans, the neural cell adhesion molecule, NCAM (1,2,4). Recent studies demonstrated the effect of polySia in a variety of basic biological processes, like neural cell regeneration and antiinflammatory processes (5).…”

Glycoengineering of plants yields glycoproteins with polysialylation and other defined N-glycoforms

“…PolySia has been shown to play multiple roles in various biological processes, such as cell regeneration and various immunological processes (10). In humans, polySia is found on neural cell adhesion molecules (NCAM), where it plays a vital role in brain development (10). Clinical studies with polysialylated insulin and erythropoietin have shown that polySia is a superb alternative to polyethyleneglycol (PEG) in endowing protein drugs with longer circulatory half-lives and reduced immunogenicity (11).…”

“…Forming oligomers is a unique property of sialic acid; polymeric structures can have up to 400 monomeric units (10). PolySia has been shown to play multiple roles in various biological processes, such as cell regeneration and various immunological processes (10).…”